CN1816548B - Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof - Google Patents
Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof Download PDFInfo
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- CN1816548B CN1816548B CN200480019102.2A CN200480019102A CN1816548B CN 1816548 B CN1816548 B CN 1816548B CN 200480019102 A CN200480019102 A CN 200480019102A CN 1816548 B CN1816548 B CN 1816548B
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- 0 CC(C)(C)OC(N(C[C@]12)C[C@@]1[C@]2(c(ccc(-c(c(F)c1)ccc1N(C[C@](CN(C=CN)N)*1)C1=O)c1)c1F)C#N)=O Chemical compound CC(C)(C)OC(N(C[C@]12)C[C@@]1[C@]2(c(ccc(-c(c(F)c1)ccc1N(C[C@](CN(C=CN)N)*1)C1=O)c1)c1F)C#N)=O 0.000 description 5
- VPKPIQMFYZFSAU-NRAANUMRSA-N CC(NC[C@@H](CN1c2ccc(-c3ccc([C@@]4([C@@H](C5)[C@H]4CS5(=O)=O)C#N)nc3)c(F)c2)OC1=O)=O Chemical compound CC(NC[C@@H](CN1c2ccc(-c3ccc([C@@]4([C@@H](C5)[C@H]4CS5(=O)=O)C#N)nc3)c(F)c2)OC1=O)=O VPKPIQMFYZFSAU-NRAANUMRSA-N 0.000 description 1
- GOAKNIUIWPGDNK-BWOOEJRBSA-N N#C[C@]1(C2[C@H]1COC2)c(cc1)ccc1-c(c(F)c1)ccc1N(C[C@H](CNc1n[o]cc1)O1)C1=O Chemical compound N#C[C@]1(C2[C@H]1COC2)c(cc1)ccc1-c(c(F)c1)ccc1N(C[C@H](CNc1n[o]cc1)O1)C1=O GOAKNIUIWPGDNK-BWOOEJRBSA-N 0.000 description 1
- DKGAHYSDXNYANR-BKJGLDIHSA-N N#C[C@]1([C@@H]2[C@H]1COC2)c(nc1)ccc1-c(c(F)c1)ccc1N(C[C@H](COc1n[o]cc1)O1)C1=O Chemical compound N#C[C@]1([C@@H]2[C@H]1COC2)c(nc1)ccc1-c(c(F)c1)ccc1N(C[C@H](COc1n[o]cc1)O1)C1=O DKGAHYSDXNYANR-BKJGLDIHSA-N 0.000 description 1
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
The cross reference of related application
The denomination of invention that the application requires on July 2nd, 2003 to submit to is the U.S. Provisional Application No.60/483 of " oxazolidone microbiotic and derivative thereof that cyclopropyl replaces " (CYCLOPROPYL GROUP SUBSTITUTEDOXAZOLIDINONE ANTIBIOTICS AND DERIVATIVES THEREOF), the denomination of invention that on February 24th, 904 and 2004 submitted to is the U.S. Provisional Application No.60/546 of " oxazolidone microbiotic and derivative thereof that cyclopropyl replaces " (CYCLOPROPYL GROUPSUBSTITUTED OXAZOLIDINONE ANTIBIOTICS ANDDERIVATIVES THEREOF), 984 rights and interests, described document is incorporated herein by reference in full.
Background of invention
The new antimicrobial drug of the first kind that the oxazolidone representative has been developed since quinolone.Oxazolidone is the synthetic antimicrobial compound, and it is by oral or at intravenously the Gram-positive organism of problematic anti-most medicines is had activity, and not and other antibiotic cross-resistance.Referring to people such as Riedl, " the antibiotic latest developments of oxazolidone (Recent Developments withOxazolidinone Antibiotics) ", Exp.Opin.Ther.Patents (1999) 9 (5), people such as Ford, " oxazolidone: new antimicrobial drug (Oxazolidinones:New AntibacterialAgents) ", Trends in Microbiology 196 Vol.5, No.5, 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 oxazolidone of cyclopropyl part, it is aerobic effective with anaerobic pathogens to resisting, described pathogenic agent is for example anti-multiple antibiotic staphylococcus, suis and faecalis, Bacteroides, fusobacterium kind and antiacid organism such as mycobacterium tuberculosis (Mycobacterium tuberculosis) and other mycobacterium kind.
Summary of the invention
The present invention relates to compound, enantiomorph, the diastereomer of formula I, or their pharmacologically acceptable salt, hydrate or prodrug:
Wherein:
R
1Expression
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、NRCO
2R、(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) randomly by 1-3 R
7The C that group replaces
5-10Heterocycle, it can connect by carbon or heteroatoms;
X represents
Or use
The C of expression
5-10Heteroaryl, this structural formula represent to contain the fragrant heterocyclic radical of 1 to 4 nitrogen-atoms and the optional replacement of at least one two key, and it connects by the key on any nitrogen-atoms, and described heteroaryl randomly is selected from R
71 to 3 substituting group replace;
Y represents NR
*, O, CN or S (O) p;
R
xExpression hydrogen or C
1-6Alkyl;
R
3Expression NR (C=X
2) R
12, NR
*R
12, C
6-10Aryl, maybe can by carbon or heteroatoms connect-(O)
nC
5-10Heterocyclic radical; Described aryl and heterocyclic radical are randomly by 1 to 3 R
7Group replaces,
R
4, R
4a, R
4bAnd 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 to Ar or HAr when ring, r and s and be less than or equal to 4;
R
5And R
6Expression independently
I) hydrogen,
The ii) optional C that is replaced by 1-3 following group
1-6Alkyl, described group is selected from: halogen, CN, OH, C
1-6Alkoxyl group, amino, imino-, hydroxyl amino, 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 randomly are selected from halogen, CN, OH, CF
3, C
1-6Alkyl or C
1-61-3 in the alkoxyl group group replaces;
The iii) optional C that is replaced by 1-3 following group
1-6Acyl group, described group is selected from: halogen, OH, SH, C
1-6Alkoxyl group, naphthyloxy, phenoxy group, amino, C
1-6Amido, 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, phthalimido, maleimide amino, succinimido, described phenoxy group, phenyl and pyridine randomly are selected from halogen, OH, CN, C
1-6Alkoxyl group, amino, C
1-6Amido, CF
3Or C
1-61-3 in the alkyl group replaces;
Iv) randomly by the C of 1 to 3 following group replacement
1-6Alkyl sulphonyl, described group is selected from: halogen, OH, C
1-6Alkoxyl group, amino, hydroxyl amino, alkoxy amino, C
1-6Acyloxy or phenyl; Described phenyl is randomly replaced by 1 to 3 following group, and described group is selected from: halogen, OH, C
1-6Alkoxyl group, amino, C
1-6Amido, CF
3Or C
1-6Alkyl;
V) randomly be selected from halogen, C
1-6Alkoxyl group, OH or C
1-6The aryl sulfonyl that in the alkyl 1 replaces to 3 groups;
Vi) randomly be selected from halogen, OH, C
1-6Alkoxyl group, C
1-6The C that 1 to 3 group in acyloxy or the phenyl replaces
1-6Alkoxy carbonyl, described phenyl randomly are selected from halogen, OH, C
1-6Alkoxyl group, amino, C
1-6Amido, CF
3Or C
1-61-3 in the alkyl group replaces;
Vii) aminocarboxyl, C
1-6Alkyl amino-carbonyl or C
1-6Dialkyl amino carbonyl, described alkyl randomly are selected from halogen, OH, C
1-61 to 3 group in alkoxyl group or the phenyl replaces;
Viii) randomly be selected from halogen, OH, CN, amino, C
1-6Amido, C
1-6Alkyl sulfonyl-amino, C
1-6Alkoxycarbonyl amino, C
1-6Alkoxyl group, C
1-6Acyloxy or C
1-65 to 6 yuan of heterocycles that in the alkyl 1 replaces to 3 groups, described alkyl randomly is selected from halogen or C
1-6In the alkoxyl group 1 to 3 groups replace;
Ix) randomly be selected from halogen, OH, C
1-6The C that 1 to 3 group among alkoxyl group or the CN replaces
3-6Naphthene base carbonyl;
X) randomly be selected from halogen, OH, C
1-6Alkoxyl group, C
1-6Alkyl, CF
3, C
1-6Alkyloyl, amino or C
1-6The benzoyl that in the amido 1 replaces to 3 groups;
Xi) randomly by 1 to 3 C
1-6The pyrryl carbonyl that alkyl replaces;
Xii) C
1-2The acyloxy ethanoyl, wherein acyl group is randomly by amino, C
1-6Alkylamino, C
1-6Dialkyl amido, 4-morpholinyl, 4-aminophenyl, 4-(dialkyl amido) phenyl, 4-(glycyl amino) phenyl replace; Or
R
5And R
6Can form with any insertion atom and contain carbon atom and 1-2 heteroatomic 3 to 7 yuan of heterocycles, described heteroatoms is independently selected from O, S, SO, SO
2, N or NR
8
R
7Expression
I) hydrogen, halogen, (CH
2)
pC
5-10Heterocyclic radical, 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, NHCO
2R ,-OCOC
1-6Alkyl;
Ii) (CH
2)
nAmino, (CH
2)
nC
1-6Alkylamino, C
1-6Amido, C
1-6Dialkyl amido, hydroxyl amino or C
1-2Alkoxy amino, they all can be randomly by C on nitrogen
1-6Acyl group, C
1-6Alkyl sulphonyl or C
1-6Alkoxy carbonyl replaces, and 1-2 the group that described acyl group and alkyl sulphonyl randomly are selected among halogen or the OH replaces;
R
8And R
9Expression independently
i)H、CN，
Ii) randomly be selected from halogen, CN, OH, C
1-6Alkoxyl group, C
1-6The C that 1 to 3 group in acyloxy or the amino replaces
1-6Alkyl,
Iii) randomly be selected from halogen, OH, C
1-6The phenyl that in the alkoxyl group 1 replaces to 3 groups; Or
R
7And R
8Can form 3 to 7 yuan of carbocyclic rings that randomly disconnected by 1 to 2 heteroatoms together, described heteroatoms is selected from O, S, SO, SO
2, NH and NR
8
X
1Expression O, S or NR
13, NCN, NCO
2R
16Or 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, C (R)
2Cl, (CH
2)
nSR, (CH
2)
nCN, (CH
2)
nSO
2R, (CH
2)
nS (O) R, C
1-6Alkylamino, C
3-6Cycloalkyl, C
5-10Heterocyclic radical or C
1-6Dialkyl amido, wherein said alkyl and cycloalkyl can be selected from halogen, CN, OH or C
1-61-3 in the alkoxyl group group replaces, and described heterocyclic radical is randomly 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, optional O, S, SO, the SO of being selected from
2, NH and NR
8In the C that disconnects of 1-4 heteroatoms
3-7Unit's carbocyclic ring, wherein said C
1-6Alkyl, aryl or C
1-6Acyl group can be selected from halogen, hydroxyl, N (R) independently
2, CO
2R, C
6-10Aryl, C
5-10Heteroaryl or C
1-6In the alkoxyl group 0 to 3 groups replace; As two R
13When group was connected to same atom or two adjacent atoms, they can form together and randomly are selected from O, S, SO, SO
2, NH and NR
8In 3 to 7 yuan of carbocyclic rings disconnecting of 1-2 heteroatoms;
R represents hydrogen or C
1-6Alkyl;
R
*Expression hydrogen, CN, C (=O) R
14, (CH
2)
pCO
2C
1-6Alkyl, (CH
2)
pC
5-10Heterocyclic radical or C
1-6Alkyl, described alkyl and heterocyclic radical are randomly by 1 to 3 R
7Group replaces;
R
14Expression is amino, C
1-6Alkyl, C
3-6Cycloalkyl, (CH
2)
pC
5-10Heterocyclic radical, C
1-6Haloalkyl, phenyl, described alkyl, cycloalkyl, phenyl, heterocyclic radical are randomly by 1 to 3 R
7Group replaces, and works as R
7For amino or hydroxyl or when forming the nitrogen of heterocyclic moiety, described amino and hydroxyl are randomly by amino or hydroxyl protecting group protection;
R
15Be C
1-6Alkyl or benzyl, described benzyl randomly are selected from halogen, OH, C
1-6Alkoxyl group, amino, C
1-6Amido or C
1-61-3 in the alkyl group replaces;
R
16Be hydrogen, C
5-10Heteroaryl, C
6-10Aryl, described heteroaryl and aryl are randomly by 1 to 3 R
7Group replaces;
P represent 0-2 and
M, n and q represent 0-1 independently.
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
Except as otherwise noted, this paper uses the term that defines below to describe the present invention in detail.
Compound of the present invention can have center of asymmetry, chiral axis and chirality face, and occurs as racemoid, racemic mixture with as independent diastereomer, comprises all possible isomer among the present invention, comprises optically active isomer.(referring to E.L.Eliel and S.H.WilenStereochemistry of Carbon Compounds (concrete page or leaf is 1119-1190 for John Wiley and Sons, New York1994).
As any variable (for example aryl, heterocyclic radical, R
5, R
6Deng) when occurring surpassing one time, its all other appearance place that are defined in all are independently when occurring at every turn.And substituting group/or the combination of variable allow, as long as the stable compound of this combination results.
Unless otherwise defined, term " alkyl " is meant the monovalence alkane (hydrocarbon) that contains 1 to 15 carbon atom base of deriving.It can be straight or branched.Preferred alkyl comprises the low alkyl group with 1 to 6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl.When alkyl was substituted, this alkyl can be at any available tie point place be selected from the highest 3 substituting groups that this paper limits in the group and be replaced.When alkyl is considered to be replaced by alkyl, can exchanges with " branched-chain alkyl " and use.
Cycloalkyl be contain 3 to 15 carbon atoms and between carbon atom not alternately or a kind of alkyl of the two keys of resonance.It can comprise by 1 to 4 ring of condensed.Preferred cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.When being substituted, cycloalkyl can be replaced by the highest 3 substituting groups of alkyl definition herein.
Alkyloyl is meant the group of being derived and being obtained by the aliphatic carboxylic acid with 2 to 4 carbon atoms.Example is ethanoyl, propionyl, butyryl radicals etc.
Term " alkoxyl group " is meant those groups that have designated length in the straight or branched structure, if two or more carbon atoms are arranged in the length, then they can comprise two keys or triple bond.The example of this alkoxyl group is methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, different hexyloxy, allyloxy, alkynes propoxy-etc.
Be meant aryl or heteroaryl, heterocycle, Het, heterocyclic radical or the assorted ring that is described below at once.
Aryl is meant any stable monocycle or the bicyclic carbocyclic that has the highest 7 atoms in each ring, and wherein at least one ring is an aromatics.This aryl member's example comprises phenyl, naphthyl, tetralyl, indanyl, indanone based (indanonyl), xenyl, tetralin base (tetralilnyl), naphthane ketone group, Fluorenone base, phenanthryl, anthryl, acenaphthenyl (acenaphthyl) and similar substituted-phenyl etc.Aryl can be equally by limit and be substituted.Preferred substituted aryl comprises phenyl and naphthyl.
Term used herein " heterocycle ", " heteroaryl ", " Het ", " heterocyclic radical " or " heterocyclic " is except indicating, all represent stable 5-to 7-unit's monocycle or dicyclo, or stable 8-to 11-unit bicyclic heterocycle system, wherein any ring all can be saturated or undersaturated, and be selected from N by carbon atom and 1 to 4, the heteroatoms of O and S is formed, and wherein nitrogen and sulfur heteroatom can be randomly oxidized, nitrogen heteroatom can be randomly by quaternized (in this case, it can suitably use the gegenion balance), and comprise that wherein any above-mentioned heterocycle is condensed into any bicyclic group of phenyl ring.Heterocycle can connect at any heteroatoms or carbon atom place, and this causes the formation of rock steady structure.Term " heterocycle " or " heterocyclic " comprise heteroaryl moieties.Therefore " heterocycle " or " heterocyclic radical " comprises above-mentioned heteroaryl, and their dihydro and tetrahydrochysene analogue.Heterocycle, heteroaryl, Het or heterocyclic can be by 1 to 3 R
7Group replaces.This heterocycle member's example includes but not limited to following: piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepine base, the azepine base, pyrryl, the 4-piperidone base, pyrrolidyl, pyrazolyl, pyrazolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, pyrazinyl, pyrimidyl, the pyrimidine ketone group, pyriconyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, the isoxzzole alkyl, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, quinuclidinyl, the isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, thiadiazolyl group, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuran base, THP trtrahydropyranyl, thiophenyl, imidazopyridyl, triazolyl, tetrazyl, triazinyl, thienyl, benzothienyl, thiomorpholine base sulfoxide, thiomorpholine base sulfone, the naphthopyridine base, the dihydro-pyrimidin base, the pyrrolin base, the dihydroquinoline base, the dihydro tetrazyl, the dihydro triazolyl, the dihydro-thiophene base, the dihydro-oxazole base, the dihydrobenzo thienyl, the dihydrofuran base, benzothiazolyl, benzothienyl, benzimidazolyl-, benzopyranyl, benzo thiophene furyl, carbolinyl, chromanyl, the cinnolines base, the benzopyrazoles base, benzo dioxolyl and oxadiazoles base.Other example of heteroaryl is represented with formula a, b, c and d:
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
1-6Alkoxy carbonyl and formamyl.
Term " thiazolinyl " is meant straight chain, side chain or the cyclic hydrocarbon group that contains 2 to 10 carbon atoms and at least one carbon-to-carbon double bond.Preferred thiazolinyl comprises vinyl, propenyl, butenyl and cyclohexenyl.
Term " quaternary nitrogen " and " positive charge " are meant the nitrogen-atoms (using gegenion balance as known in the art as required) of band tetravalence positive charge, comprise nitrogen positively charged in the tetraalkyl ammonium (as tetramethylammonium) for example, assorted virtue (for example N-methyl-pyridine), under physiological pH by protonated basic nitrogen etc.Therefore, cation group comprise positively charged nitrogen-containing group and under physiological pH by protonated basic nitrogen.
Term " heteroatoms " is meant O, S or N, is independently selecting on the basis.
Term " prodrug " is meant the compound into prodrug, after administration and absorbing, can discharge medicine in vivo by some metabolic processes.Exemplary prodrug comprises the acid amides of aminocompound of the present invention, as alkane (C
1-6) acid amides, the acid amides and the alkane (C of aromatic acid (for example phenylformic acid) of acid
1-6) acid amides of diacid.
Halogen and " halogen " are meant bromine, chlorine, fluorine and iodine.
When group is named as " replacement ", unless otherwise indicated, this means that group comprises 1 to 3 substituting group thereon.
When functional group is named as " protected ", this means that this group is in modified form to get rid of unwanted side reaction at protected position.The appropriate protection base that is used for The compounds of this invention can recognize that from the application described textbook is for example Greene by state of the art and the reference standard textbook of considering this area, people such as T.W.,
Protective Groups in OrganicSynthesisWiley, New York (1991).The example of appropriate protection base is included in the whole specification sheets.
The suitable hydroxyl and the example of amino protecting group are: trimethyl silyl, triethylsilyl, adjacent nitro benzyloxycarbonyl, to nitro benzyloxycarbonyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, benzyloxycarbonyl, tertbutyloxycarbonyl, 2; 2,2-trichlorine ethoxy carbonyl, allyloxy carbonyl etc.The example of suitable carboxyl-protecting group is diphenyl-methyl, adjacent nitrobenzyl, to nitrobenzyl, 2-menaphthyl, allyl group, 2-chlorallyl, benzyl, 2; 2,2-three chloroethyls, trimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethyl silyl) ethyl, phenacyl, to methoxy-benzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, the tertiary butyl etc.
