Oxazolidinone Combinatorial Libraries, Compositions and Methods of Preparation

专利摘要:
The present invention provides oxazolidinones and methods for their preparation. The present invention also provides a combinatorial library comprising oxazolidinone and a method of making the library. The present invention also provides a method of preparing a pharmaceutically acceptable composition comprising biologically active oxazolidinone, and oxazolidinone. The library preparation method involves binding oxazolidinone to a solid phase support. In an embodiment the method for preparing the compound comprises the reaction of an iminophosphoran with a polymeric support containing carbonyl.
公开号:KR20010015910A
申请号:KR1020007008059
申请日:1999-01-22
公开日:2001-02-26
发明作者:미카일 에프. 고르디에프；게리 떠블유. 루에르；디네쉬 브이. 파텔；지-지에 니；에릭 고든
申请人:로렌스 티. 마이젠헬더；파마시아 앤드 업존 캄파니；
IPC主号:

专利说明:

Oxazolidinone Combinatorial Libraries, Compositions and Methods of Preparation}
This application is part of US Application No. 09 / 012,535, filed Jan. 23, 1998, and US Application No. 09 / 086,702, filed May 28, 1998, the disclosures of which are incorporated herein in its entirety. Include in the specification.
Oxazolidinones are compounds in which an amine group and a hydroxyl group on adjacent carbon atoms are cyclized together to form a 5-membered ring including a carbonyl group. Some oxazolidinones have been found to exhibit a variety of biological activities. For example, some oxazolidinones are inhibitors of monoamine oxidase-B, an enzyme associated with Parkinson's disease [Ding et al., J. Med. Chem. 36: 3606-3610 (1993).
U.S. Patent No. 5,547,950 describes a ten step synthesis of oxazolidinone antibiotics. Schauss et al., Tetrahedron Letters, 37: 7937-7940 (1996) also describe a four-step synthesis of the antimicrobial compound U-100592. De Parrodi et al., Tetrahedron: Asymmetry, 8: 1075-1082 (1997) describe 5 of enantiomerically pure cis- and trans-N- (propionyl) hexahydrobenzoxazolidin-2-ones. Step recipes have been reported.
Scientists report that some oxazolidinone derivatives have beneficial antimicrobial effects. For example, N- [3- [3-fluoro-4- (morpholin-4-yl) phenyl] -2-oxooxazolidin-5 (s) -ylmethyl] acetamide is a bacterium of the formula It has been reported to be useful for the treatment of infections (Lizondo et al., Drugs of the Future, 21: 1116-1123 (1996)).

Wang et al., Tetrahedron, 45: 1323-1326 (1989) reported the synthesis of an oxazolidinone antimicrobial agent of the formula This oxazolidinone was prepared using the method of obtaining amino alcohol by reacting aniline and glycidol, and cyclizing the amino alcohol via diethyl carbonate to obtain oxazolidinone.

U.S. Pat. No. 4,705,799 reports the synthesis of oxazolidinone antimicrobials, including compounds of the formula: The method used to prepare the compounds of the formulas involved the reduction of sulfonyl chloride via metal to obtain sulfides.

US 4,948,801 reports the synthesis of oxazolidinone antimicrobials, including pyridyl compounds of the formula: The method used here involved the coupling of an organotin compound to aryl iodide via an organometallic compound.