Oxazolidone compound itself that contains cyclopropyl of the present invention and pharmaceutically useful salt thereof and ester-formin can both be used for the treatment of the infectation of bacteria among the animal and human patient.Term " pharmaceutically useful ester, salt or hydrate " is meant those salt, ester and the hydrate forms to the conspicuous The compounds of this invention of pharmacist, promptly nontoxic substantially and can advantageously influence the pharmacokinetics performance of described compound such as palatability, absorption, distribution, metabolism and excretory those.More practical in nature and also in selection important other factors stability, solvability, water absorbability and the flowability of raw materials cost, crystallization easiness, yield, gained body medicine (bulk drug) are arranged.Easily, pharmaceutical composition can be made in conjunction with pharmaceutically acceptable carrier by activeconstituents.Therefore, the invention still further relates to the method for the novel oxazolidone compound that contains cyclopropyl of utilizing as the pharmaceutical composition and the treatment infectation of bacteria of activeconstituents.
Pharmacologically acceptable salt above-mentioned also comprises acid addition salt.Therefore, when formula I compound is alkalescence, can be by comprising that the pharmaceutically acceptable non-toxic acid of mineral acid or organic acid prepares salt.Comprise in this class acid salt following these: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, glucoheptose salt, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, isethionate, lactic acid salt, maleate, mandelate, malate, maleate, mesylate, mucate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, embonate, tooth hydrochlorate (pectinate), persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, phosphoric acid salt, pantothenate, pamoate (pamoic), vitriol, succinate, tartrate, thiocyanate-, tosylate and undecane hydrochlorate.
When compound of the present invention was acidity, suitable " pharmacologically acceptable salt " was meant the salt by the pharmaceutically acceptable nontoxic alkali preparation that comprises mineral alkali and organic bases.The salt that is obtained by mineral alkali comprises aluminium, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salt, inferior manganese, potassium, sodium, zinc etc.Especially preferred is ammonium, calcium, magnesium, potassium and sodium salt.The salt that obtains by pharmaceutically acceptable inorganic nontoxic alkali comprise primary amine, secondary amine and tertiary amine salt, comprise replacement amine, cyclammonium and the deacidite of natural replacement amine, as arginine, trimethyl-glycine, trimethyl-xanthine, choline, N, N
1-dibenzyl-ethylenediamin, diethylamine, 2-DEAE diethylaminoethanol, 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, Proscillaridin, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, trometamol etc.
Pharmaceutically acceptable ester is those esters of easily being understood by the pharmacist, and be included in those esters of hydrolysis under the physiological conditions, as " biolabile ester ", oxy acid methyl neopentyl, acetoxy-methyl, phthalidene, indanyl and methoxymethyl, and some other.But biolabile ester is the biology hydrolysis, and can be suitable for oral because they have the good absorption by stomach or intestines (intenstinal) mucous membrane, stomach juice-resistant degraded and other factors.The example of biolabile ester comprises compound.
Work as R
1Represent H, NR independently
5R
6, CN, OH or CR
7R
8R
9And when all other variablees are as described herein, realize one embodiment of the invention.
When
With
Be phenyl, pyridyl, pyrimidyl or piperidyl and all other variablees when as described herein independently, realize another embodiment of the invention.
Work as R
1Be CN and all other variablees when as described herein, realize another embodiment of the present invention.
When Y is NR
*And when all other variablees are as described herein, realize one embodiment of the invention.
When X is
The C of expression
5-10During heteroaryl, realize another embodiment of the present invention, this structural formula represents to contain the fragrant heterocyclic radical of 1 to 4 nitrogen-atoms and the optional replacement of at least one two key, and it connects by the key on any nitrogen.Exemplary group is a 1,2,3-triazoles, 1,2,4-triazole, oso-triazole, tetrazolium, pyrazoles and imidazoles, and wherein any one all can comprise 1 to 3 and is selected from R
7Substituting group.
When X is
And when all other variablees are as described herein, realize another embodiment of the present invention.When Y is NR
*And R
1Be CN or NH
2The time, realize a sub-embodiment of the present invention.
Work as R
3Be C
5-10When heteroaryl and all other variablees are as described herein, realize another embodiment of the invention, wherein said heteroaryl is randomly by 1 to 3 R
7Group replaces.
Work as R
3For
The C of expression
5-10During heteroaryl, realize another embodiment of the present invention, this structural formula represents to contain the fragrant heterocyclic radical of 1 to 4 nitrogen-atoms and the optional replacement of at least one two key, and it connects by the key on any nitrogen.Exemplary group is a 1,2,3-triazoles, 1,2, and 4-triazole, oso-triazole, tetrazolium, pyrazoles and imidazoles, all these groups all can comprise 1 to 3 and be selected from R
7Substituting group.
Work as R
5And R
6Be following group and all other variablees when as described herein independently, realize another embodiment of the present invention:
i)H，
The ii) optional C that is replaced by 1-3 following group
1-6Alkyl, described group is selected from halogen, CN, OH, C
1-6Alkoxyl group, amino, hydroxyl amino, 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 randomly are selected from halogen, CN, OH, CF
3, C
1-6Alkyl or C
1-61-3 in the alkoxyl group group replaces;
The iii) optional C that is replaced by 1-3 following group
1-6Acyl group, described group is selected from halogen, OH, SH, C
1-6Alkoxyl group, naphthyloxy, phenoxy group, amino, C
1-6Amido, 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
1-6Alkyl sulphinyl, phthalimido, maleimide amino, succinimido, described phenoxy group, phenyl and pyridine randomly are selected from halogen, OH, CN, C
1-6Alkoxyl group, amino, C
1-6Amido, CF
3Or C
1-61-3 in the alkyl group replaces; Or
Iv) randomly be selected from halogen, OH, C
1-6Alkoxyl group, C
1-6Alkyl, CF
3, C
1-6Alkyloyl, amino or C
1-6The benzoyl that in the amido 1 replaces to 3 groups.
Work as X
1When expression O and all other variablees are as described herein, realize another embodiment of the present invention.
When structural formula is III, realize a kind of preferred embodiment of the present invention:
R wherein
4, R
4aAnd R
3As described herein, and
Be 1,2,3-triazoles, 1,2,4-triazole, oso-triazole, tetrazolium, pyrazoles or imidazoles, wherein any one group all can comprise 1 to 3 and is selected from R
7Substituting group.
Work as R
3For
The C of expression
5-10During heteroaryl, realize sub-embodiment of the present invention, this structural formula represents to contain the fragrant heterocyclic radical of 1 to 4 nitrogen-atoms and the optional replacement of at least one two key, and it connects by the key on any nitrogen.
When structural formula is IV, realize another preferred embodiment of the present invention:
Formula IV
R wherein
1, R
4, R
4a, Y and R
3As described herein.Work as R
3For
The C of expression
5-10Realize sub-embodiment of the present invention during heteroaryl, this structural formula represents to contain the fragrant heterocyclic radical of 1 to 4 nitrogen-atoms and the optional replacement of at least one two key, and it connects by the key on any nitrogen.
Preferred compound of the present invention is:
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[3-fluoro-4-[2-(1-methyl tetrazolium-5-yl) pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[3,5-two fluoro-4-[2-(1-methyl tetrazolium-5-yl) pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide S-oxide compound,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
4-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 4-triazole,
4-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 4-triazole,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-5-[N-(tertbutyloxycarbonyl)-N-(isoxzzole-3-yl)] amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-methyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3,6-dicyano-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[(1-t-butoxycarbonyl amino ring third-1-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-the amino ring of 3-[(1-third-1-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[2-(phthalic imidine-2-yl) ethyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-(2-amino-ethyl)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[2-(1,2,4-triazole-4-yl) ethyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-bromo ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(morpholine-4-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(5-cyanopyridine-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(1,3-dihydroxyl third-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S)-1-tertbutyloxycarbonyl tetramethyleneimine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S)-tetramethyleneimine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4R)-1-tertbutyloxycarbonyl-4-hydroxyl pyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4R)-4-hydroxyl pyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4S)-1-tertbutyloxycarbonyl-4-fluoropyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4S)-4-fluoropyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-(tertbutyloxycarbonyl) amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles dihydrochloride,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-acetoxyl ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano-3-hydroxy ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides,
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] carbamate
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] carbamate
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3,6-dicyano-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-methyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[3-fluoro-4-[2-[(1 α, 5 α, 6 β)-6-hydroxymethyl-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-5-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-5-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-(4-tert-butoxycarbonyl-piperazine-1-yl) ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(piperazine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles dihydrochloride,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] thiophene-4-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(piperidines-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(tetramethyleneimine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(4-dimethylamino phenylpiperidines-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S)-1-tertbutyloxycarbonyl tetramethyleneimine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S)-tetramethyleneimine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4R)-4-hydroxyl pyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazolium salt hydrochlorate
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4R)-1-tertbutyloxycarbonyl-4-hydroxyl pyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4S)-1-tertbutyloxycarbonyl-4-fluoropyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4S)-4-fluoropyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(4-methylpiperazine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(1,3-diacetoxyl third-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[(3R, 4S)-1-azabicyclo [2.2.1] heptan-3-yl] carbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(pyridine-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(thiatriazole-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thioacetamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thioacetamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] lsothiocyanates,
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thiocarbamate,
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thiocarbamate,
Or their enantiomorph, diastereomer, or its pharmacologically acceptable salt, hydrate or prodrug.
The patient who is fit to use preparation of the present invention comprises Mammals, primate, people and other animal.When infecting the organic administration composition of susceptible bacteria, antibacterial activity in vitro can indicate activity in vivo.
Utilize the test of standard susceptibility, determine that composition of the present invention infects effectively opposing MRSA and faecalis.
By compound of the present invention is combined with pharmaceutically acceptable carrier, in pharmaceutical composition, allocate this compound into.The example of this carrier is set forth hereinafter.Can be with powder or crystallized form, in liquor or in suspension, use compound.They can pass through the variety of way administration; Those main modes comprise: local, oral and parenteral injection (intravenously or intramuscular).
Composition is used in the injection (preferably passing the medicine approach) that can prepare unit dosage form in ampoule or in multi-dose container.Injectable composition can be taked following form, as suspension, solution or the emulsion in oil or water vehicle, and can comprise various preparatons.Perhaps, activeconstituents can be powder (freeze-drying or non-freeze dried) form, is used for restoring when sending with suitable vehicle such as sterilized water.In Injectable composition, carrier generally comprises sterilized water, salt solution or other injectable liquids, for example is used for the peanut oil of intramuscularly.In addition, can comprise various buffer reagents, sanitas etc.
The topical application thing can be formulated in carrier such as the hydrophobic or hydrophilic base-material forming ointment, emulsifiable paste, lotion, in water-soluble, oiliness or pure class I liquid I preparation forming paint, or in dried thinner preparation to form powder.
Oral compositions can be taked following form, as tablet, capsule, oral suspensions and oral liquid.Oral compositions can use carrier, as conventional preparaton, and can comprise sustained release performance and quick delivery form.
The dosage of using depends on by treatment patient's symptom and size, route of administration and frequency, pathogenic agent to a great extent to the susceptibility of the specific compound selected, the virulence and the other factors of infection.But according to the principle of reatment of knowing in the antibiotic field, these problems can be left doctor's routine for and judge.Except infecting character and being treated the individual abnormal characteristic, another factor that influences the exact dosage desired scheme is the molecular weight of compound.
For sending of people's per unit dosage, new antibiotic composition of the present invention, no matter be liquid or solid, all comprise the oxazolidone compound that contain cyclopropyl of about 0.01% paramount about 99%, preferable range for this paper discussion of about 10-60%, with about 1% to about one or more other microbiotic of 99.99%, preferably from about 40% to about 90%, those that discuss as this paper.Composition comprise usually about 125mg to about 3.0g, but the oxazolidone compound that contains cyclopropyl of this paper discussion usually preferably in about 250mg to 1000mg scope; With about 200mg to about 5g, preferred about 250mg other microbiotic of this paper discussion of about 1000mg extremely.In administered parenterally, unit dosage form generally comprise in aseptic aqueous solution or solution with the pure compound of soluble powder form, described solution can be adjusted to neutral pH and equipressure.
Invention described herein also comprises the method for infectation of bacteria in a kind of Mammals for the treatment of this treatment of needs, and what be included as described administration significant quantity requires composition to treat described infection.
Known oxazolidone causes side effect sometimes, as sideroblastic anemia, peripheral sensory neuropathy, optic neuropathy, epileptic seizures, thrombocytopenia, cheilosis, seborrheic dermatitis, subcutaneous reproducibility anaemia, megaloblastic anemia or normocytic anemia.Compound of the present invention can with one or more combination of vitamins of significant quantity, with prevention or reduce the generation of the side effect that oxazolidone is relevant among the patient.Associable VITAMIN is Wei ShengsuB2, vitamin B6, vitamin B12 and folic acid.VITAMIN can be used as independent composition with the oxazolidone administration, or VITAMIN can be present in the identical composition with oxazolidone.
Therefore, another aspect of the present invention is to use in Wei ShengsuB2, vitamin B6, vitamin B12 and the folic acid of the oxazolidone of structural formula I of significant quantity and significant quantity one or more by the patient to needs to treat or prevent the method for oxazolidone related side effects.
Another aspect of the present invention relates to the Wei ShengsuB2 of using significant quantity by the patient to needs and treats or prevent oxazolidone relevant normocytic anemia or the neuropathic method of peripheral sensory.
Of the present inventionly relate in one aspect to the method that relevant sideroblastic anemia, peripheral sensory neuropathy, optic neuropathy, epileptic seizures, thrombocytopenia, cheilosis and seborrheic dermatitis of oxazolidone was treated or prevented to the vitamin B6 of using significant quantity by the patient to needs again.
The relevant subcutaneous reproducibility anaemia of oxazolidone, the method for megaloblastic anemia are treated or prevented to the vitamin B12 of using significant quantity by the patient to needs that also relates in one aspect to of the present invention with folic acid.
The method of infectation of bacteria is treated or prevented in Wei ShengsuB2, vitamin B6, vitamin B12 and the folic acid one or more of being selected from of using the formula I compound of significant quantity and significant quantity by the patient to needs that also relate in one aspect to of the present invention.
The preferred method of using the composition of requirement comprises oral and parenteral, and for example i.v. injects, i.v. injects and the i.m. injection, and some are measured approximately thereby unitary dose comprises the various active ingredients for the treatment of significant quantity or its.
For the adult, give 1 to 4 preferred every day, each dosage be about 5-50mg/kg body weight, preferably everyone about 250mg extremely about 1000mg contain extremely other microbiotic of about 1000mg of the oxazolidone antimicrobial compounds of cyclopropyl and everyone about 250mg.More specifically, for low-grade infection, suggestion every day 2 or 3 dosage are the oxazolidone antimicrobial compounds that contains cyclopropyl of about 250mg and other microbiotic of every day 2 or 3 about 250mg.For the organic grade and moderate infection of extremely sensitive Gram-positive, advise that each dosage is the oxazolidone that contains cyclopropyl of about 500mg and other microbiotic, every day 3 or 4 times.For the life-threatening infection of organic severe that is in the antibiotics sensitivity upper limit, can advise each dosage the oxazolidone compound that contains cyclopropyl and other microbiotic, every day 3 to 4 times for about 500-2000mg.
For children, give 2,3 or 4 preferred every day, and dosage is about 5-25mg/kg body weight; The dosage of general recommendations 10mg/kg.
Compound of the present invention can use suitable material to prepare according to the step of following synoptic diagram and general embodiment, and further specifies by the following specific embodiments.But the compound that illustrates among the embodiment can not be considered to form and be considered as unique kind of the present invention.The following examples further illustrate the preparation details of The compounds of this invention.Those skilled in the art can easily recognize, can utilize the condition of following preparation process and the known variant of process to prepare compound of the present invention.Unless otherwise indicated, all temperature all are degree centigrade.
Synoptic diagram 1
" or " expression among the figure " or ".
Compound of the present invention can use suitable material preparation according to synoptic diagram 1, and further specifies by the following specific embodiments.But the compound that illustrates among the embodiment can not be considered to form and be considered as unique kind of the present invention.The following examples further illustrate the preparation details of The compounds of this invention.Those skilled in the art can easily recognize, can utilize the condition of following preparation process and the known variant of process to prepare compound of the present invention.Unless otherwise indicated, all temperature all are degree centigrade.
In step 1, aromatic amine or assorted aromatic amine are changed into corresponding 5-hydroxyl oxazolidone by method well known to those skilled in the art.Typical condition comprises with benzyloxycarbonyl chlorine acylated amine; obtain corresponding carbamate; then with it with deprotonations such as suitable highly basic such as n-Butyl Lithium, propyl carbinol lithiums, the negatively charged ion that obtains is with the Glycidyl butyrate or other the suitable glycidyl ester cancellation that need.Behind processing and the purifying, obtain the methylol oxazolidone.Those skilled in the art can recognize, the acidylate that needs can be come catalysis with a large amount of suitable organic or inorganic alkali under laboratory technician's judgement, same, and a large amount of suitable acylating agents can be imagined and are used to carry out step 1.In addition, it shall yet further be noted that the 5-methylol oxazolidone that then obtains will be the S-configuration, and carry out the 5-methylol oxazolidone that step 1 has generation the R-configuration with the S-glycidyl ester if step 1 uses the R-glycidyl ester to carry out.
In step 2, use suitable electrophilic halogenating agent halogenation aromatic nucleus under suitable condition.An example of this halogenating agent is an iodine monochloride, but those skilled in the art can recognize very soon and can use other halogenating agent.Can recognize that halogen if desired is iodine, then will use iodinating agent, but other if desired halogen then needs to select suitable halogenating agent.These are well-known for those of ordinary skill in the art.
It is the R described in the specification sheets that step 3 has been described hydroxyl modified
3Substituting group.It should be understood that definite step, condition and reagent will be with required R
3Substituent precise chemical structure characteristic and changing, and representational conversion has been described, but be not limited in the specific embodiment those.
Step 4 has been described fragrant halogen and has been changed into suitable borate or boric acid, and it is for being coupled to the appropriate precursors of AR or HAra subsequently.These conditions are well-known for those skilled in the art, and are included in suitable Pd (II) catalyzer and handle initial halogenide with two tetramethyl ethylene ketone (pinacolato) two boron or other suitable boron precursor down as the existence of [two (diphenyl phosphine) ferrocene] palladium chloride II methylene dichloride complex compound etc. and suitable alkali.
Step 5 has been described HAr (or AR) the b component that describes in detail in the specification sheets and the coupling of appropriate H Ar (or AR) a component.This conversion is called the Suzuki coupling by those skilled in the art usually, and uses palladium (0) class as four (triphenyl phosphine) palladium (0) catalysis in the presence of suitable alkali such as alkaline carbonate, obtains compound of the present invention.Chemical conversion subsequently is well-known for a person skilled in the art, can be used for making in the specification sheets with X describing and various member's changes of the wide variety described.
Further describe the present invention in conjunction with following non-limiting example.
Embodiment 1
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg), 1-bromo-4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3-fluorobenzene (19.7mg) and four (triphenyl phosphine) palladium (0) (6.2mg) mixture in dioxan (0.5mL) and 2M sodium carbonate solution (135 μ L) heated 4 hours at 80 ℃ times.Mixture dilutes with ethyl acetate, washs with saturated sodium bicarbonate solution.Organic extract salt water washing is used anhydrous magnesium sulfate drying, then vacuum concentration.By preparative thin layer chromatography (silicon-dioxide, ethyl acetate: acetone=9: 1) handle resistates, obtain title compound 1 (19.4mg).
MS(FAB
+)m/z：545(MH
+).
For C
29H
30FN
6O
4(MH
+) HRMS (FAB
+) analyze: calculated value 545.2313; Detected value 545.2341.
Embodiment 2
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
To 1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, add the dioxan solution (4M of hydrogenchloride in methylene chloride-methanol (10: the 1) solution (2.5mL) of 3-triazole (316mg), 2.5mL), under room temperature, stirred 3.5 hours, then vacuum concentration.Use the Ethanol Treatment resistates, obtain title compound 2 (236mg).
MS (FAB
+) m/z:445 (MH
+) (being free alkali).
For C
24H
22FN
6O
2(MH
+) HRMS (FAB
+) analyze: calculated value 445.1788; Detected value 445.1765.
Embodiment 3
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (19.7mg), to prepare title compound 3 (22.3mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：528(MH
+).
For C
28H
30N
7O
4(MH
+) HRMS (FAB
+) analyze: calculated value 528.2359; Detected value 528.2352.
Embodiment 4
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
To 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, add the dioxan solution (4M of hydrogenchloride in methylene chloride-methanol (10: the 1) solution (1.7mL) of 3-triazole (209mg), 1.7mL), mixture stirred under room temperature 2.5 hours, then vacuum concentration.After resistates is used methylene chloride-methanol (10: 1) solution dilution, make the mixture alkalize by adding the 2N sodium hydroxide solution.Gained mixture methylene chloride-methanol (10: 1) solution extraction.Organic extract anhydrous magnesium sulfate drying, vacuum concentration then.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain title compound 4 (134mg).
Embodiment 5
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
Under 0 ℃, to 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, add the dioxan solution (4M, 168 μ L) of hydrogenchloride in methylene chloride-methanol (10: the 1) solution (2.5mL) of 3-triazole (287mg), with the mixture vacuum concentration.Use the Ethanol Treatment resistates, obtain title compound 5 (292mg).
MS (EI
+) m/z:428 (M
+) (being free alkali).
For C
23H
22N
7O
2(M
+) HRMS (EI
+) analyze: calculated value 428.1835; Detected value 428.1848.
Embodiment 6
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and 1-bromo-4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3-fluorobenzene (19.6mg), to prepare title compound 6 with embodiment 1 described identical method.
MS(FAB
+)m/z：563(MH
+).
For C
29H
29F
2N
6O
4(MH
+) HRMS (FAB
+) analyze: calculated value 563.2218; Detected value 563.2222.
Embodiment 7
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
By 1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (273mg) is to prepare title compound 7 (212mg) with embodiment 2 described identical methods.
MS (EI
+) m/z:462 (M
+) (being free alkali).
For C
24H
20F
2N
6O
2(M
+) HRMS (EI
+) analyze: calculated value 462.1616; Detected value 462.1631.
Embodiment 8
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (18.8mg), to prepare title compound 8 (15.8mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：546(MH
+).
For C
28H
29FN
7O
4(MH
+) HRMS (FAB
+) analyze: calculated value 546.2265; Detected value 546.2247.
Embodiment 9
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (500mg) is to prepare title compound 9 (278mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:446 (MH
+) (being free alkali).
For C
23H
21FN
7O
2(MH
+) HRMS (FAB
+) analyze: calculated value 446.1741; Detected value 446.1733.
Embodiment 10
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (18.9mg) and 1-bromo-4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3-fluorobenzene (20.0mg), to prepare title compound 10 (24.9mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：535(MH
+).
For C
29H
32FN
4O
5(MH
+) HRMS (FAB
+) analyze: calculated value 535.2357; Detected value 535.2375.
Embodiment 11
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride
By N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (360mg), to prepare title compound 11 (281mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:435 (MH
+) (being free alkali).
For C
24H
24FN
4O
3(MH
+) HRMS (FAB
+) analyze: calculated value 435.1832; Detected value 435.1821.
Embodiment 12
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (20.0mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (20.2mg), to prepare title compound 12 (20.3mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：518(MH
+).
For C
28H
32N
5O
5(MH
+) HRMS (FAB
+) analyze: calculated value 518.2403; Detected value 518.2412.
Embodiment 13
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (366mg), to prepare title compound 13 (254mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:418 (MH
+) (being free alkali).
For C
23H
24N
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 418.1879; Detected value 418.1885.
Embodiment 14
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (20.0mg) and 1-bromo-4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3-fluorobenzene (20.2mg), to prepare title compound 14 (24.9mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：553(MH
+).
For C
29H
31F
2N
4O
5(MH
+) HRMS (FAB
+) analyze: calculated value 553.2263; Detected value 553.2250.
Embodiment 15
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride
By N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (367mg), to prepare title compound 15 (290mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:453 (MH
+) (being free alkali).
For C
24H
23F
2N
4O
3(MH
+) HRMS (FAB
+) analyze: calculated value 453.1738; Detected value 453.1747.
Embodiment 16
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (350mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (337mg), to prepare title compound 16 (354mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：536(MH
+).
For C
28H
31FN
5O
5(MH
+) HRMS (FAB
+) analyze: calculated value 536.2309; Detected value 536.2296.
Embodiment 17
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (400mg), to prepare title compound 17 (259mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:436 (MH
+) (being free alkali).
For C
23H
23FN
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 436.1785; Detected value 436.1776.
Embodiment 18
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (67.2mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (63.1mg), to prepare title compound 18 (62.7mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：527(MH
+).
For C
27H
32FN
4O
6(MH
+) HRMS (FAB
+) analyze: calculated value 527.2306; Detected value 527.2329.
Embodiment 19
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
Under 0 ℃, to N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (52.0mg) adds trifluoroacetic acid (0.5mL) in the solution of methylene dichloride (1mL), mixture at room temperature stirred 2 hours.By add saturated sodium bicarbonate solution with the quencher reaction after, with chloroform-methanol (9: 1) solution extraction mixture.Organic extract anhydrous magnesium sulfate drying, vacuum concentration then.By flash chromatography method (NH silicon-dioxide, methylene dichloride: methyl alcohol=20: 1) handle resistates, obtain title compound 19 (36.7mg).
MS(EI
+)m/z：426(M
+)
For C
22H
23FN
4O
4(M
+) HRMS (EI
+) analyze: calculated value 426.1703; Detected value 426.1741.
Embodiment 20
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (65.6mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (60.0mg), to prepare title compound 20 (71.1mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：537(MH
+).
For C
27H
30FN
6O
5(MH
+) HRMS (FAB
+) analyze: calculated value 537.2262; Detected value 537.2276.
Embodiment 21
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (433mg) is to prepare title compound 21 (238mg) with embodiment 18 described identical methods.
MS(FAB
+)m/z：437(MH
+)
For C
22H
22FN
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 437.1737;
Detected value 437.1755.
Embodiment 22
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (378mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (337mg), to prepare title compound 22 (302mg) with embodiment 1 described identical method.
MS(EI
+)m/z：436(M
+)
For C
23H
21FN
4O
4(M
+) HRMS (EI
+) analyze: calculated value 436.1547; Detected value 436.1516.
Embodiment 23
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (388mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (265mg), to prepare title compound 23 (353mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：447(MH
+)
For C
23H
20FN
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 447.1581; Detected value 447.1589.
Embodiment 24
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (406mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (400mg), to prepare title compound 24 (387mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：509(MH
+)
For C
27H
33N
4O
6(MH
+) HRMS (FAB
+) analyze: calculated value 509.2400; Detected value 509.2384.
Embodiment 25
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (380mg), to prepare title compound 25 (262mg) with embodiment 18 described identical methods.
MS(FAB
+)m/z：409(MH
+)
For C
22H
25N
4O
4(MH
+) HRMS (FAB
+) analyze: calculated value 409.1876; Detected value 409.1838.
Embodiment 26
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (418mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (400mg), to prepare title compound 26 (313mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：519(MH
+)
For C
27H
31N
6O
5(MH
+) HRMS (FAB
+) analyze: calculated value 519.2356; Detected value 519.2382.
Embodiment 27
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (310mg) is to prepare title compound 27 (210mg) with embodiment 18 described identical methods.
MS(FAB
+)m/z：419(MH
+)
For C
22H
23N
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 419.1832; Detected value 419.1835.
Embodiment 28
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (360mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (265mg), to prepare title compound 28 (318mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：419(MH
+)
For C
23H
23N
4O
4(MH
+) HRMS (FAB
+) analyze: calculated value 419.1719; Detected value 419.1712.
Embodiment 29
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (419mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (300mg), to prepare title compound 29 (344mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：429(MH
+)
For C
23H
21N
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 429.1675; Detected value 429.1677.
Embodiment 30
1-[5 (R)-3-[3-fluoro-4-[2-(1-methyl tetrazolium-5-yl) pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (500mg) and 5-bromo-2-(1-methyl tetrazolium-5-yl) pyridine (309mg) is to prepare title compound 30 (480mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：422(MH
+)
For C
19H
17FN
9O
2(MH
+) HRMS (FAB
+) analyze: calculated value 422.1489; Detected value 422.1508.
Embodiment 31
1-[5 (R)-3-[3,5-two fluoro-4-[2-(1-methyl tetrazolium-5-yl) pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 5-bromo-2-(1-methyl tetrazolium-5-yl) pyridine (312mg), two (tetramethyl ethylene ketone) two boron (363mg), 2 ethyl hexanoic acid potassium (355mg) and [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (the II)-mixture of methylene dichloride adducts (53.1mg) in dioxan (13mL) stirred 1.5 hours down in 80 ℃, vacuum concentration then.In dioxan (29mL) solution of gained resistates, add 1-[5 (R)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl]-1; 2; 3-triazole (500mg), tetrakis triphenylphosphine palladium (0) (135mg) and 2M sodium carbonate solution (2.9mL), mixture stirred 6 hours down at 90 ℃.By flash chromatography method (NH silicon-dioxide, ethyl acetate) treating mixture, obtain title compound 31 (246mg).
MS(FAB
+)m/z：440(MH
+)
For C
19H
16F
2N
9O
2(MH
+) HRMS (FAB
+) analyze: calculated value 440.1395; Detected value 440.1395.
Embodiment 32
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (260mg) and 1-bromo-4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3,5-two fluorobenzene (267mg) are to prepare title compound 32 (362mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：581(MH
+)
For C
29H
28F
3N
6O
4(MH
+) HRMS (FAB
+) analyze: calculated value 581.2124; Detected value 581.2149.
Embodiment 33
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
By 1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (360mg) is to prepare title compound 33 (281mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:481 (MH
+) (being free alkali).
For C
24H
20F
3N
6O
2(MH
+) HRMS (FAB
+) analyze: calculated value 481.1600; Detected value 481.1598.
Embodiment 34
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (19.6mg) and 5-bromo-2-[(1 α; 5 α; 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (20.0mg), to prepare title compound 34 (15.5mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：554(MH
+)
For C
28H
30F
2N
5O
5(MH
+) HRMS (FAB
+) analyze: calculated value 554.2215; Detected value 554.2201.
Embodiment 35
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (235mg), to prepare title compound 35 (185mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:454 (MH
+) (being free alkali).
For C
23H
22F
2N
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 454.1691; Detected value 454.1651.
Embodiment 36
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl)-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (300mg) and 1-bromo-4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3,5-two fluorobenzene (317mg) are to prepare title compound 36 (347mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：571(MH
+)
For C
29H
30F
3N
4O
5(MH
+) HRMS (FAB
+) analyze: calculated value 571.2168; Detected value 571.2159.
Embodiment 37
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride
By N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (347mg), to prepare title compound 37 (251mg) with embodiment 2 described identical methods.
MS (EI
+) m/z:470 (M
+) (being free alkali).
For C
24H
21F
3N
4O
3(M
+) HRMS (EI
+) analyze: calculated value 470.1566; Detected value 470.1551.
Embodiment 38
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl)-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (300mg) and 1-bromo-4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] benzene (288mg), to prepare title compound 38 (274mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：535(MH
+)
For C
29H
32FN
4O
5(MH
+) HRMS (FAB
+) analyze: calculated value 535.2357; Detected value 535.2325.
Embodiment 39
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride
By N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (274mg), to prepare title compound 39 (212mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:435 (MH
+) (being free alkali)
For C
24H
24FN
4O
3(MH
+) HRMS (FAB
+) analyze: calculated value 435.1832; Detected value 435.1818.
Embodiment 40
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (641mg) and 1-bromo-4-[(1 α; 5 α; 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3-fluorobenzene (700mg), to prepare title compound 40 (427mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：571(MH
+)
For C
29H
30F
3N
4O
5(MH
+) HRMS (FAB
+) analyze: calculated value 571.2168; Detected value 571.2134.
Embodiment 41
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride
By N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (420mg), to prepare title compound 41 (340mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:471 (MH
+) (being free alkali)
For C
24H
22F
3N
4O
3(MH
+) HRMS (FAB
+) analyze: calculated value 471.1644; Detected value 471.1611.
Embodiment 42
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
By 1-[5 (R)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl]-1; 2; 3-triazole (561mg) and 1-bromo-4-[(1 α; 5 α; 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3-fluorobenzene (600mg), to prepare title compound 42 (273mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：581(MH
+)
For C
29H
28F
3N
6O
4(MH
+) HRMS (FAB
+) analyze: calculated value 581.2124; Detected value 581.2141.
Embodiment 43
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
Title compound 43 1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazolium salt hydrochlorate (223mg) by (270mg) with the described identical methods preparation of embodiment 2.
MS (FAB
+) m/z:481 (MH
+) (being free alkali)
For C
24H
20F
3N
6O
2(MH
+) HRMS (FAB
+) analyze: calculated value 481.1600; Detected value 481.1624.
Embodiment 44
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl]-1; 2; 3-triazole (19.6mg) and 5-bromo-2-[(1 α; 5 α; 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (20.0mg), to prepare title compound 44 (14.5mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：564(MH
+)
For C
28H
28F
2N
7O
4(MH
+) HRMS (FAB
+) analyze: calculated value 564.2171; Detected value 564.2147.
Embodiment 45
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
By 1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (360mg) is to prepare title compound 45 (294mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:464 (MH
+) (being free alkali)
For C
23H
20F
2N
7O
2(MH
+) HRMS (FAB
+) analyze: calculated value 464.1647; Detected value 464.1648.
Embodiment 46
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (300mg) and 1-bromo-4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] benzene (281mg), to prepare title compound 46 (305mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：545(MH
+)
For C
29H
30FN
6O
4(MH
+) HRMS (FAB
+) analyze: calculated value 545.2313; Detected value 545.2318.
Embodiment 47
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
By 1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (305mg) is to prepare title compound 47 (265mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:445 (MH
+) (being free alkali)
For C
24H
22FN
6O
2(MH
+) HRMS (FAB
+) analyze: calculated value 445.1788; Detected value 445.1826.
Embodiment 48
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl]-1; 2; 3-triazole (750mg) and 5-bromo-2-[(1 α; 5 α; 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (684mg), to prepare title compound 48 (482mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：555(MH
+)
For C
27H
29F
2N
6O
5(MH
+) HRMS (FAB
+) analyze: calculated value 555.2167; Detected value 555.2159.
Embodiment 49
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine]-the 5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Under room temperature to 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, add trifluoroacetic acid (4mL) in the dichloromethane solution of 3-triazole (465mg), mixture stirred 1 hour under uniform temp, then vacuum concentration.After adding aqueous sodium carbonate, with methylene chloride-methanol (10: 1) extraction mixture.Organic extract anhydrous magnesium sulfate drying, filtration, vacuum concentration then.By flash chromatography method (NH silicon-dioxide, chloroform: methyl alcohol=9: 1) handle resistates, obtain 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine]-the 5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (299mg).
MS(FAB
+)m/z：455(MH
+)
For C
22H
21F
2N
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 455.1643; Detected value 455.1649.
Embodiment 50
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (500mg) and 5-bromo-2-[(1 α; 5 α; 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (467mg), to prepare title compound 50 (269mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：545(MH
+)
For C
27H
31F
2N
4O
6(MH
+) HRMS (FAB
+) analyze: calculated value 545.2212; Detected value 545.2224.
Embodiment 51
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-tert-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (442mg), to prepare title compound 51 (278mg) with embodiment 49 described identical methods.
MS(FAB
+)m/z：445(MH
+)
For C
22H
23F
2N
4O
4(MH
+) HRMS (FAB
+) analyze: calculated value 445.1687; Detected value 445.1699.
Embodiment 52
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (600mg) and 5-bromo-2-[(1 α; 5 α; 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (419mg), to prepare title compound 52 (349mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：455(MH
+)
For C
23H
21F
2N
4O
4(MH
+) HRMS (FAB
+) analyze: calculated value 455.1531; Detected value 455.1505.
Embodiment 53
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3; 5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl]-1; 2; 3-triazole (612mg) and 5-bromo-2-[(1 α; 5 α; 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (419mg), to prepare title compound 53 (319mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：465(MH
+)
For C
23H
19F
2N
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 465.1487; Detected value 465.1460.
Embodiment 54
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
By N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl)-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (1.51g) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine (1.13g), to prepare title compound 54 (1.32g) with embodiment 1 described identical method.
MS(FAB
+)m/z：453(MH
+)
For C
23H
22FN
4O
3S (MH
+) HRMS (FAB
+) analyze: calculated value 453.1397; Detected value 453.1402.
Embodiment 55
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide S-oxide compound
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (294mg), to prepare title compound 55 (233mg) with embodiment 58 described identical methods.
MS(FAB
+)m/z：469(MH
+)
For C
23H
22FN
4O
4S (MH
+) HRMS (FAB
+) analyze: calculated value 469.1346; Detected value 469.1359.
Embodiment 56
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide S, the S-dioxide
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (317mg), to prepare title compound 56 (292mg) with embodiment 59 described identical methods.
MS(FAB
+)m/z：485(MH
+)
For C
23H
22FN
4O
5S (MH
+) HRMS (FAB
+) analyze: calculated value 485.1295; Detected value 485.1282.
Embodiment 57
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (582mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine (422mg), to prepare title compound 57 (546mg) with embodiment 1 described identical method.
H
+)
For C
23H
20FN
6O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 463.1352; Detected value 463.1355.
Embodiment 58
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound
Under-19 ℃ to 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the methylene chloride-methanol of 3-triazole (118mg) (5: 1,8mL) add in the solution metachloroperbenzoic acid (74.5mg) methylene chloride-methanol (5: 1,1mL) solution, mixture stirred 70 minutes down at 0 ℃.By flash chromatography method (NH silicon-dioxide, methylene dichloride: treating mixture tetrahydrofuran (THF)=7: 3), obtain 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole S-oxide compound (111mg).
MS(FAB
+)m/z：479(MH
+)
For C
23H
20FN
6O
3S (MH
+) HRMS (FAB
+) analyze: calculated value 479.1302; Detected value 479.1306.
Embodiment 59
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide
Under 0 ℃, to 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, and the methylene chloride-methanol of 3-triazole (254mg) (5: 1,14mL) add the methylene chloride-methanol (5: 1 of metachloroperbenzoic acid (438mg) in the solution, 2.0mL) solution, mixture at room temperature stirred 1.25 hours.(5: 1,0.7mL) behind the solution, mixture at room temperature stirred 2 hours at the methylene chloride-methanol that adds metachloroperbenzoic acid (146mg) in mixture.By flash chromatography method (NH silicon-dioxide, methylene dichloride: treating mixture tetrahydrofuran (THF)=2: 1), obtain 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole S, S-dioxide (261mg).
MS(FAB
+)m/z：495(MH
+)
For C
23H
20FN
6O
4S (MH
+) HRMS (FAB
+) analyze: calculated value 495.1251; Detected value 495.1256.
Embodiment 60
4-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 4-triazole
By 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (700mg), to prepare title compound 60 (64.0mg) with embodiment 83 described identical methods.
Rf value (TCL): 0.26 (methylene dichloride: methyl alcohol=10: 1).
Embodiment 61
4-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,4-triazolium salt hydrochlorate
By 4-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,4-triazole (64.0mg) is to prepare title compound 61 (37.9mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:446 (MH
+) (being free alkali)
For C
23H
21FN
7O
2(MH
+) HRMS (FAB
+) analyze: calculated value 446.1741; Detected value 446.1756.
Embodiment 62
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-methylol oxazolidine-2-ketone (50.0mg), to prepare title compound 62 (53.8mg) with embodiment 66 described identical methods.
MS(FAB
+)m/z：562(MH
+)
For C
29H
29FN
5O
6(MH
+) HRMS (FAB
+) analyze: calculated value 562.2102; Detected value 562.2074.