Synthetic routes of oxazolidinones often allow chemists to obtain only one compound at a time. Such a difficult method can limit the number of compounds that can be evaluated in biological screening. However, these methods cannot provide the various compounds needed to provide high throughput biological screening, for example, analytical techniques that can analyze the activity of thousands of drug candidates per week. In the discovery of new drugs, screening methods with high material throughput are preferred and effective, and the limitation of providing such compounds is practically important.
Summary of the Invention
The present invention provides oxazolidinones and their combinatorial libraries, compositions comprising oxazolidinones, and methods and uses for their synthesis. Using the methods provided herein, one skilled in the art can readily produce a variety of compounds required for high throughput screening methods.
In one embodiment, the present invention provides a method for solid phase synthesis of oxazolidinones.
In one embodiment, the method is obtained using the steps of bonding an olefin to a solid support, oxidizing the olefin to provide an epoxide function, ring opening the epoxide with an amine, and using a phosgene equivalent. Cyclizing the amino alcohol.
In another embodiment, the process comprises the steps of: binding the allylic amine to the solid support, oxidizing the olefin of the allylic amine to provide an epoxide, ring opening the epoxide with the amine, and phosgene equivalents. Cyclizing the amino alcohol obtained using.
In another embodiment, the method comprises the steps of binding allylamine to a solid support, oxidizing the olefin of arylamine to provide an epoxide, ring opening the epoxide with an amine, and using a phosgene equivalent. Cyclizing the obtained amino alcohol.
In another embodiment, the method comprises binding an olefin to a solid support, oxidizing the olefin to provide an epoxide, ring opening the epoxide with amino acids, and amino alcohols obtained using phosgene equivalents. Cyclization.
In another embodiment, the process comprises the steps of bonding an olefin to a solid support, oxidizing the olefin to provide an epoxide, ring opening the epoxide with an aromatic amine, and an amino alcohol obtained using a phosgene equivalent. Cyclization.
In the present invention, a method for synthesizing an oxazolidinone combinatorial library is also provided.
In one embodiment, the method comprises combining olefin groups to a series of solid phase supports, oxidizing each olefin group to provide an epoxide bonded to the series of solid phase supports, and ring opening the epoxide using amine units. And cyclizing the resulting amino alcohol solid support array using a phosgene equivalent.
In another embodiment, the method comprises the steps of: coupling allylic amines to a solid support solid phase support arrangement, oxidizing each olefin group to provide an epoxide arrangement bonded to the solid phase support, and opening the epoxide using an amine unit. And cyclizing the resulting amino alcohol configuration using phosgene equivalents.
In another embodiment, the method comprises combining allyl amines to a solid support array, oxidizing each olefin group to provide an epoxide array bonded to the solid support, ring opening the epoxide using amine units, And cyclizing the obtained amino alcohol sequence using a phosgene equivalent.
In another embodiment, the method comprises combining olefins to a solid support array, oxidizing each olefin group to provide an epoxide array bonded to the solid support, ring opening epoxides using amino acid units, and Cyclizing the obtained amino alcohol configuration using a phosgene equivalent.
In another embodiment, the method comprises combining olefins to a solid support array, oxidizing each olefin group to provide an epoxide array bonded to the solid support, ring opening epoxides using aromatic amine units, And cyclizing the obtained amino alcohol sequence using a phosgene equivalent.
The present invention provides various oxazolidinones and their combinatorial libraries. In one embodiment, the oxazolidinone has the structure of Formula 1a.
Where
R ₁ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl,
R ₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₃ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₁ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, oxazolidinones and combinatorial libraries are provided, wherein the oxazolidinones are of the structure of Formula 1b.
Where
R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl or sulfonyl,
R ₁ is C (O) NR ₇ R ₈ (wherein R ₇ and R ₈ are independently of each other hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), C (O) OR ₉ (here, R ₉ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), C (O) R ₁₀ (wherein R ₁₀ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), SR ₁₁ (where R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, S (O) ₂ R ₁₁ , wherein R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, S (O) R ₁₁ (Wherein R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), NR ₁₂ R ₁₃ (wherein R ₁₂ and R ₁₃ are independently of each other hydrogen, acyl, sulfonyl, alkyl, heteroalkyl , Aryl or heteroaryl, 2-oxazolyl having R ₁₄ at position 4 of oxazolyl and R ₁₅ at position 5 of oxazolyl, wherein R ₁₄ and R ₁₅ are independently of each other hydrogen , Alkyl, heteroal , Aryl, heteroaryl or giim attract electrons), and in position 4 of the thiazole is R _16, 2- amino-thiazolyl group, a 5-position of thiazole is R ₁₇ (where, R ₁₆ and R ₁₇ is Independently of one another, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group, and CH ₂ NR ₁₈ R ₁₉ , wherein R ₁₈ and R ₁₉ are independently of each other hydrogen, alkyl, heteroalkyl, Aryl, heteroaryl, acyl or sulfonyl).