Embodiment 63
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-keto hydrochloride
By 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone (400mg), to prepare title compound 63 (303mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:462 (MH
+) (being free alkali)
For C
24H
21FN
5O
4(MH
+) HRMS (FAB
+) analyze: calculated value 462.1578; Detected value 462.1534.
Embodiment 64
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxzzole-3-yl) amino methyl oxazolidine-2-ketone
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-methylol oxazolidine-2-ketone (50.0mg), to prepare title compound 64 (58.2mg) with embodiment 67 described identical methods.
MS(FAB
+)m/z：661(MH
+)
For C
34H
38FN
6O
7(MH
+) HRMS (FAB
+) analyze: calculated value 661.2786; Detected value 661.2760.
Embodiment 65
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxzzole-3-yl) amino methyl oxazolidine-2-keto hydrochloride
By 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxzzole-3-yl) amino methyl oxazolidine-2-ketone (600mg), to prepare title compound 65 (280mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:461 (MH
+) (being free alkali)
For C
24H
22FN
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 461.1737; Detected value 461.1712.
Embodiment 66
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone
To N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-add diisopropyl azo-2-carboxylic acid (133mg) in tetrahydrofuran (THF) (5mL) suspension of 5-methylol oxazolidine-2-ketone (200mg), 3-hydroxyl isoxzzole (55.9mg) and triphenyl phosphine (199mg), mixture at room temperature stirred 1 hour, then vacuum concentration.After handling resistates with ethyl acetate and ether, the gained resistates is dissolved in chloroform, leach insolubles, vacuum concentrated filtrate, obtain 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone (205mg).
MS(FAB
+)m/z：463(MH
+)
For C
24H
20FN
4O
5(MH
+) HRMS (FAB
+) analyze: calculated value 463.1418; Detected value 463.1439.
Embodiment 67
5 (R)-5-[N-tert-butoxycarbonyl-N-(isoxzzole-3-yl)] amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone
To N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-toluene (7.5mL) suspension of 5-methylol oxazolidine-2-ketone (300mg), 3-N-(tert-butoxycarbonyl) amido isoxazole (168mg) and tetramethyl-azodicarboxy acid amides (196mg), add tributylphosphine (230mg), mixture stirred 2 hours down at 50 ℃.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=1: 1) treating mixture, obtain 5 (R)-5-[N-tert-butoxycarbonyl-N-(isoxzzole-3-yl)] amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (392mg).
MS(FAB
+)m/z：562(MH
+)
For C
29H
29FN
5O
6(MH
+) HRMS (FAB
+) analyze: calculated value 562.2102; Detected value 562.2123.
Embodiment 68
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone
Under 0 ℃, to 5 (R)-5-[N-tert-butoxycarbonyl-N-(isoxzzole-3-yl)] amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] add trifluoroacetic acid (2.0mL) in methylene dichloride (4.0mL) solution of oxazolidine-2-ketone (375mg), mixture at room temperature stirred 2 hours, then vacuum concentration.Behind ethyl acetate dilution resistates, with 5% solution of potassium carbonate purging compound, use anhydrous magnesium sulfate drying, vacuum concentration then, obtain 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone (189mg).
MS(FAB
+)m/z：462(MH
+)
For C
24H
21FN
5O
4(MH
+) HRMS (FAB
+) analyze: calculated value 462.1578; Detected value 462.1602.
Embodiment 69
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide
By 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (200mg), to prepare title compound 69 (213mg) with embodiment 70 described identical methods.
MS(FAB
+)m/z：451(MH
+)
For C
24H
24FN
4O
4(MH
+) HRMS (FAB
+) analyze: calculated value 451.1782; Detected value 451.1753.
Embodiment 70
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides
Under 0 ℃, to 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] add difluoroacetic acid acid anhydride (159mg) in pyridine (5mL) suspension of oxazolidine-2-ketone (200mg), mixture at room temperature stirred 2 hours, then vacuum concentration.Behind methylene dichloride dilution resistates,, use anhydrous magnesium sulfate drying, vacuum concentration with 3% hydrochloric acid and 5% sodium hydrogen carbonate solution purging compound.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=15: 1) handle resistates, obtain N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides (230mg).
MS(FAB
+)m/z：473(MH
+)
For C
23H
20F
3N
4O
4(ME
+) HRMS (FAB
+) analyze: calculated value 473.1437; Detected value 473.1426.
Embodiment 71
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides
Under room temperature, to 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] add 1-[3-(dimethylamino) propyl group in oxazolidine-2-ketone (200mg) and cyclopropyl-carboxylic acid's (56.8mg) methylene dichloride (10mL) solution]-3-ethyl-carbodiimide hydrochloride (146mg), mixture stirred 2 hours under uniform temp.Water and 5% sodium hydrogen carbonate solution purging compound are used anhydrous magnesium sulfate drying, then vacuum concentration.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=15: 1) handle resistates, obtain N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides (167mg).
MS(FAB
+)m/z：463(MH
+)
For C
25H
24FN
4O
4(MH
+) HRMS (FAB
+) analyze: calculated value 463.1782; Detected value 463.1774.
Embodiment 72
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide
By 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (300mg) and propionyl chloride (58 μ L), to prepare title compound 72 (305mg) with embodiment 92 described identical methods.
MS(FAB
+)m/z：550(MH
+)
Embodiment 73
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide (295mg), to prepare title compound 73 (165mg) with embodiment 49 described identical methods.
H
+)
For C
24H
25FN
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 450.1941; Detected value 450.1905.
Embodiment 74
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides
By 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (300mg), to prepare title compound 74 (260mg) with embodiment 71 described identical methods.
MS(FAB
+)m/z：562(MH
+)
Embodiment 75
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxamide hydrochloride
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides (250mg), to prepare title compound 75 (183mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:462 (MH
+) (being free alkali)
For C
25H
25FN
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 462.1941; Detected value 462.1938.
Embodiment 76
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides
By 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (300mg), to prepare title compound 76 (258mg) with embodiment 70 described identical methods.
MS(FAB
+)m/z：572(MH
+)
Embodiment 77
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] the difluoro acetamide hydrochloride
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides (250mg), to prepare title compound 77 (170mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:472 (MH
+) (being free alkali)
For C
23H
21F
3N
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 472.1596; Detected value 472.1590.
Embodiment 78
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-methyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Under room temperature to 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, add acetate (5.1 μ L), 35% formaldehyde solution (35.6 μ L) and sodium solution (20.0mg) in tetrahydrofuran (THF) (0.45mL) suspension of 3-triazole (20.0mg), mixture stirred 3 hours under uniform temp.After 0 ℃ the saturated sodium hydrogen carbonate solution quencher of interpolation is reacted down, with methylene chloride-methanol (5: 1) solution extraction mixture.Organic extract salt water washing is used anhydrous magnesium sulfate drying, then vacuum concentration.By preparative thin layer chromatography (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-methyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (15.0mg).
MS(FAB
+)m/z：460(MH
+)
For C
24H
23FN
7O
2(MH
+) HRMS (FAB
+) analyze: calculated value 460.1897; Detected value 460.1888.
Embodiment 79
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3,6-dicyano-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, methyl alcohol (20mL) suspension of 3-triazole (300mg) and sodium acetate (390mg) stirred under room temperature 30 minutes.Under 0 ℃, (5M, 0.4mL), mixture stirred 8 hours under uniform temp the dichloromethane solution of interpolation cyanogen bromide in gained suspension.Leach insolubles, then vacuum concentrated filtrate.Water and methyl alcohol are handled resistates, obtain 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3,6-dicyano-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (138mg).
MS(FAB
+)m/z：471(MH
+)
For C
24H
20FN
8O
2(MH
+) HRMS (FAB
+) analyze: calculated value 471.1693; Detected value 471.1709.
Embodiment 80
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-the amino ring of 3-[(1-tert-butoxycarbonyl third-1-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg), 1-(tert-butoxycarbonyl amino) cyclopropane-1-carboxylic acid (13.6mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (12.9mg) and the mixture of 4-(dimethylamino) pyridine (8.2mg) in methylene dichloride stirred 5 hours under room temperature.Behind the dilute with water mixture, use the salt solution purging compound, use anhydrous magnesium sulfate drying, then vacuum concentration.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain title compound 80 (28.6mg).
MS(FAB
+)m/z：629(MH
+)
For C
32H
34FN
8O
5(MH
+) HRMS (FAB
+) analyze: calculated value 629.2636; Detected value 629.2633.
Embodiment 81
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-the amino ring of 3-[(1-third-1-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-the amino ring of 3-[(1-tert-butoxycarbonyl third-1-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (26.6mg) is to prepare title compound 81 (18.4mg) with embodiment 2 described identical methods.
MS (FAB
+) m/z:529 (MH
+) (being free alkali)
For C
27H
26FN
8O
3(MH
+) HRMS (FAB
+) analyze: calculated value 529.2112; Detected value 529.2105.
Embodiment 82
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-(2-amino-ethyl)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[2-(phthalic imidine-2-yl) ethyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, acetonitrile (0.2mL) the suspension returning heated overnight of 3-triazole (20.0mg), 2-bromotrifluoromethane phthalic imidine (11.4mg) and salt of wormwood (9.3mg), vacuum concentration.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain the compound (25.2mg) of step 1 among the embodiment 82.
MS(FAB
+)m/z：619(MH
+)
For C
33H
28FN
8O
4(MH
+) HRMS (FAB
+) analyze: calculated value 619.2218; Detected value 619.2214.
Step 2
Title compound 82
With the compound (20.0mg) of step 1 among the embodiment 82 and the mixture reflux of methylhydrazine (34.4 μ L) in ethanol 2 days.Behind salt solution diluted mixture thing, use the ethyl acetate extraction mixture.Organic extract anhydrous magnesium sulfate drying, vacuum concentration then.By preparative thin layer chromatography (NH silicon-dioxide, ethyl acetate: methyl alcohol=10: 1) handle resistates, obtain title compound 82 (10.8mg)
MS(FAB
+)m/z：489(MH
+)
For C
25H
26FN
8O
2(MH
+) HRMS (FAB
+) analyze: calculated value 489.2163; Detected value 489.2195.
Embodiment 83
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[2-(1,2,4-triazole-4-yl) ethyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-(2-amino-ethyl)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (29.7mg), dimethyl formamide azine (8.6mg) and the mixture reflux of tosic acid (0.6mg) in toluene 16 hours, vacuum concentration.By preparative thin layer chromatography (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain title compound 83 (10.9mg).
MS(FAB
+)m/z：541(MH
+)
For C
27H
26FN
10O
2(MH
+) HRMS (FAB
+) analyze: calculated value 541.2224; Detected value 541.2203.
Embodiment 84
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(morpholine-4-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-acetyl bromide-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Under 0 ℃, in methylene dichloride (0.3mL) solution of bromoacetyl bromide (9.8 μ L), add 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-the assorted dicyclo [3.1.0] of 6-cyano group-3-ammonia oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, methylene dichloride (1.5mL) solution of 3-triazole (50.0mg) and triethylamine (15.6 μ L), mixture stirred 3 hours under uniform temp, vacuum concentration.Behind methylene chloride-methanol (10: 1) solution dilution resistates, with 2N hydrochloric acid purging compound, use anhydrous magnesium sulfate drying, vacuum concentration then obtains the compound (88.1mg) of step 1 among the embodiment 84.
Step 2
Compound 84
Under 0 ℃, in acetonitrile (1.0mL) solution of morpholine (29.3 μ L), add acetonitrile (1.5mL) solution of the crude compound (88.1mg) of embodiment 84 steps 1, mixture stirred 5 hours under uniform temp.Behind the dilute with water resistates, with methylene chloride-methanol (10: 1) solution washing mixture.Organic extract salt water washing is used anhydrous magnesium sulfate drying, then vacuum concentration.By preparative thin layer chromatography (silicon-dioxide, methylene dichloride: methyl alcohol=5: 1) handle resistates, obtain title compound 84 (17.5mg).
MS(FAB
+)m/z：573(MH
+)
For C
29H
30FN
8O
4(MH
+) HRMS (FAB
+) analyze: calculated value 573.2374; Detected value 573.2381.
Embodiment 85
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(5-cyanopyridine-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
To 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, add diisopropylethylamine (78 μ L) in methyl-sulphoxide (0.5mL) suspension of 3-triazole (20.0mg), mixture stirred under room temperature 5 minutes.Add 2-bromo-5-cyanopyridine (16.4mg) to the gained mixture, mixture stirred 9 hours down in 60 ℃.Behind ethyl acetate and water diluted mixture thing, use the ethyl acetate extraction mixture.Anhydrous magnesium sulfate drying is used in organic extract water and salt water washing, filters, then vacuum concentration.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=20: 1) handle resistates, obtain title compound 85 (12.8mg).
MS(FAB
+)m/z：548(MH
+)
For C
29H
23FN
9O
2(MH
+) HRMS (FAB
+) analyze: calculated value 548.1959; Detected value 548.1984.
Embodiment 86
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(1,3-dihydroxyl third-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
To 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the methylene chloride-methanol of 3-triazole (50.0mg) (10: 1,1.0mL) add 1 in the solution, 3-otan dimer (60.7mg), methyl alcohol (4.0mL), acetate (0.5mL) and sodium cyanoborohydride (21.2mg), mixture stirred under room temperature 7.5 hours.After adding 2N hydrochloric acid, mixture stirred under room temperature 1 hour.Mixture dilutes with salt solution, with methylene chloride-methanol (10: 1) extraction.Organic extract Anhydrous potassium carbonate drying is filtered, then vacuum concentration.By preparative thin layer chromatography (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain title compound 86 (13.2mg).
MS(FAB
+)m/z：520(MH
+)
For C
26H
27FN
7O
4(MH
+) HRMS (FAB
+) analyze: calculated value 520.2109; Detected value 520.2086.
Embodiment 87
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S)-tetramethyleneimine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S)-1-tert-butoxycarbonyl tetramethyleneimine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and N-tertbutyloxycarbonyl-L-proline(Pro) (11.6mg) is to prepare the compound (27.1mg) of step 1 among the embodiment 87 with the described identical method of embodiment 71.
MS(FAB
+)m/z：643(MH
+)
For C
33H
36FN
8O
5(MH
+) HRMS (FAB
+) analyze: calculated value 643.2793; Detected value 643.2744.
Step 2
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S)-tetramethyleneimine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S)-1-tert-butoxycarbonyl tetramethyleneimine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (26.9mg) is to prepare the compound (16.8mg) of step 2 among the embodiment 87 with the described identical method of embodiment 2.
MS (FAB
+) m/z:543 (MH
+) (being free alkali)
For C
28H
28FN
8O
3(MH
+) HRMS (FAB
+) analyze: calculated value 543.2268; Detected value 543.2243.
Embodiment 88
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4R)-4-hydroxyl pyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazolium salt hydrochlorate
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4R)-1-tert-butoxycarbonyl-4-hydroxyl pyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and N-tertbutyloxycarbonyl-4-hydroxyl-L-proline(Pro) (12.3mg) is to prepare the compound (28.4mg) of step 1 among the embodiment 88 with the described identical method of embodiment 71.
MS(FAB
+)m/z：659(MH
+)
For C
33H
36FN
8O
6(MH
+) HRMS (FAB
+) analyze: calculated value 659.2742; Detected value 659.2775.
Step 2
With the compound (27.4mg) of step 1 among the embodiment 88, to prepare compound 88 (15.6mg) with embodiment 2 described identical methods.
MS(FAB
+)m/z：559(MH
+)
For C
28H
28FN
8O
4(MH
+) HRMS (FAB
+) analyze: calculated value 559.2218; Detected value 559.2247.
Embodiment 89
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4S)-4-fluoropyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazolium salt hydrochlorate
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4S)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (50.0mg) and N-tertbutyloxycarbonyl-(4S)-fluoro-L-proline(Pro) (31.5mg) is to prepare the compound (73.6mg) of step 1 among the embodiment 89 with the described identical method of embodiment 71.
MS(FAB
+)m/z：661(MH
+)
For C
33H
35F
2N
8O
5(MH
+) HRMS (FAB
+) analyze: calculated value 661.2698; Detected value 661.2656.
Step 2
With the compound (69.3mg) of step 1 among the embodiment 89, to prepare the compound (44.0mg) of embodiment 89 with the described identical method of embodiment 2.
MS(FAB
+)m/z：561(MH
+)
For C
28H
27F
2N
8O
3(MH
+) HRMS (FAB
+) analyze: calculated value 561.2174; Detected value 561.2142.
Embodiment 90
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-(tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl)-phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (600mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-(tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (702mg), to prepare title compound 90 (473mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：636(MH
+)
For C
32H
39FN
7O
6(MH
+) HRMS (FAB
+) analyze: calculated value 636.2946; Detected value 636.2931.
Embodiment 90
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-(tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl)-phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (600mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-(tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (702mg), to prepare title compound 90 (473mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：636(MH
+)
For C
32H
39FN
7O
6(MH
+) HRMS (FAB
+) analyze: calculated value 636.2946; Detected value 636.2931.
Embodiment 91
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles dihydrochloride
By 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-(tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (397mg) is to prepare title compound 91 (305mg) with embodiment 2 described identical methods.
MS(FAB
+)m/z：436(MH
+)
For C
22H
23FN
7O
2(MH
+) HRMS (FAB
+) analyze: calculated value 436.1897; Detected value 436.1898.
Embodiment 92
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-acetoxyl group ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Under 0 ℃, to 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, add triethylamine (28 μ L) and alpha-Acetoxyacetyl chloride (7.0 μ L) in methylene dichloride (0.7mL) suspension of 3-triazole (30.0mg), mixture stirred 1 hour under uniform temp.Behind the dilute with water mixture, use the dichloromethane extraction mixture.Anhydrous sodium sulfate drying is used in organic extract water and salt water washing, filters, then vacuum concentration.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain title compound 92 (34.7mg).
MS(FAB
+)m/z：546(MH
+)
For C
27H
25FN
7O
5(MH
+) HRMS (FAB
+) analyze: calculated value 546.1901; Detected value 546.1888.
Embodiment 93
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano-3-hydroxy ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Under room temperature; to 1-[5 (R)-3-[4-[2-[(1 α; 5 α; 6 β)-3-acetoxyl group ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1; 2; add salt of wormwood (130mg) in the methyl alcohol (4.5mL) of 3-triazole (255mg) and the solution of tetrahydrofuran (THF) (1.3mL), mixture stirred 2 hours under uniform temp, then vacuum concentration.Behind methylene chloride-methanol (5: 1) solution dilution resistates, mixture salt water washing.The organic extract anhydrous magnesium sulfate drying filters, then vacuum concentration.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=5: 1) handle resistates, obtain the title compound (137mg) among the embodiment 93.
MS(FAB
+)m/z：504(MH
+)
For C
25H
23FN
7O
4(MH
+) HRMS (FAB
+) analyze: calculated value 504.1796; Detected value 504.1800.
Embodiment 94
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides
Diastereomer A and diastereomer B
By 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (269mg) and 2,2-dichloro cyclopropane-carboxylic acid (110mg), to prepare title compound 94 (diastereomer A:100mg, diastereomer B:76.6mg) with embodiment 71 described identical methods.
Diastereomer A (than low-pole):
MS(FAB
+)m/z：630(MH
+)
Diastereomer B (strong polarity):
MS(FAB
+)m/z：630(MH
+)
Embodiment 95
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides diastereomer A '
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-and 1-carboxylic acid amides (diastereomer A:97.0mg), to prepare title compound 95 (diastereomer A ': 78.9mg) with embodiment 49 described identical methods.
MS(FAB
+)m/z：530(MH
+)
For C
25H
23Cl
2FN
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 530.1162; Detected value 530.1198.
Embodiment 96
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides diastereomer B '
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-and 1-carboxylic acid amides (diastereomer B:73.0mg), to prepare title compound 96 (diastereomer B ': 57.2mg) with embodiment 49 described identical methods.
MS(FAB
+)m/z：530(MH
+)
For C
25H
23Cl
2FN
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 530.1162; Detected value 530.1137.
Embodiment 97
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides
Diastereomer C and diastereomer D
By 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (300mg) and 2,2-difluoro cyclopropane-carboxylic acid (96.5mg), to prepare title compound 97 (diastereomer C:125mg, diastereomer D:125mg) with embodiment 71 described identical methods.
Embodiment 98
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides diastereomer C '
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-and 1-carboxylic acid amides (diastereomer C:122mg), to prepare title compound 98 (diastereomer C ': 75.8mg) with embodiment 49 described identical methods.
MS(FAB
+)m/z：498(MH
+)
For C
25H
23F
3N
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 498.1753; Detected value 498.1783.
Embodiment 99
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides diastereomer D '
By N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-and 1-carboxylic acid amides (diastereomer D:122mg), to prepare title compound 99 (diastereomer D ': 62.2mg) with embodiment 49 described identical methods.
MS(FAB
+)m/z：498(MH
+)
For C
25H
23F
3N
5O
3(MH
+) HRMS (FAB
+) analyze: calculated value 498.1753; Detected value 498.1740.
Embodiment 100
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] carbamate
By 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (200mg) and methyl-chloroformate (37 μ L), to prepare title compound 100 (53.2mg) with embodiment 92 described identical methods.
MS(FAB
+)m/z：552(MH
+)
Embodiment 101
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclic [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] carbamate
By O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tert-butoxycarbonyl-6-cyano group-3-azabicyclic [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] carbamate (50.0mg), to prepare title compound 101 (32.7mg) with embodiment 49 described identical methods.
MS(FAB
+)m/z：452(MH
+)
For C
23H
23FN
5O
4(MH
+) HRMS (FAB
+) analyze: calculated value 452.1734; Detected value 452.1729.
Embodiment 102
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3,6-dicyano-3-azabicyclic [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclic [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (15.0mg) is to prepare title compound 102 (12.2mg) with embodiment 79 described identical methods.
MS(FAB
+)m/z：489(MH
+)
For C
24H
19F
2N
8O
2(MH
+) HRMS (FAB
+) analyze: calculated value 489.1599; Detected value 489.1634.
Embodiment 103
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-methyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (15.0mg) is to prepare title compound 103 (14.8mg) with embodiment 78 described identical methods.
MS(FAB
+)m/z：478(MH
+)
For C
24H
22F
2N
7O
2(MH
+) HRMS (FAB
+) analyze: calculated value 478.1803; Detected value 478.1825.
Embodiment 104
1-[5 (R)-3-[3-fluoro-4-[2-[(1 α, 5 α, 6 β)-6-methylol-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
By 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl)-phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (83.4mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-methylol-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (58.0mg), to prepare title compound 104 (73.2mg) with embodiment 1 described identical method.
MS(FAB
+)m/z：452(MH
+).
For C
23H
23FN
5O
4(MH
+) HRMS (FAB
+) analyze: calculated value 452.1734; Detected value 452.1735.
Embodiment 105
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles
By 4-fluoro-1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (125mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (122mg), to prepare title compound 105 (101mg) with embodiment 31 described identical methods.
MS(FAB
+)m/z：465(MH
+).
For C
23H
19F
2N
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 465.1487; Detected value 465.1514.
Embodiment 106
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles
Press and embodiment 1 described identical method, from 4-fluoro-1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (370mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (332mg) preparation title compound 106 (301mg).
MS(FAB
+)m/z：564(MH
+)。
For C
28H
28F
2N
7O
4(MH
+) HRMS (FAB
+) analyze: calculated value 564.2171; Detected value 564.2168.
Embodiment 107
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles hydrochloride
Press and embodiment 2 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazole (290mg) preparation title compound 107 (231mg).
MS (FAB
+) m/z:464 (MH
+) (as free alkali).
For C
23H
20F
2N
7O
2(MH
+) HRMS (FAB
+) analyze: calculated value 464.1647; Detected value 464.1645.
Embodiment 108
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-5-fluoro-1,2,3-triazoles
Press and embodiment 31 described identical methods, from 1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-5-fluoro-1,2,3-triazole (150mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo-[3.1.0] oneself-the 6-yl] pyridine (202mg) preparation title compound 108 (169mg).
MS(FAB
+)m/z：564(MH
+)。
For C
28H
28F
2N
7O
4(MH
+) HRMS (FAB
+) analyze: calculated value 564.2171; Detected value 564.2189.
Embodiment 109
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-5-fluoro-1,2,3-triazoles hydrochloride
Press and embodiment 2 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-5-fluoro-1,2,3-triazole (151mg) preparation title compound 109 (118mg).
MS (FAB
+) m/z:464 (MH
+) (being free alkali).
For C
23H
20F
2N
7O
2(MH
+) HRMS (FAB
+) analyze: calculated value 464.1647; Detected value 464.1679.
Embodiment 110
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-(4-tert-butoxycarbonyl-piperazine-1-yl) ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 78 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (50.0mg) and 1-tert-butoxycarbonyl-piperazine (62.6mg) preparation title compound 110 (60.7mg).
MS(FAB
+)m/z：672(MH
+)。
For C
34H
39FN
9O
5(MH
+) HRMS (FAB
+) analyze: calculated value 672.3058; Detected value 672.3040.
Embodiment 111
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(piperazine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles dihydrochloride
Press and embodiment 2 described identical methods; from 1-[5 (R)-3-[4-[2-[(1 α; 5 α; 6 β)-3-(4-tert-butoxycarbonyl-piperazine-1-yl)-ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1; 2,3-triazole (59.7mg) preparation title compound 111 (57.0mg).
MS (FAB
+) m/z:572 (MH
+) (being free alkali).
For C
29H
31FN
9O
3(MH
+) HRMS (FAB
+) analyze: calculated value 572.2534; Detected value 572.2535.
Embodiment 112
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] thiophene-4-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 1 described identical method, from 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl)-phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (3 88mg) and 4-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] thiophene (270mg) preparation title compound 112 (261mg).
MS(FAB
+)m/z：452(MH
+)。
For C
22H
19FN
5O
3S (MH
+) HRMS (FAB
+) analyze: calculated value 452.1193; Detected value 452.1180.
Embodiment 113
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(piperidines-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 84 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and piperidines (17.8 μ L) preparation title compound 113 (15.7mg).
MS(FAB
+)m/z：571(MH
+)。
For C
30H
32FN
8O
3(MH
+) HRMS (FAB
+) analyze: calculated value 571.2581; Detected value 571.2579.
Embodiment 114
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(tetramethyleneimine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 84 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and tetramethyleneimine (15 μ L) preparation title compound 114 (20.7mg).
MS(FAB
+)m/z：557(MH
+)。
For C
30H
32FN
8O
3(MH
+) HRMS (FAB
+) analyze: calculated value 557.2425; Detected value 557.2467.
Embodiment 115
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(4-dimethylamino phenylpiperidines-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 84 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and 4-dimethylamino phenylpiperidines dihydrochloride (36.2mg) preparation title compound 115 (22.0mg).
MS(FAB
+)m/z：614(MH
+)。
For C
32H
37FN
9O
3(MH
+) HRMS (FAB
+) analyze: calculated value 614.3003; Detected value 614.3049.
Embodiment 116
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S)-tetramethyleneimine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S)-1-tertbutyloxycarbonyl tetramethyleneimine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
Press and embodiment 71 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0]-oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the compound (13.3mg) of 3-triazole (10.0mg) and N-tertbutyloxycarbonyl-L-proline(Pro) (5.6mg) preparation embodiment 116 steps 1.
MS(FAB
+)m/z：661(MH
+)。
For C
33H
35F
2N
8O
5(MH
+) HRMS (FAB
+) analyze: calculated value 661.2698; Detected value 661.2691.
Step 2
Press and embodiment 2 described identical methods, from compound (13.3mg) the preparation title compound 116 (8.4mg) of embodiment 116 steps 1.
MS (FAB
+) m/z:561 (MH
+) (being free alkali).
For C
28H
27F
2N
8O
3(MH
+) HRMS (FAB
+) analyze: calculated value 561.2174; Detected value 561.2220.
Embodiment 117
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4R)-4-hydroxyl pyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4R)-1-tertbutyloxycarbonyl-4-hydroxyl pyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 71 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the compound (12.9mg) of 3-triazole (10.0mg) and N-tertbutyloxycarbonyl-4-hydroxyl-L-proline(Pro) (6.0mg) preparation embodiment 117 steps 1.
MS(FAB
+)m/z：677(MH
+)。
For C
33H
35F
2N
8O
6(MH
+) HRMS (FAB
+) analyze: calculated value 677.2698; Detected value 677.2691.
Step 2
Press and embodiment 2 described identical methods, from compound (11.7mg) the preparation title compound 117 (2.7mg) of embodiment 117 steps 1.
MS (FAB
+) m/z:577 (MH
+) (being free alkali).
For C
28H
27F
2N
8O
4(MH
+) HRMS (FAB
+) analyze: calculated value 577.2123; Detected value 577.2123.
Embodiment 118
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4S)-4-fluoropyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4S)-1-tertbutyloxycarbonyl-4-fluoropyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 71 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the compound (12.8mg) of 3-triazole (10.0mg) and N-tertbutyloxycarbonyl-(4S)-fluoro-L-proline(Pro) (6.0mg) preparation embodiment 118 steps 1.
MS(FAB
+)m/z：679(MH
+)。
For C
33H
34F
3N
8O
5(MH
+) HRMS (FAB
+) analyze: calculated value 679.2604; Detected value 679.2625.
Step 2
Press and embodiment 2 described identical methods, from compound (12.6mg) the preparation title compound 118 (8.8mg) of embodiment 118 steps 1.
MS (FAB
+) m/z:579 (MH
+) (being free alkali).
For C
28H
26F
3N
8O
3(MH
+) HRMS (FAB
+) analyze: calculated value 579.2080; Detected value 579.2055.
Embodiment 119
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 1 described identical method, from 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (22.3mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] compound (9.8mg) of pyridine (18.4mg) preparation embodiment 119 steps 1.
MS(FAB
+)m/z：553(MH
+)。
For C
27H
30FN
6O
4S (MH
+) HRMS (FAB
+) analyze: calculated value 553.2033; Detected value 553.2039.
Step 2
Press and embodiment 49 described identical methods, from compound (4.0mg) the preparation title compound 119 (1.2mg) of embodiment 119 steps 1.
MS(FAB
+)m/z：453(MH
+)。
For C
22H
22FN
6O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 453.1509; Detected value 453.1520.
Embodiment 120
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound diastereomer E ' and diastereomer F '
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound diastereomer E and diastereomer F
Press and embodiment 58 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl]-pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the diastereomer E (4.8mg) and the diastereomer F (10.2mg) of 3-triazole (20.0mg) preparation embodiment 120 step 1 compounds.
Diastereomer E (than low-pole):
MS(FAB
+)m/z：569(MH
+)。
For C
27H
30FN
6O
5S (MH
+) HRMS (FAB
+) analyze: calculated value 569.1982; Detected value 569.1945.
Diastereomer F (strong polarity):
MS(FAB
+)m/z：569(MH
+)。
For C
27H
30FN
6O
5S (MH
+) HRMS (FAB
+) analyze: calculated value 569.1982; Detected value 569.1947.
Step 2
By and embodiment 49 described identical methods, from the diastereomer E ' of the diastereomer E (3.7mg) of embodiment 120 step 1 compounds preparation title compound 120 (2.4mg).
MS(FAB
+)m/z：469(MH
+)。
For C
23H
20FN
6O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 469.1458; Detected value 469.1411.
Embodiment 121
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide
Press and embodiment 59 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the compound (10.6mg) of 3-triazole (20.0mg) preparation embodiment 121 steps 1.
MS(FAB
+)m/z：585(MH
+)。
For C
27H
30FN
6O
6S (MH
+) HRMS (FAB
+) analyze: calculated value 585.1932; Detected value 585.1923.
Step 2
Press and embodiment 49 described identical methods, from compound (3.0mg) the preparation title compound 121 (2.3mg) of embodiment 121 steps 1.
MS(FAB
+)m/z：485(MH
+)。
For C
22H
22FN
6O
4S (MH
+) HRMS (FAB
+) analyze: calculated value 485.1407; Detected value 485.1397.
Embodiment 122
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 31 described identical methods, from 1-[5 (R)-3-(3,5-two fluoro-4-iodophenyls)-and 2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (188mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] compound (141mg) of pyridine (200mg) preparation embodiment 122 steps 1.
MS(FAB
+)m/z：571(MH
+)。
For C
27H
29F
2N
6O
4S (MH
+) HRMS (FAB
+) analyze: calculated value 571.1939; Detected value 571.1899.
Step 2
Press and embodiment 49 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (10.0mg) preparation title compound 122 (4.2mg).
MS(FAB
+)m/z：471(MH
+)。
For C
22H
21F
2N
6O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 471.1415; Detected value 471.1436.
Embodiment 123
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole S-oxide compound diastereomer G ' and diastereomer H '
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole S-oxide compound diastereomer G and diastereomer H
Press and embodiment 58 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the diastereomer G (10.2mg) and the diastereomer H (18.6mg) of 3-triazole (30.0mg) preparation embodiment 123 step 1 compounds.
Diastereomer G (than low-pole):
MS(FAB
+)m/z：587(MH
+)。
For C
27H
29F
2N
6O
5S (MH
+) HRMS (FAB
+) analyze: calculated value 587.1888; Detected value 587.1860.
Diastereomer H (strong polarity):
MS(FAB
+)m/z：587(MH
+)。
For C
27H
29F
2N
6O
5S (MH
+) HRMS (FAB
+) analyze: calculated value 587.1888; Detected value 587.1921.
Step 2
Press and embodiment 49 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the diastereomer G ' of 3-triazole diastereomer G (2.2mg) preparation title compound 123 (0.8mg).
MS(FAB
+)m/z：487(MH
+)。
For C
22H
21F
2N
6O
3S (MH
+) HRMS (FAB
+) analyze: calculated value 487.1364; Detected value 487.1348.
Embodiment 124
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide
Step 1
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide
Press and embodiment 59 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the compound (19.2mg) of 3-triazole (20.0mg) preparation embodiment 124 steps 1.
MS(FAB
+)m/z：603(MH
+)。
For C
27H
29F
2N
6O
6S (MH
+) HRMS (FAB
+) analyze: calculated value 603.1837; Detected value 603.1873.
Step 2
Press and embodiment 49 described identical methods, from compound (4.0mg) the preparation title compound 124 (2.7mg) of embodiment 124 steps 1.
MS(FAB
+)m/z：503(MH
+)。
For C
22H
21F
2N
6O
4S (MH
+) HRMS (FAB
+) analyze: calculated value 503.1313; Detected value 503.1306.
Embodiment 125
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone
Press and embodiment 66 described identical methods, from N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-methylol oxazolidine-2-ketone (50.0mg) preparation title compound 125 (47.8mg).
MS(FAB
+)m/z：580(MH
+)。
For C
29H
28F
2N
5O
6(MH
+) HRMS (FAB
+) analyze: calculated value 580.2008; Detected value 580.1965.
Embodiment 126
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-keto hydrochloride
Press and embodiment 2 described identical methods, from 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone (47.0mg) preparation title compound 126 (26.5mg).
MS (FAB
+) m/z:480 (MH
+) (being free alkali).
For C
24H
20F
2N
5O
4(MH
+) HRMS (FAB
+) analyze: calculated value 480.1483; Detected value 480.1449.
Embodiment 127
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(4-methylpiperazine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 84 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and N methyl piperazine (20 μ L) preparation title compound 127 (17.9mg).
MS(FAB
+)m/z：586(MH
+)。
For C
30H
33FN
9O
3(MH
+) HRMS (FAB
+) analyze: calculated value 586.2690; Detected value 586.2642.
Embodiment 128
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 1 described identical method, from 1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (263mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo-[3.1.0] oneself-the 6-yl] pyridine (200mg) preparation title compound 128 (201mg).
MS(FAB
+)m/z：445(MH
+)。
For C
23H
21N
6O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 445.1447; Detected value 445.1434.
Embodiment 129
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound
Press and embodiment 58 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (22.3mg) preparation title compound 129 (21.9mg).
MS(FAB
+)m/z：461(MH
+)。
For C
23H
21N
6O
3S (MH
+) HRMS (FAB
+) analyze: calculated value 461.1396; Detected value 461.1390.
Embodiment 130
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide
Press and embodiment 58 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (22.3mg) preparation title compound 130 (18.2mg).
MS(FAB
+)m/z：477(MH
+)。
For C
23H
21N
6O
4S (MH
+) HRMS (FAB
+) analyze: calculated value 477.1345; Detected value 477.1329.
Embodiment 131
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and embodiment 31 described identical methods; from 1-[5 (R)-3-[3; 5-two fluoro-4 (trifluoromethyl sulfonyl)-hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl]-1; 2; 3-triazole (254mg) and 5-bromo-2-[(1 α; 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine (200mg) preparation title compound 131 (142mg).
MS(FAB
+)m/z：481(MH
+)。
For C
23H
19F
2N
6O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 481.1258; Detected value 481.1241.
Embodiment 132
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound
Press and embodiment 58 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) preparation title compound 132 (18.5mg).
MS(FAB
+)m/z：497(MH
+)。
For C
23H
19F
2N
6O
3S (MH
+) HRMS (FAB
+) analyze: calculated value 497.1207; Detected value 497.1251.
Embodiment 133
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide
Press and embodiment 58 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) preparation title compound 133 (18.9mg).
MS(FAB
+)m/z：513(MH
+)。
For C
23H
19F
2N
6O
4S (MH
+) HRMS (FAB
+) analyze: calculated value 513.1157; Detected value 513.1181.
Embodiment 134
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(1,3-diacetoxyl third-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
At room temperature, to 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(1,3-dihydroxyl third-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, add diacetyl oxide in methylene dichloride (0.2m1) solution of 3-triazole (7.7mg), under uniform temp, mixture was stirred 5 hours.Add 4-(dimethylamino) pyridine (9.0mg) to mixture, at room temperature mixture was stirred 1 hour vacuum concentration.By preparative thin layer chromatography (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain title compound 134 (5.8mg).
MS(FAB
+)m/z：604(MH
+)。
For C
30H
31FN
7O
6(MH
+) HRMS (FAB
+) analyze: calculated value 604.2320; Detected value 604.2300.
Embodiment 135
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[(3R, 4S)-1-azabicyclo [2.2.1] heptan-3-yl] carbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
Press and embodiment 71 described identical methods, from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (20.0mg) and (3R, 4S)-1-azabicyclo heptan-3-carboxylic acid hydrochloride (9.5mg) preparation title compound 135 (3.9mg).
MS(FAB
+)m/z：569(MH
+)。
For C
30H
30FN
8O
3(MH
+) HRMS (FAB
+) analyze: calculated value 569.2425; Detected value 569.2380.
Embodiment 136
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(pyridine-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Under 90 ℃, with 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, diisopropylethylamine (0.2ml) suspension of 3-triazole (50.0mg) and 2-pyridyl trifluoromethanesulfonic acid (0.86ml) stirred 44 hours.(silicon-dioxide, ethyl acetate: treating mixture methyl alcohol=5: 1) obtains title compound 136 (18.6mg) by the flash chromatography method.
MS(FAB
+)m/z：523(MH
+)。
For C
28H
24FN
8O
2(MH
+) HRMS (FAB
+) analyze: calculated value 523.2006; Detected value 523.1978.
Embodiment 137
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone
Press and embodiment 67 described identical methods, from N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-methylol oxazolidine-2-ketone (50.0mg) preparation title compound 137 (54.9mg).
MS(FAB
+)m/z：679(MH
+)。
For C
34H
37F
2N
6O
7(MH
+) HRMS (FAB
+) analyze: calculated value 679.2692; Detected value 679.2672.
Embodiment 138
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-keto hydrochloride
Press and embodiment 2 described identical methods, from 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone (51.8mg) preparation title compound 138 (20.7mg).
1H?NMR(DMSO-d
6)δ3.03-3.09(m，2H)，3.40-3.47(m，4H)，3.85(dd，J＝9.2Hz，6.1Hz，1H)，3.90-4.00(m，2H)，4.20(t，J＝9.2Hz，1H)，4.90-4.98(m，1H)，6.00(d，J＝1.8Hz，1H)，6.57(t，J＝6.1Hz，1H)，7.45-7.53(m，2H)，7.72(d，J＝7.9Hz，1H)，8.01(d，J＝7.9Hz，1H)，8.39(d，J＝1.8Hz，1H)，8.64(s，1H)。
Embodiment 139
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(thiatriazole-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
At room temperature, to 1,1 '-add 1-[5 (R)-3-[4-[2-[(1 α in acetonitrile (1.0ml) solution of thio-carbonyldiimidazole (21.6mg), 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (50.0mg) stirs mixture 1 hour under uniform temp.In mixture, add methyl iodide (67.9 μ L), at room temperature mixture is stirred and spend the night vacuum concentration.At room temperature, acetonitrile (1.0ml) the suspension stirring of resistates and sodiumazide (21.3mg) is spent the night.Behind the dilute with water mixture, filter and collect insolubles.By preparative thin layer chromatography (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle insolubles, obtain title compound 139 (13.7mg).
MS(FAB
+)m/z：531(MH
+)。
For C
24H
20FN
10O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 531.1475; Detected value 531.1466.
Embodiment 140
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thioacetamide
Step 1
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thioacetamide
At room temperature, with 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] mixture of oxazolidine-2-ketone (100mg), ethyl dithiocarbamate (28.0 μ L), triethylamine (62.2 μ L) and tetrahydrofuran (THF) (3ml) stirs and spends the night vacuum concentration.By flash chromatography method (silicon-dioxide, methylene dichloride: methyl alcohol=10: 1) handle resistates, obtain N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thioacetamide (82.0mg).
MS(FAB
+)m/z：552(MH
+)。
Step 2
Press and embodiment 49 described identical methods, from compound (77.0mg) the preparation title compound 140 (46.2mg) of embodiment 140 steps 1.
MS(FAB
+)m/z：452(MH
+)。
For C
23H
23FN
5O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 452.1557; Detected value 452.1531.
Embodiment 141
The O-methyl N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thiocarbamate
Step 1
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] lsothiocyanates
At 0 ℃, to 5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] add dithiocarbonic anhydride (36.6 μ L) and triethylamine (42.4 μ L) in tetrahydrofuran (THF) (2.0ml) solution of oxazolidine-2-ketone (150mg), under uniform temp with mixture stirring 4 hours.At 0 ℃, in mixture, add Vinyl chloroformate (29.1 μ L), under uniform temp, mixture was stirred 30 minutes vacuum concentration.Use the water treatment resistates, obtain crude product.With the dichloromethane solution of anhydrous sodium sulfate drying crude product, filter, then vacuum concentration.Handle resistates by flash chromatography method (silicon-dioxide, ethyl acetate), obtain the compound (125mg) of embodiment 141 steps 1.
MS(FAB
+)m/z：536(MH
+)。
Step 2
The O-methyl N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thiocarbamate
At 0 ℃, methyl alcohol (1.0ml) suspension to methanol solution (making from sodium hydride (26.5mg) and methyl alcohol (1.0ml)) the interpolation embodiment of sodium methylate 141 step 1 compounds (119mg) at room temperature stirs mixture 5 hours vacuum concentration.Behind the dilute with water resistates, with methylene chloride-methanol (10: 1) extraction mixture.Use the anhydrous sodium sulfate drying organic extract, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, methylene dichloride: ethyl acetate=1: 1) handle resistates, obtain the compound (93.5mg) of embodiment 141 steps 2.
MS(FAB
+)m/z：568(MH
+)。
Step 3
Press and embodiment 49 described identical methods, from compound (85.0mg) the preparation title compound 141 (43.6mg) of embodiment 141 steps 2.
MS(FAB
+)m/z：468(MH
+)。
For C
23H
23FN
5O
3S (MH
+) HRMS (FAB
+) analyze: calculated value 468.1506; Detected value 468.1524.
Reference example 1
N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
Under 80 ℃, with N-[5 (S)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl] ethanamide (2.00g), two (tetramethyl ethylene ketone) two boron (1.61g), potassium acetate (1.56g) and [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (II)-mixture heating up of methylene dichloride adducts (432mg) in methyl-sulphoxide (50ml) 1 hour.The dilute with water mixture is used ethyl acetate extraction.With salt water washing organic extract, use anhydrous magnesium sulfate drying, then vacuum concentration.By flash chromatography method (silicon-dioxide, ethyl acetate: acetone=9: 1) handle resistates, obtain N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide (889mg).
For C
18H
24BFN
2O
5(M
+) HRMS (EI
+) analyze: calculated value 378.1762; Detected value 378.1779.
Reference example 2
N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
Press and reference example 1 described identical method, from N-[5 (S)-3-(4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl] ethanamide (108mg) and two (tetramethyl ethylene ketone) two boron (855mg) preparation reference example 2 (92.5mg).
MS(EI
+)m/z：360(M
+)。
For C
18H
25BN
2O
5(M
+) HRMS (EI
+) analyze: calculated value 360.1857; Detected value 360.1875.
Reference example 3
1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and reference example 1 described identical method, from 1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (2.69g) and two (tetramethyl ethylene ketone) two boron (1.86g) preparation reference example 3 (1.53g).
MS(EI
+)m/z：388(M
+)。
For C
18H
22BFN
4O
4(M
+) HRMS (EI
+) analyze: calculated value 388.1718; Detected value 388.1752.
Reference example 4
1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and reference example 1 described identical method, from 1-[5 (R)-3-(4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (200mg) and two (tetramethyl ethylene ketone) two boron (151mg) preparation reference example 4 (147mg).
MS(EI
+)m/z：370(M
+)。
For C
18H
23BN
4O
4(M
+) HRMS (EI
+) analyze: calculated value 370.1812; Detected value 370.1814.
Reference example 5
5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-(3-fluoro-4-iodophenyl) oxazolidine-2-ketone
Under 0 ℃, methylene dichloride (30m1) solution interpolation imidazoles (1.33g) and tert-butyldimethylsilyl chloride (1.48g) to 5 (R)-3-(3-fluoro-4-iodophenyl)-5-methylol oxazolidine-2-ketone (3.00g) at room temperature stir mixture 2 hours.Water, 2N hydrochloric acid, saturated sodium bicarbonate solution and salt solution purging compound are used anhydrous magnesium sulfate drying, and vacuum concentration obtains reference example 5 (3.66g) then.
MS(EI
+)m/z：451(M
+)。
For C
16H
23FINO
3Si (M
+) HRMS (EI
+) analyze: calculated value 451.0476; Detected value 451.0511.
Reference example 6
5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl] oxazolidine-2-ketone
Press and reference example 1 described identical method, from 5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-(3-fluoro-4-iodophenyl) oxazolidine-2-ketone (100mg) and two (tetramethyl ethylene ketone) two boron (67.0mg) preparation reference example 6 (64.4mg).
MS(CI
+)m/z：452(MH
+)。
For C
22H
36BFNO
5Si (MH
+) HRMS (CI
+) analyze: calculated value 452.2440; Detected value 452.2394.
Reference example 7
3,5-two fluoro-4-(methoxymethyl) hydroxyl oil of mirbane
Under 0 ℃, to 2, add diisopropylethylamine (50.2ml) and methoxymethyl chlorine (17.5ml) in methylene dichloride (300ml) solution of 6-two fluoro-4-nitrophenol (35.0g), at room temperature mixture was stirred 2 hours.Water, 5% sodium hydrogen carbonate solution and salt solution purging compound are used anhydrous magnesium sulfate drying, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=9: 1) handle resistates, obtain reference example 7 (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-benzyl oxygen carbonylamino-2,6-two fluoro-1-(methoxymethyl) oxybenzenes
Under 1atm, with 3,5-two fluoro-4-(methoxymethyl) hydroxyl oil of mirbane (35.0g) and palladium catalyst (10% charcoal carries palladium, methyl alcohol 3.00g) (250ml)) suspension hydrogenation at room temperature 2 hours.Behind the filtering catalyst,, obtain 4-amino-2,6-two fluoro-1-(methoxymethyl) oxybenzenes with the filtrate vacuum concentration.This compound need not to be further purified and just can be used for next step.Under 0 ℃, continuation is to thus obtained thick 4-amino-2, add sodium bicarbonate (17.4g), water (100ml) and chloroformic acid benzyl ester (30.0g) in tetrahydrofuran (THF) (500ml) solution of 6-two fluoro-1-(methoxymethyl) oxybenzenes, at room temperature mixture was stirred 15 minutes.With saturated sodium bicarbonate solution diluted mixture thing, use ethyl acetate extraction.With salt water washing organic extract, use anhydrous magnesium sulfate drying, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=6: 1) handle resistates, obtain reference example 8 (49.10g).
MS(EI
+)m/z：323(M
+)。
C
16H
15F
2NO
4(M
+) HRMS (EI
+) analyze: calculated value 323.0969; Detected value 323.0963.
Reference example 9
5 (R)-3-[3,5-two fluoro-4-(methoxymethyl) hydroxyphenyl]-5-methylol oxazolidine-2-ketone
Under-78 ℃, to 4-benzyloxycarbonyl amino-2, (1.6M, 90.0ml) solution stir mixture 30 minutes under uniform temp the hexane of interpolation n-Butyl Lithium then in dry tetrahydrofuran (400ml) solution of 6-two fluoro-1-(methoxymethyl) oxybenzenes (46.3g).Under-78 ℃, butyric acid (R)-glycidyl ester (20.3ml) is added in the mixture, mixture was at room temperature left standstill 3 hours.After adding aqueous ammonium chloride solution quencher reaction, use the ethyl acetate extraction mixture.With salt water washing organic extract, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.In methyl alcohol (300ml) solution of resistates, add salt of wormwood (20.0g), at room temperature mixture was stirred 30 minutes, then vacuum concentration.Behind the dilute with water resistates, use the ethyl acetate extraction mixture.With salt water washing organic extract, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=1: 4) handle resistates, obtain reference example 9 (36.1g).
MS(EI
+)m/z：289(M
+)。
For C
12H
13F
2NO
5(M
+) HRMS (EI
+) analyze: calculated value 289.0762; Detected value 289.0743.
Reference example 10
N-[5 (S)-3-[3,5-two fluoro-4-(methoxymethyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
Under 0 ℃, continuation is to 5 (R)-3-[3,5-two fluoro-4-(methoxymethyl) hydroxyphenyl]-add triethylamine (4.82ml) and methylsulfonyl chloride (2.53ml) in methylene dichloride (20ml) solution of 5-methylol oxazolidine-2-ketone (5.00g), under uniform temp, mixture was stirred 1 hour.Wash mixture with water, use anhydrous magnesium sulfate drying, filter, vacuum concentration obtains 5 (R)-3-[3,5-two fluoro-4-(methoxymethyl) hydroxyphenyl then]-5-methylsulfonyl methylol oxazolidine-2-ketone.This compound need not to be further purified and just can be used for next step.Under 60 ℃; with thus obtained thick 5 (R)-3-[3; 5-two fluoro-4-(methoxymethyl) hydroxyphenyl]-5-methyl sulphonyl methylol oxazolidine-2-ketone and sodiumazide (3.93g) be at N, the mixture heating up in the dinethylformamide (20ml) 8 hours, vacuum concentration then.Dilute resistates with ethyl acetate, water and salt water washing.Use the anhydrous magnesium sulfate drying organic extract, filter, vacuum concentration obtains 5 (R)-azido-methyl-3-[3,5-two fluoro-4-(methoxymethyl) hydroxyphenyl then] oxazolidine-2-ketone (5.43g).This compound need not to be further purified and just can be used for next step.At room temperature, under 1atm, with 5 (R)-azido-methyl-3-[3,5-two fluoro-4-(methoxymethyl) hydroxyphenyl] oxazolidine-2-ketone (3.53g) and Lindlar catalyzer (5%CaCO
3Carry palladium, part is lead poisoning, methyl alcohol 700mg) (110ml) suspension hydrogenation 6 hours.Behind the filtering catalyst, with the filtrate vacuum concentration.At room temperature, in tetrahydrofuran (THF) (15ml) solution of resistates, add triethylamine (6.30ml) and diacetyl oxide (2.10ml), under uniform temp, mixture was stirred 2 hours.After adding saturated sodium bicarbonate solution quencher reaction, use the ethyl acetate extraction mixture.Use the anhydrous magnesium sulfate drying organic extract, filter, then vacuum concentration.Handle resistates by flash chromatography method (silicon-dioxide, ethyl acetate), obtain reference example 10 (3.45g).
MS(EI
+)m/z：330(M
+)。
For C
14H
16F
2N
2O
5(M
+) HRMS (EI
+) analyze: calculated value 330.1027; Detected value 330.1001.
Reference example 11
N-[5 (S)-3-(3,5-two fluoro-4-hydroxy phenyls)-2-oxo oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[3,5-two fluoro-4-(methoxymethyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl] add concentrated hydrochloric acid (0.50ml) in methyl alcohol (5ml) solution of ethanamide (200mg), at room temperature mixture was stirred 1 day, then vacuum concentration.Use the water treatment resistates, obtain reference example 11 (144mg).
MS(EI
+)m/z：286(M
+)。
For C
12H
12F
2N
2O
4(M
+) HRMS (EI
+) analyze: calculated value 286.0765; Detected value 286.0747.
Reference example 12
N-[5 (S)-3-[3,5-two fluoro-4-(trifluoromethyl sulfonyl) hydroxyphenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide
Under 0 ℃, to N-[5 (S)-3-(3,5-two fluoro-4-hydroxy phenyls)-2-oxo oxazolidine-5-ylmethyl] add trifluoromethanesulfanhydride anhydride (2.38ml) in pyridine (15ml) solution of ethanamide (2.70g), at room temperature mixture was stirred 12 hours.Behind the dilute with water mixture, use the ethyl acetate extraction mixture.With 5% hydrochloric acid and salt water washing organic extract, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, ethyl acetate: methyl alcohol=19: 1) handle resistates, obtain reference example 12 (3.48g).
MS(EI
+)m/z：418(M
+)。
For C
13H
11F
5N
2O
6S (M
+) HRMS (EI
+) analyze: calculated value 418.0258; Detected value 418.0210.
Reference example 13
1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Step 1
5 (R)-acetoxyl methyl-3-(3-fluorophenyl) oxazolidine-2-ketone
In tetrahydrofuran (THF) (53ml) solution of 5 (R)-3-(3-fluorophenyl)-5-methylol oxazolidine-2-ketone (5.28g), add triethylamine (3.83ml), diacetyl oxide (2.55ml) and (4-dimethylamino) pyridine (152mg), at room temperature mixture was stirred 1 hour.After adding 1N hydrochloric acid quencher reaction, use the ethyl acetate extraction mixture.With salt water washing organic extract, use anhydrous sodium sulfate drying, filter, vacuum concentration obtains thick 5 (R)-acetoxyl methyl-3-(3-fluorophenyl) oxazolidine-2-ketone (6.33g) then.
Step 2
5 (R)-acetoxyl methyl-3-(3-fluoro-4-iodophenyl) oxazolidine-2-ketone
In acetate (40ml) solution of 5 (R)-acetoxyl methyl-3-(3-fluorophenyl) oxazolidine-2-ketone (6.33g), add iodine monochloride (1.91ml), at room temperature mixture was stirred 18 hours, then vacuum concentration.With acetic acid ethyl dissolution gained resistates, with sodium bicarbonate aqueous solution, 20% sodium sulfite solution and salt solution purging compound, use anhydrous sodium sulfate drying, filter, vacuum concentration obtains thick 5 (R)-acetoxyl methyl-3-(3-fluoro-4-iodophenyl) oxazolidine-2-ketone (9.48g) then.
Step 2
5 (R)-3-(3-fluoro-4-iodophenyl)-5-methylol oxazolidine-2-ketone
In methyl alcohol (95ml) solution of thick 5 (R)-acetoxyl methyl-3-(3-fluoro-4-iodophenyl) oxazolidine-2-ketone (9.48g), add salt of wormwood (6.91g), at room temperature mixture was stirred 2.5 hours.After removing by filter insolubles, vacuum concentrated filtrate.Use the acetic acid ethyl dissolution resistates, use the salt solution purging compound, use anhydrous sodium sulfate drying, filter, then vacuum concentration.Behind Virahol processing resistates, filter and collect the gained throw out, obtain 5 (R)-3-(3-fluoro-4-iodophenyl)-5-methylol oxazolidine-2-ketone, with the filtrate vacuum concentration.Handle resistates by flash chromatography method (silicon-dioxide, ethyl acetate), obtain the more product of volume (amounting to 6.24g).
MS(EI
+)m/z：337(M
+)。
1H?NMR(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-iodophenyl) oxazolidine-2-ketone
Under 0 ℃, in methylene dichloride (30ml) solution of 5 (R)-3-(3-fluoro-4-iodophenyl)-5-methylol oxazolidine-2-ketone (2.00g), add triethylamine (1.24ml) and methylsulfonyl chloride (551 μ L), under uniform temp, mixture was stirred 30 minutes.Use the frozen water purging compound, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.Under 80 ℃, at N, the mixture in the dinethylformamide (30ml) stirred 2 hours, vacuum concentration with resistates and sodiumazide (964mg).Behind the dilute with water resistates, use the ethyl acetate extraction mixture.Use the anhydrous magnesium sulfate drying organic extract, filter, vacuum concentration obtains 5 (R)-azido-methyl-3-(3-fluoro-4-iodophenyl) oxazolidine-2-ketone (2.18g) then.
MS(EI
+)m/z：361(M
+)。
For C
10H
8FIN
4O
2(M
+) HRMS (EI
+) analyze: calculated value 361.9676; Detected value 361.9698.
Step 5
1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 5 (R)-azido-methyl-3-(3-fluoro-4-iodophenyl) oxazolidine-2-ketone (2.18g) and 2, the mixture of 5-norbornadiene (6.40ml) in dioxan (45.6ml) stirred 2 hours down at 80 ℃, stirred 4 hours down at 110 ℃, vacuum concentration obtains reference example 13 (1.70g) then.
MS(EI
+)m/z：388(M
+)。
For C
12H
10FIN
4O
2(M
+) HRMS (EI
+) analyze: calculated value 387.9833; Detected value 387.9835.
Reference example 14
5 (R)-azido-methyl-3-(4-iodophenyl) oxazolidine-2-ketone
Press and reference example 13 described identical methods, from 5 (R)-3-(4-iodophenyl)-5-hydroxymethyl oxazolidine-2-ketone (70.0g) preparation reference example 14 (75.3g).
MS(EI
+)m/z：344(M
+)。
For C
10H
9IN
4O
2(M
+) HRMS (EI
+) analyze: calculated value 343.9770; Detected value 343.9740.
Reference example 15
1-[5 (R)-3-(4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and reference example 13 described identical methods, from 5 (R)-azido-methyl-3-(4-iodophenyl) oxazolidine-2-ketone (100mg) preparation reference example 15 (62.5mg).
MS(EI
+)m/z：370(M
+)。
For C
12H
11IN
4O
2(M
+) HRMS (EI
+) analyze: calculated value 369.9927; Detected value 369.9919.
Reference example 16
5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-(4-iodophenyl) oxazolidine-2-ketone
Press and reference example 5 described identical methods, from 5 (R)-3-(4-iodophenyl)-5-methylol oxazolidine-2-ketone (2.00g) preparation reference example 16 (2.66g).
MS(EI
+)m/z：433(M
+)。
C
16H
24INO
3Si (M
+) HRMS (EI
+) analyze: calculated value 433.0570; Detected value 433.0544.
Reference example 17
Cis-N-tertbutyloxycarbonyl tetramethyleneimine-3, the 4-glycol
In the solution of tetrahydrofuran (THF) (340ml), the trimethyl carbinol (210ml) and the water (100ml) of N-tertbutyloxycarbonyl-3-pyrroline (69.3g) and NMO (72.2g), add OsO
4(2.5% t-butanol solution, 4.8ml), with mixture reflux 2.5 hours, vacuum concentration then.Behind salt solution dilution resistates, use the ethyl acetate extraction mixture.With the organic extract vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=1: 1) handle resistates, obtain reference example 17 (55.0g).
MS(FAB
+)m/z：204(MH
+)。
For C
9H
18NO
4(MH
+) HRMS (FAB
+) analyze: calculated value 204.1236; Detected value 204.1240.
Reference example 18
Cis-N-tertbutyloxycarbonyl tetramethyleneimine-3,4-ring-type vitriol
Under 0 ℃, to cis-N-tertbutyloxycarbonyl tetramethyleneimine-3, add thionyl chloride (220 μ L) in methylene dichloride (10ml) solution of 4-glycol (406mg) and triethylamine (1.1ml), under uniform temp, mixture was stirred 10 minutes.After adding water (1ml) quencher reaction, with hexane and water diluted mixture thing.Water, saturated sodium bicarbonate solution and salt water washing organic extract are used anhydrous magnesium sulfate drying, filter, and vacuum concentration obtains thick ring-type sulphite (482mg) then.Under 0 ℃, in tetracol phenixin (6ml), acetonitrile (6ml) and water (9ml) solution of thick ring-type sulphite (482mg), add ruthenium chloride (III) hydrate (6.0mg) and sodium periodate (856mg), under uniform temp, mixture was stirred 2 hours.Behind hexane and ether diluted mixture thing, use the hexane extraction mixture.With salt water washing organic extract, use anhydrous magnesium sulfate drying, filter vacuum-drying then.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=1: 1) handle resistates, obtain reference example 18 (438mg).
MS(FAB
+)m/z：266(MH
+)。
For C
9H
16NO
6S (MH
+) HRMS (FAB
+) analyze: calculated value 266.0698; Detected value 266.0730.
Reference example 19
5-bromo-2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine
Under 0 ℃, to sodium hydride (60% oil dispersion, 2.24g) glycol dimethyl ether (110ml) suspension in add glycol dimethyl ether (20ml) solution and the cis-N-tertbutyloxycarbonyl tetramethyleneimine-3 of 5-bromo-2-pyridyl acetonitrile (5.0g), glycol dimethyl ether (20ml) solution of 4-ring-type vitriol (7.41g) at room temperature stirs mixture 3 hours.Behind salt solution diluted mixture thing, use the ethyl acetate extraction mixture.Use the anhydrous magnesium sulfate drying organic extract, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=4: 1) handle resistates, obtain reference example 19 (7.50g).
MS(EI
+)m/z：363(M
+)。
For C
16H
18BrN
3O
2(M
+) HRMS (EI
+) analyze: calculated value 363.0582; Detected value 363.0582.
Reference example 20
1-bromo-4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorobenzene
Press and reference example 19 described identical methods, from 4-bromo-2-fluorophenyl acetonitrile (214mg) and cis-N-tertbutyloxycarbonyl tetramethyleneimine-3,4-ring-type vitriol (292mg) preparation reference example 20 (334mg).
MS(FAB
+)m/z：381(MH
+)。
For C
17H
19BrFN
2O
2(MH
+) HRMS (FAB
+) analyze: calculated value 381.0614; Detected value 381.0622.
Reference example 21
5-bromo-2-chloro-3-fluorine pyridine
Under 150 ℃, with phosphoryl chloride (50ml) suspension of 5-bromo-3-fluoro-2 hydroxy pyrimidine (10.0g) heating 4 hours.Mixture is poured in the ice, added salt of wormwood the gained mixture is adjusted into pH10, use dichloromethane extraction.Use the anhydrous magnesium sulfate drying organic extract, filter, vacuum concentration obtains reference example 21 (10.9g) then.
MS(EI
+)m/z：209(M
+)。
For C
5H
2BrClFN (M
+) HRMS (EI
+) analyze: calculated value 208.9043; Detected value 208.9064.
Reference example 22
5-bromo-3-fluoro-2-pyridine acetonitrile
Under 150 ℃, the mixture heating up in methyl-sulphoxide (14ml) is 12 hours with 5-bromo-2-chloro-3-fluorine pyridine (700mg) and Potassium monofluoride (773mg).In the gained mixture, add methyl-sulphoxide (14ml) solution [making] of the sodium negative ion of the cyanoacetic acid tert-butyl ester, at room temperature mixture was stirred 2.5 days from methyl-sulphoxide (14ml) solution of the cyanoacetic acid tert-butyl ester (1.27g) and sodium hydride (346mg).Behind saturated ammonium chloride solution diluted mixture thing, use the ethyl acetate extraction mixture.With salt water washing organic extract, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=5: 1) handle resistates, obtain the thick 5-bromo-3-fluoro-2-pyridine cyanoacetic acid tert-butyl ester.Under 0 ℃, in acetonitrile (5ml) solution of the thick 5-bromo-3-fluoro-2-pyridine cyanoacetic acid tert-butyl ester, add trifluoroacetic acid (5ml), at room temperature mixture was stirred 2 hours, pour in frozen water and the salt of wormwood.Use the ethyl acetate extraction mixture.With salt water washing organic extract, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=4: 1) handle resistates, obtain reference example 22 (179mg).
MS(EI
+)m/z：214(M
+)。
For C
7H
4BrFN
2(M
+) HRMS (EI
+) analyze: calculated value 213.9542; Detected value 213.9558.
Reference example 23
5-bromo-2-pyridine acetonitrile
Under 10 ℃, in methyl-sulphoxide (200ml) suspension of sodium hydride (3.76g), add the cyanoacetic acid tert-butyl ester (13.9ml), at room temperature mixture was stirred 1 hour.In mixture, add 5-bromo-2-chloropyridine (7.00g), at room temperature mixture was stirred 2 hours, pour in frozen water and the ammonium chloride.Use the ethyl acetate extraction mixture.Use the anhydrous magnesium sulfate drying organic extract, filter, vacuum concentration obtains the thick 5-bromo-2-pyrimidine cyanoacetic acid tert-butyl ester then.Under 0 ℃, in methylene dichloride (75ml) suspension of the thick 5-bromo-2-pyrimidine cyanoacetic acid tert-butyl ester (3.9g), add trifluoroacetic acid (75ml), at room temperature mixture was stirred 18 hours vacuum concentration.Behind saturated sodium bicarbonate solution dilution resistates, use the ethyl acetate extraction mixture.Use the anhydrous magnesium sulfate drying organic extract, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=2: 1) handle resistates, obtain reference example 23 (3.71g).
MS(EI
+)m/z：197(M
+)。
For C
6H
4BrN
3(M
+) HRMS (EI
+) analyze: calculated value 196.9589; Detected value 196.9572.
Reference example 24
1-[5 (R)-3-(3,5-two fluoro-4-iodophenyls)-2-oxo 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-iodophenyls) add diisopropylethylamine (262 μ L) and asymmetric-Dichloro acetone tosylhydrazone (108mg) in methyl alcohol (2ml) solution of oxazolidine-2-ketone (100mg), at room temperature mixture was stirred 20 hours vacuum concentration.Handle resistates by flash chromatography method (silicon-dioxide, ethyl acetate), obtain reference example 24 (110mg).
MS(EI
+)m/z：420(M
+)。
For C
13H
11F
2IN
4O
2(M
+) HRMS (EI
+) analyze: calculated value 420.9895; Detected value 420.9904.
Reference example 25
Cis-tetrahydrofuran (THF)-3,4-ring-type vitriol
To 1, add thionyl chloride (4.2ml) in tetracol phenixin (48ml) suspension of 4-dehydration tetrahydroxybutane (5.00g), with mixture reflux 1 hour.Mixture is cooled to 0 ℃, with acetonitrile (48ml) dilution.Under 0 ℃, add sodium periodate (15.4g), n hydrate ruthenium trichloride (49.8mg) to mixture, add water then, at room temperature mixture was stirred 3 hours.Behind ether diluted mixture thing, wash mixture with water.Wash organic extract with water, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=1: 1) handle resistates, obtain reference example 25 (6.70g).
MS(CI
+)m/z：167(MH
+)。
For C
4H
7O
5S (MH
+) HRMS (CI
+) analyze: calculated value 167.0014; Detected value 166.9993.
Reference example 26
5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine
Press and reference example 19 described identical methods, from 5-bromo-2-pyridyl acetonitrile (197mg) and cis-tetrahydrofuran (THF)-3,4-ring-type vitriol (183mg) preparation reference example 26 (187mg).
MS(CI
+)m/z：265(MH
+)。
For C
11H
10BrN
2O (MH
+) HRMS (CI
+) analyze: calculated value 264.9976; Detected value 264.9981.
Reference example 27
6-(5-bromopyridine-2-yl)-(1 α, 5 α, 6 β)-3-oxabicyclo [3.1.0] hexane-6-carboxylic acid amides
With 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (4.00g) and the mixture reflux of 25% sodium hydroxide solution (66ml) in ethanol (200ml) 6 hours, vacuum concentration.Use the water treatment resistates, obtain reference example 27 (4.20g).
MS(EI
+)m/z：282(M
+)。
For C
11H
11BrN
2O
2(M
+) HRMS (EI
+) analyze: calculated value 282.0004; Detected value 281.9966.
Reference example 28
5-bromo-2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine
With 6-(5-bromopyridine-2-yl)-(1 α, 5 α, 6 β)-3-oxabicyclo [3.1.0] hexane-6-carboxylic acid amides (2.50g) and the mixture reflux of lead tetraacetate (7.83g) in the trimethyl carbinol (125ml) 8 hours.After adding saturated sodium bicarbonate solution quencher reaction, with ethyl acetate diluted mixture thing.After removing by filter insolubles, use ethyl acetate extraction filtrate.With salt water washing organic extract, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.By flash chromatography method (NH silicon-dioxide, hexane: ethyl acetate=7: 3) handle resistates, obtain reference example 28 (2.10g).
MS(FAB
+)m/z：355(MH
+)。
For C
15H
20BrN
2O
3(MH
+) HRMS (FAB
+) analyze: calculated value 355.0657; Detected value 355.0656.
Reference example 29
1-bromo-4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3,5-two fluorobenzene
Press and reference example 19 described identical methods, from 4-bromo-3,5-difluorophenyl acetonitrile (1.50g) and cis-N-tertbutyloxycarbonyl tetramethyleneimine-3,4-ring-type vitriol (1.89g) preparation reference example 29 (1.06g).
MS(FAB
+)m/z：399(MH
+)。
For C
17H
18BrF
2N
2O
2(MH
+) HRMS (FAB
+) analyze: calculated value 399.0520; Detected value 399.0522.
Reference example 30
1-bromo-4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] benzene
Press and reference example 19 described identical methods, from 4-bromophenyl acetonitrile (1.00g) and cis-N-tertbutyloxycarbonyl tetramethyleneimine-3,4-ring-type vitriol (1.49g) preparation reference example 30 (809mg).
MS(FAB
+)m/z：363(MH
+)。
For C
17H
20BrN
2O
2(MH
+) HRMS (FAB
+) analyze: calculated value 363.0708; Detected value 363.0730.
Reference example 31
5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine
Press and reference example 19 described identical methods, from 5-bromo-2-pyridyl acetonitrile (32.3mg) and cis-tetramethylene sulfide-3,4-ring-type vitriol (32.9mg) preparation reference example 31 (5.5mg).
MS(FAB
+)m/z：281(MH
+)。
For C
11H
10BrN
2S (MH
+) HRMS (FAB
+) analyze: calculated value 280.9748; Detected value 280.9743.
Reference example 32
Cis-tetramethylene sulfide-3,4-ring-type vitriol
Under-78 ℃, to cis-tetramethylene sulfide-3, add methylene dichloride (0.4ml) solution of sulfuryl chloride (48.9 μ L) in methylene dichloride (2ml) solution of 4-glycol (48.8mg) and triethylamine (22.6 μ L), under uniform temp, mixture was stirred 1.5 hours.After adding ice quencher reaction, use the ethyl acetate extraction mixture.With salt water washing organic extract, use anhydrous sodium sulfate drying, filter, then vacuum concentration.Handle resistates by flash chromatography method (silicon-dioxide, ethyl acetate), obtain reference example 32 (14.6mg).
MS(EI
+)m/z：182(M
+)。
For C
4H
6O
4S
2(M
+) HRMS (EI
+) analyze: calculated value 182.0582; Detected value 182.0582.
Reference example 33
Step 1
5-bromo-2-[(1 α, 5 α, 6 β)-6-carboxyl-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine
Under 0 ℃, to 6-(5-bromopyridine-2-yl)-(1 α, 5 α), 6 β)-and add Sodium Nitrite (73.1mg) in the vitriol oil (1.0ml) of 3-oxabicyclo [3.1.0] hexane-6-carboxylic acid amides (100mg) and water (0.5ml) solution, at room temperature mixture was stirred 30 minutes.After adding frozen water (1.5ml), at room temperature mixture was stirred 30 minutes.Under 0 ℃, add salt of wormwood mixture is adjusted into pH7.Add 5% hydrochloric acid mixture is adjusted into pH4, use the chloroform extraction mixture.Use the anhydrous magnesium sulfate drying organic extract, filter, vacuum concentration obtains 5-bromo-2-[(1 α, 5 α, 6 β then)-6-carboxyl-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (87.9mg).
MS(EI
+)m/z：283(M
+)。
For C
11H
10BrNO
3(M
+) HRMS (EI
+) analyze: calculated value 282.9844; Detected value 282.9874.
Step 2
5-bromo-2-[(1 α, 5 α, 6 β)-6-hydroxymethyl-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine
Under 0 ℃, to 5-bromo-2-[(1 α, 5 α, 6 β)-6-carboxyl-3-oxabicyclo [3.1.0] oneself-the 6-yl] add the toluene (1.0M of diisobutylaluminium hydride in tetrahydrofuran (THF) (5.3ml) solution of pyridine (150mg), 1.32ml) solution, at room temperature mixture was stirred 1 hour, stirred 1 hour at 60 ℃.After adding saturated ammonium chloride solution quencher reaction, at room temperature mixture was stirred 30 minutes.Use the ethyl acetate extraction mixture.Use the anhydrous magnesium sulfate drying organic extract, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=1: 3) handle resistates, obtain 5-bromo-2-[(1 α, 5 α, 6 β)-6-hydroxymethyl-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (62.3mg).
MS(EI
+)m/z：269(M
+)。
For C
11H
12BrNO
2(M
+) HRMS (EI
+) analyze: calculated value 269.0051; Detected value 269.0045.
Reference example 34
4-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] thiophene
Press and reference example 26 described identical methods, from 4-bromo-2 thiophene acetonitrile (100mg) and cis-tetrahydrofuran (THF)-3,4-ring-type vitriol (90.4mg) preparation reference example 34 (104mg).
MS(EI
+)m/z：269(M
+)。
For C
10H
8BrNOS (M
+) HRMS (EI
+) analyze: calculated value 268.9510; Detected value 268.9519.
Reference example 35
5-bromo-2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-(tertbutyloxycarbonyl) amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine
Step 1
5-bromo-2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-formamyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine
With 5-bromo-2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] ethanol (210ml) the solution reflux 8 hours of pyridine (4.00g) and 25% sodium hydroxide solution (70ml), vacuum concentration.Handle resistates with frozen water, obtain the compound (3.88g) of reference example 35 steps 1.
MS(FAB
+)m/z：382(MH
+)。
For C
16H
21BrN
3O
3(MH
+) HRMS (FAB
+) analyze: calculated value 382.0766; Detected value 382.0776.
Step 2
Press and reference example 28 described identical methods, from compound (3.50g) the preparation reference example 35 (2.42g) of reference example 35 steps 1.
MS(FAB
+)m/z：454(MH
+)。
For C
20H
29BrN
3O
4(MH
+) HRMS (FAB
+) analyze: calculated value 454.1341; Detected value 454.1323.
Reference example 36
5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone
Press and embodiment 1 described identical method, from 5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl] oxazolidine-2-ketone (5.00g) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (2.94g) preparation reference example 36 (5.42g).
MS(FAB
+)m/z：510(MH
+)。
For C
27H
33FN
3O
4Si (MH
+) HRMS (FAB
+) analyze: calculated value 510.2224; Detected value 510.2204.
Reference example 37
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-methylol oxazolidine-2-ketone
Under 0 ℃, to 5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] add the tetrahydrofuran (THF) (1.0M of tetrabutyl ammonium fluoride in tetrahydrofuran (THF) (93ml) solution of oxazolidine-2-ketone (4.75g), 11.2ml) solution, at room temperature mixture was stirred 1 hour.After adding saturated ammonium chloride solution quencher reaction, use the ethyl acetate extraction mixture.With salt water washing organic extract, use anhydrous magnesium sulfate drying, filter, then vacuum concentration.Handle resistates with ether, obtain 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-hydroxymethyl oxazolidine-2-ketone (3.07g).
MS(EI
+)m/z：395(M
+)。
For C
21H
18FN
3O
4(M
+) HRMS (EI
+) analyze: calculated value 395.1281; Detected value 395.1261.
Reference example 38
5 (R)-azido-methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone
Press and reference example 13 described identical methods, from 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-methylol oxazolidine-2-ketone (1.90g) preparation reference example 38 (1.72g).
MS(FAB
+)m/z：421(MH
+)。
For C
21H
18FN
6O
3(MH
+) HRMS (FAB
+) analyze: calculated value 421.1424; Detected value 421.1431.
Reference example 39
5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone
Press and reference example 10 described identical methods, from 5 (R)-azido-methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (1.60g) preparation reference example 39 (1.40g).
MS(FAB
+)m/z：395(MH
+)。
For C
21H
20FN
4O
3(MH
+) HRMS (FAB
+) analyze: calculated value 395.1519; Detected value 395.1513.
Reference example 40
5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone
Press and embodiment 1 described identical method, from 5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl] oxazolidine-2-ketone (100mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine (80.9mg) preparation reference example 40 (109mg).
MS(FAB
+)m/z：609(MH
+)。
For C
32H
42FN
4O
5Si (MH
+) HRMS (FAB
+) analyze: calculated value 609.2909; Detected value 609.2886.
Reference example 41
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-5-methylol oxazolidine-2-ketone
Press and reference example 36 described identical methods, from 5 (R)-5-(tertiary butyl dimethyl methyl siloxy) methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (4.24g) preparation reference example 41 (3.21g).
MS(FAB
+)m/z：495(MH
+)。
For C
26H
28FN
4O
5(MH
+) HRMS (FAB
+) analyze: calculated value 495.2044; Detected value 495.2048.
Reference example 42
5 (R)-azido-methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] oxazolidine-2-ketone
Press and reference example 13 described identical methods, from 5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-5-hydroxymethyl oxazolidine-2-ketone (2.00g) preparation reference example 42 (1.88g).
MS(FAB
+)m/z：520(MH
+)。
For C
26H
27FN
7O
4(MH
+) HRMS (FAB
+) analyze: calculated value 520.2109; Detected value 520.2137.
Reference example 43
5 (S)-amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone
Press and reference example 10 described identical methods, from 5 (R)-azido-methyl-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (100mg) preparation reference example 43 (48.0mg).
MS(FAB
+)m/z：494(MH
+)。
For C
26H
29FN
5O
4(MH
+) HRMS (FAB
+) analyze: calculated value 494.2204; Detected value 494.2197.
Reference example 44
5-bromo-2-(4-cyano group tetrahydropyran-4-base) pyridine
Under 70 ℃, the mixture of 5-bromo-2-pyridine acetonitrile (400mg), triethyl benzyl ammonia chloride (462mg), two (2-bromotrifluoromethane) ether (281 μ L) and 50% sodium hydroxide solution (10ml) was stirred 1 hour.Behind the decant water-yielding stratum, dilute resistates, use ethyl acetate extraction with saturated ammonium chloride solution.Use the anhydrous magnesium sulfate drying organic extract, filter, then vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=7: 3) handle resistates, obtain 5-bromo-2-(4-cyano group tetrahydropyran-4-base) pyridine (104mg).
MS(EI
+)m/z：266(M
+)。
For C
11H
11BrN
2O (M
+) HRMS (EI
+) analyze: calculated value 266.0055; Detected value 266.0038.
Reference example 45
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-5-hydroxymethyl oxazolidine-2-ketone
Press and reference example 31 described identical methods, from 5 (R)-3-(3,5-two fluoro-4-iodophenyls)-5-hydroxymethyl oxazolidine-2-ketone (813mg) and 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine (1.00g) preparation reference example 45 (105mg).
MS(FAB
+)m/z：513(MH
+)。
For C
26H
27F
2N
4O
5(MH
+) HRMS (FAB
+) analyze: calculated value 513.1950; Detected value 513.1978.
Reference example 46
5 (R)-3-(3,5-two fluoro-4-iodophenyls)-5-methylol oxazolidine-2-ketone
Press and reference example 13 described identical methods, from 5 (R)-3-(3, the 5-difluorophenyl)-5-methylol oxazolidine-2-ketone (2.00g) preparation reference example 46 (1.91g).
MS(EI
+)m/z：354(M
+)。
For C
10H
8F
2INO
3(M
+) HRMS (EI
+) analyze: calculated value 354.9517; Detected value 354.9522.
Reference example 47
5 (R)-azido-methyl-3-(3,5-two fluoro-4-iodophenyls) oxazolidine-2-ketone
Press and reference example 13 described identical methods, from 5 (R)-3-(3,5-two fluoro-4-iodophenyls)-5-hydroxymethyl-oxazolidine-2-ketone (2.30g) preparation reference example 47 (2.44g).
MS(FAB
+)m/z：381(MH
+)。
For C
10H
8F
2IN
4O
2(MH
+) HRMS (FAB
+) analyze: calculated value 380.9660; Detected value 380.9685.
Reference example 48
1-[5 (R)-3-(3,5-two fluoro-4-iodophenyls)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and reference example 13 described identical methods, from 5 (R)-azido-methyl-3-(3,5-two fluoro-4-iodophenyls) oxazolidine-2-ketone (875mg) preparation reference example 48 (876mg).
MS(EI
+)m/z：406(M
+)。
For C
12H
9F
2IN
4O
2(M
+) HRMS (EI
+) analyze: calculated value 405.9738; Detected value 405.9750.
Reference example 49
4-fluoro-1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles and 5-fluoro-1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Under 110 ℃, with the mixture heating up of 5 (R)-azido-methyl-3-(3-fluoro-4-iodophenyl) oxazolidine-2-ketone (700mg) and 1-fluoro-1-ethenylphenyl sulfoxide (987mg) 15 hours.By flash chromatography method (silicon-dioxide, toluene: ethyl acetate=2: 1) handle resistates, obtain 4-fluoro-1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (125mg) and 5-fluoro-1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazole (258mg).
4-fluoro-1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles:
MS(EI
+)m/z：406(M
+)。
For C
12H
9F
2IN
4O
2(M
+) HRMS (EI
+) analyze: calculated value 405.9738; Detected value 405.9744.
5-fluoro-1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles:
MS(EI
+)m/z：406(M
+)。
For C
12H
9F
2IN
4O
2(M
+) HRMS (EI
+) analyze: calculated value 405.9738; Detected value 405.9753.
Reference example 50
4-fluoro-1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-borolyl) phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles
Press and reference example 1 described identical method, from 4-fluoro-1-[5 (R)-3-(3-fluoro-4-iodophenyl)-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles (430mg) preparation reference example 50 (380mg).
MS(FAB
+)m/z：407(MH
+)。
For C
18H
22BF
2N
4O
4(MH
+) HRMS (FAB
+) analyze: calculated value 407.1702; Detected value 407.1693.
Reference example 51
5-bromo-2-[(1 α, 5 α, 6 β)-6-carboxyl-3-thia dicyclo [3.1.0] oneself-the 6-yl pyridines
Under 80 ℃, with 5-bromo-2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] mixture heating up 70 minutes of pyridine (1.77g) and concentrated hydrochloric acid (17ml), vacuum concentration.Use the water treatment resistates, obtain reference example 51 (1.81g).
MS(FAB
+)m/z：299(MH
+)。
For C
11H
10BrNO
2S (MH
+) HRMS (FAB
+) analyze: calculated value 298.9616; Detected value 298.9612.
Reference example 52
5-bromo-2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine
At room temperature; to 5-bromo-2-[(1 α; 5 α; 6 β)-6-carboxyl-3-thia dicyclo [3.1.0] oneself-the 6-yl] add diphenyl phosphoryl azide (0.60ml) and triethylamine (0.46ml) in toluene (10ml) suspension of pyridine (760mg), under uniform temp with mixture stirring 75 minutes.Water and salt solution purging compound.Use the anhydrous magnesium sulfate drying organic extract, filter, then vacuum concentration.Under 120 ℃, with the trimethyl carbinol (5ml) solution stirring of resistates 9.5 hours, vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=9: 1) handle resistates, obtain reference example 52 (502mg).
MS(FAB
+)m/z：371(MH
+)。
For C
15H
20BrN
2O
2S (MH
+) HRMS (FAB
+) analyze: calculated value 371.0429; Detected value 371.0407.
Reference example 53
5-bromo-2-pyridyl acetonitrile
Step 1
(5-bromo-2 (1H)-pyridylidene (pyridinylidene)) cyanoacetic acid tert-butyl ester
Under 18-25 ℃, in 1 hour, in dried DMSO (1.5L) suspension of NaH (66.4g, 60% oil dispersion), add the cyanoacetic acid tert-butyl ester (243ml), at room temperature mixture was stirred 2 hours.Add 2 in the gained mixture, 5-dibromo pyridine (150g) stirs mixture 6.5 hours under 120 ℃.After the cooling, mixture is poured in the saturated ammonium chloride solution, filtered and collect the gained throw out, water and cold EtOH washing obtain (5-bromo-2 (1H)-pyridylidene) cyanoacetic acid tert-butyl ester (166g).
1H?NMR(CDCl
3)δ1.53(s，9H)，7.20(dd，J＝9.8，1.8Hz，1H)，7.53(dd，J＝9.8，2.4Hz，1H)，7.64(dd，J＝6.1，1.8Hz，1H)，14.15(brs，1H)。
Step 2
Reference example 53
With acetonitrile (800ml) the solution reflux of reference example 53 step 1 compounds (120g) and KSF clay (80g) 6 hours.After removing by filter insolubles, with the filtrate vacuum concentration.By flash chromatography method (silicon-dioxide, hexane: ethyl acetate=4: 1) handle resistates, obtain reference example 53 (57.2g).
MS(EI
+)m/z：197(M
+)。
Anti-microbial activity
Pharmaceutically acceptable compound of the present invention is the useful antiseptic-germicide that reference culture is had good external activity spectrum, and described reference culture is used to screen the activity to pathogenic bacterium.Significantly, pharmaceutically acceptable compound exhibits of the present invention has activity to faecalis, the suis of vancomycin resistance, and described bacterium comprises streptococcus aureus (S.aureus), moraxelle catarrhalis (M.catarrhalis) and the Chlamydia pneumoniae (C.pneumoniae) of penicillin-fast streptococcus pneumoniae (S.pneumoniae), anti-Staphcillin.Can in the standard test system, determine particular compound antimicrobial spectrum and tire.
Obtain following in vitro results based on the agar dilution method, except Chlamydia pneumoniae.Active with minimal inhibitory concentration (MIC) expression.
On Mueller-Hinton agar, with about 1 * 10
4The inoculation of cfu/ point was cultivated 24 hours under 35 ℃ temperature, test streptococcus aureus and moraxelle catarrhalis.MIC is defined as the Cmin that can not observe visible bacterial growth.
On the Mueller-Hinton agar that replenishes 5% defibrinated horse blood, with about 1 * 10
4The inoculation of cfu/ point is under 35 ℃ temperature, at 5% CO
2Cultivated 24 hours testing chain coccus and faecalis in the atmosphere.MIC is defined as the Cmin that can not observe visible bacterial growth.
With the minimum essential medium test Chlamydia pneumoniae of replenishing 10% heat-inactivated fetal bovine serum, 2mM L-L-glutamic acid, 1mg/ml cycloheximide and non-essential amino acid.With 10
4Form the unitary Chlamydia pneumoniae bacterial strain of inclusion/milliliter inoculation sea and draw (Hela) 229 cells.Under 35 ℃, in perfect medium, at 5%CO
2In the atmosphere, cells infected was cultivated 72 hours with test-compound.Cell monolayer is fixed in the methyl alcohol, uses and the dyeing of the anti-chlamydozoan monoclonal antibody of fluorescein conjugated chlamydia inclusion, use fluorescence microscope.MIC is defined as the Cmin that can not observe inclusion.
The anti-paraxin of CR=
The anti-Staphcillin of MR=
PRQR=penicillin resistant, anti-quinolone
VRQR=vancomycin resistance, anti-quinolone
NT=does not test
With above non-limiting example invention described herein has been described.According to " manuscript prepares the general guideline (General Guidelines for Manuscript Preparation) of usefulness ", J.Org.Chem.Vol.66, pg.19A, Issue 1,2001 marks the compound data.
Claims (15)
1. the compound of formula I, its enantiomorph, diastereomer, or their pharmacologically acceptable salt:
Wherein:
R
1Expression (CH
2)
nNR
5R
6, CN, (CH
2)
pOH,
X represents
Y represents NR
*, O or S (O) p;
R
3Expression NR (C=X
2) R
12, NR
*R
12, C
6-10Aryl, maybe can by carbon or heteroatoms connect-(O)
nC
5-10Heterocyclic radical; Described aryl and heterocyclic radical are randomly by 1 to 3 R
7Group replaces,
R
4, R
4a, R
4bAnd R
4cExpression independently
I) hydrogen,
Ii) halogen,
Iii) C
1-6Alkoxyl group, or
Iv) C
1-6Alkyl;
R and s are 1-3 independently, bar
Part is as (R
4a)
s(R
4)
rOr (R
4b)
s(R
4c)
rBe connected to Ar or HAr when ring, r and s and be less than or equal to 4;
R
5And R
6Represent hydrogen, C independently
1-6Alkoxy carbonyl,
R
7Expression:
I) hydrogen, halogen, (CH
2)
pC
5-10Heterocyclic radical, CN, CO
2R, CON (R)
2, CHO, (CH
2)
0-3NHAc, OH, C
1-6Alkoxyl group, C
1-6Alkyl, C
2-10Thiazolinyl, hydroxyl C
1-6Alkyl, (CH
2)
1-3NHC (O) C
1-6Alkyl, (CH
2)
0-3N (C
1-6Alkyl)
2, NHCO
2R ,-OCOC
1-6Alkyl;
Ii) (CH
2)
nAmino, (CH
2)
nC
1-6Alkylamino, C
1-6Amido, hydroxyl amino or C
1-2Alkoxy amino, they all can be randomly by C on nitrogen
1-6Acyl group, C
1-6Alkyl sulphonyl or C
1-6Alkoxy carbonyl replaces, and described acyl group and alkyl sulphonyl are randomly by the 1-2 among halogen or the OH replacement;
X
2Expression O, S, NH or NSO
2R
14
R
12Expression hydrogen, C
1-6Alkyl, NH
2, OR, CHF
2, CHCl
2, C (R)
2Cl, (CH
2)
nSR, (CH
2)
nCN, (CH
2)
nSO
2R, (CH
2)
nS (O) R, C
1-6Alkylamino, C
3-6Cycloalkyl, C
5-10Heterocyclic radical or C
1-6Dialkyl amido, wherein said alkyl and cycloalkyl can be selected from halogen, CN, OH or C
1-61-3 in the alkoxyl group group replaces, and described heterocyclic radical is randomly by 1-3 R
7Group replaces;
R represents hydrogen or C
1-6Alkyl;
R
*Expression hydrogen, CN, C (=O) R
14, (CH
2)
pCO
2C
1-6Alkyl, (CH
2)
pC
5-10Heterocyclic radical or C
1-6Alkyl, described alkyl and heterocyclic radical are randomly by 1 to 3 R
7Group replaces;
R
14Expression is amino, C
1-6Alkyl, C
3-6Cycloalkyl, (CH
2)
pC
5-10Heterocyclic radical, C
1-6Haloalkyl, phenyl, described alkyl, cycloalkyl, phenyl, heterocyclic radical are randomly by 1 to 3 R
7Group replaces, and works as R
7For amino or hydroxyl or when forming the nitrogen of heterocyclic moiety, described amino and hydroxyl are randomly by amino or hydroxyl protecting group protection;
P represent 0-2 and
N represents 0-1.
2. according to the compound of claim 1, its enantiomorph, diastereomer, or their pharmacologically acceptable salt, wherein
Ar and HAr be phenyl, pyridyl or pyrimidyl independently, and r+s sum≤3 of a and b.
3. according to the compound of claim 2, its enantiomorph, diastereomer, or their pharmacologically acceptable salt, wherein Y is NR
*, R
1Be NR
5R
6, CN or OH.
4. according to the compound of claim 3, its enantiomorph, diastereomer, or their pharmacologically acceptable salt, wherein R
1Be NR
5R
6Or CN.
5. according to the compound of claim 4, its enantiomorph, diastereomer, or their pharmacologically acceptable salt, wherein R
3Be C
5-10Heteroaryl, described heteroaryl are randomly by 1 to 3 R
7Group replaces.
6. according to the compound of claim 1, its enantiomorph, diastereomer, or their pharmacologically acceptable salt have structural formula IV:
R wherein
4, R
4aAccording to claim 1, R
3Be 1,2,3-triazoles, 1,2 independently, 4-triazole, oso-triazole, tetrazolium, pyrazoles or imidazoles, wherein any one all can comprise 1 to 3 and is selected from R
7Substituting group.
7. compound, it is:
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide S-oxide compound,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
4-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 4-triazole,
4-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 4-triazole,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-5-[N-(tertbutyloxycarbonyl)-N-(isoxzzole-3-yl)] amino methyl-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] propionic acid amide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-methyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3,6-dicyano-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[(1-t-butoxycarbonyl amino ring third-1-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-the amino ring of 3-[(1-third-1-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[2-(phthalic imidine-2-yl) ethyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-(2-amino-ethyl)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[2-(1,2,4-triazole-4-yl) ethyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-bromo ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(morpholine-4-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(5-cyanopyridine-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(1,3-dihydroxyl third-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S)-1-tertbutyloxycarbonyl tetramethyleneimine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S)-tetramethyleneimine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4R)-1-tertbutyloxycarbonyl-4-hydroxyl pyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4R)-4-hydroxyl pyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4S)-1-tertbutyloxycarbonyl-4-fluoropyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4S)-4-fluoropyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-(tertbutyloxycarbonyl) amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-amino-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles dihydrochloride,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-acetoxyl ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano-3-hydroxy ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-two Cyclopropanoyl Chlorides)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-(2,2-difluoro cyclopropane)-1-carboxylic acid amides,
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] carbamate
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] carbamate
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3,6-dicyano-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-methyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[3-fluoro-4-[2-[(1 α, 5 α, 6 β)-6-hydroxymethyl-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-4-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-5-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-5-fluoro-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-(4-tert-butoxycarbonyl-piperazine-1-yl) ethanoyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(piperazine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles dihydrochloride,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] thiophene-4-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(piperidines-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(tetramethyleneimine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(4-dimethylamino phenylpiperidines-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S)-1-tertbutyloxycarbonyl tetramethyleneimine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S)-tetramethyleneimine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4R)-4-hydroxyl pyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazolium salt hydrochlorate
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4R)-1-tertbutyloxycarbonyl-4-hydroxyl pyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[((2S, 4S)-1-tertbutyloxycarbonyl-4-fluoropyrrolidine-2-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-[((2S, 4S)-4-fluoropyrrolidine-2-yl) carbonyl]-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-t-butoxycarbonyl amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(4-methylpiperazine-1-yl) ethanoyl-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S-oxide compound,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-thia dicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles S, the S-dioxide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(1,3-diacetoxyl third-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-[(3R, 4S)-1-azabicyclo [2.2.1] heptan-3-yl] carbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 3-triazole
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(pyridine-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-(thiatriazole-2-yl)-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thioacetamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thioacetamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] lsothiocyanates,
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thiocarbamate,
O-methyl-N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] thiocarbamate.
8. according to the compound of claim 7, it is:
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-amino-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-3, the 5-difluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] phenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles,
4-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2, the 4-triazole,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[(isoxzzole-3-yl) oxygen] methyl oxazolidine-2-ketone,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxzzole-3-yl)] amino methyl oxazolidine-2-ketone,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] ring third carboxylic acid amides,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] two monofluoroacetamides,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-the amino ring of 3-[(1-third-1-yl) carbonyl]-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles.
9. compound according to Claim 8, it is:
1-[5 (R)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride,
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl] phenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl]-the 3-fluorophenyl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride, or
N-[5 (S)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl] acetamide hydrochloride.
10. compound, it is:
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-azabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles or its pharmacologically acceptable salt.
11. compound, it is:
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxo oxazolidine-5-ylmethyl]-1,2,3-triazoles or its pharmacologically acceptable salt.
12. compound, it is:
N-[5 (S)-3-[4-[4-[(1 α, 5 α, 6 β)-6-cyano group-3-oxabicyclo [3.1.0] oneself-the 6-yl] pyridine-5-yl] phenyl]-2-oxo oxazolidine]-the 5-ylmethyl] ethanamide or its pharmacologically acceptable salt.
13. a pharmaceutical composition is made up of compound and pharmaceutically acceptable carrier of claim 1, described composition randomly is combined with the VITAMIN that is selected from Wei ShengsuB2, vitamin B6, vitamin B12 and the folic acid.
14. one or more VITAMIN that are selected from Wei ShengsuB2, vitamin B6, vitamin B12 and the folic acid of the compound of the claim 1 of significant quantity and optional significant quantity are used for the treatment of or prevent application in the medicine of the relevant side effect of infectation of bacteria in the mammalian subject of needs or oxazolidone in preparation.
15. according to the application of claim 14, wherein the side effect that oxazolidone is relevant is normocytic anemia, sideroblastic anemia, peripheral sensory neuropathy, optic neuropathy, epileptic seizures, thrombocytopenia, cheilosis, seborrheic dermatitis, subcutaneous reproducibility anaemia or megaloblastic anemia.
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| US54698404P | 2004-02-24 | 2004-02-24 | |
| US60/546,984 | 2004-02-24 | ||
| PCT/US2004/020734 WO2005005398A2 (en) | 2003-07-02 | 2004-06-29 | Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001094342A1 (en) * | 2000-06-05 | 2001-12-13 | Dong A Pharm. Co., Ltd. | Novel oxazolidinone derivatives and a process for the preparation thereof |
| WO2003027083A1 (en) * | 2001-04-17 | 2003-04-03 | Merck & Co., Inc. | Bicyclo[3,1,0]hexane containing oxazolidinone antibiotic and derivatives thereof |
| WO2003048136A1 (en) * | 2001-11-29 | 2003-06-12 | Merck & Co., Inc. | Cyclopropyl hexane containing oxazolidinone antibiotics and derivatives thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001094342A1 (en) * | 2000-06-05 | 2001-12-13 | Dong A Pharm. Co., Ltd. | Novel oxazolidinone derivatives and a process for the preparation thereof |
| WO2003027083A1 (en) * | 2001-04-17 | 2003-04-03 | Merck & Co., Inc. | Bicyclo[3,1,0]hexane containing oxazolidinone antibiotic and derivatives thereof |
| WO2003048136A1 (en) * | 2001-11-29 | 2003-06-12 | Merck & Co., Inc. | Cyclopropyl hexane containing oxazolidinone antibiotics and derivatives thereof |
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