All compounds disclosed herein may exist in a variety of isomeric forms, including stereoisomeric and enantiomerically pure forms, all of which isomers and forms are within the scope of the present invention. For example, Formula 1b is shown in the preferred embodiment, which is the S isomer at position 5 of the oxazolidinone, but it is within the scope of the present invention to be the R isomer. Similarly, for all remaining oxazolidinone compounds, both stereoisomers are within the scope of the present invention when the preferred stereoisomers are exemplified at position 5 of the oxazolidinone.
In one embodiment of Formula 1b, R ₁ is C (O) R ₇ R ₈ .
In another embodiment of Formula (1b), R ₁ is C (O) OR ₉ .
In another embodiment of Formula (1b), R ₁ is C (O) R ₁₀ .
In another embodiment of Formula (1b), R ₁ is SR ₁₁ .
In another embodiment of Formula (1b), R ₁ is S (O) ₂ R ₁₁ .
In another embodiment of Formula (1b), R ₁ is S (O) R ₁₁ .
In another embodiment of Formula (1b), R ₁ is NR ₁₂ R ₁₃ . In another embodiment, R ₁ is NR _x (C═O) R _y , wherein R _x and R _y are independently of each other hydrogen, alkyl, heteroalkyl, aryl, or heteroaryl, or NR _x ( SO ₂ ) R _y , wherein R _x and R _y are, independently from each other, hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, provided that R _y is not H.
In another embodiment of Formula (1b), R ₁ is 2-oxazolyl, wherein R ₁₄ is at position 4 of the oxazole group and R ₁₅ is at position 5 of the oxazole group.
In another embodiment of Formula 1b, R ₁ is 2-aminothiazolyl, wherein R ₁₆ is at position 4 of the aminothiazolyl group and R ₁₇ is at position 5 of the aminothiazolyl group.
In another embodiment of Formula (1b), R ₁ is CH ₂ NR ₁₈ R ₁₉ .
In another embodiment of Formula (1b), R ₁ is C (O) NR ₇ R ₈ and R ₃ , R ₄ and R ₅ are hydrogen.
In another embodiment of Formula (1b), R ₁ is C (O) NR ₇ R ₈ , R ₃ , R ₄ and R ₅ are hydrogen, and R ₂ is fluorine.
In another embodiment of Formula (Ib), R ₁ is C (O) NR ₇ R ₈ , R ₃ , R ₄ and R ₅ are hydrogen, R ₂ is fluorine, R ₆ is C (O) CH ₃ .
In another embodiment of Formula 1b, R ₁ is C (O) NR ₇ R ₈ , R ₃ , R ₄ and R ₅ are hydrogen, R ₂ is fluorine, R ₆ is C (O) CH ₃ and , R ₇ is hydrogen.
In another embodiment of Formula 1b, R ₁ is C (O) NR ₇ R ₈ , R ₃ , R ₄ and R ₅ are hydrogen, R ₂ is fluorine, R ₆ is C (O) CH ₃ and , R ₇ is hydrogen and R ₈ is heteroaryl.
In the present invention, various methods for preparing a combinatorial library comprising oxazolidinone are provided.
In one embodiment, this method is for preparing oxazolidinone, such as a compound of Formula 1b. The method comprises combining various aryl oxazolidinones to various solid phase supports, functionalizing the position 4 of the aryl group of the bound oxazolidinones, and optionally removing oxazolidinones from the solid support. Include.
In another embodiment, the aryl oxazolidinone is bonded to the solid support by reacting iminophosphoran with a resin containing carbonyl to form an imine. In another embodiment, the aryl oxazolidinone is bound to the solid support by reacting the amine with a resin containing carbonyl to form an imine.
In another embodiment, iminophosphoran is reacted with a resin containing carbonyl to form imines, thereby binding aryl oxazolidinone to the solid support and reducing this imine to form an amine. In another embodiment, the amine is reacted with a resin containing carbonyl to form imines, thereby binding the aryl oxazolidinones to the solid support and the imines are reduced to form amines.
Also provided herein are compositions comprising biologically active oxazolidinone and biologically active oxazolidinone. For example, oxazolidinone may have antibiotic activity.
In one embodiment, the biologically active oxazolidinone is the structure of Formula 1b.
In another embodiment, the biologically active oxazolidinone is the structure of Formula 1b wherein R ₁ of oxazolidinone is C (O) NR ₇ R ₈ .
In another embodiment, the biologically active oxazolidinone is the structure of Formula 1b wherein R ₁ of the oxazolidinone is 2-oxazolyl containing R ₁₄ at position 4 and R ₁₅ at position 5.
In another embodiment, the biologically active oxazolidinone is the structure of Formula 1b wherein R ₁ of the oxazolidinone is 2-aminothiazolyl containing R ₁₆ at position 4 and R ₁₇ at position 5.
In another embodiment, the biologically active oxazolidinone is the structure of Formula 1b wherein R ₁ of oxazolidinone is C (O) NR ₇ R ₈ and R ₃ , R ₄ and R ₅ are hydrogen.
In another embodiment, the biologically active oxazolidinone is 2-oxazolyl wherein R ₁ of the oxazolidinone contains R ₁₄ at position 4, R ₁₅ at position 5, and R ₃ , R _4, and R _{And 5} is hydrogen.
In another embodiment, the biologically active oxazolidinone is 2-aminothiazolyl wherein R ₁ of the oxazolidinone contains R ₁₆ at position 4, R ₁₇ at position 5, and R ₃ , R ₄ and R ₅ is hydrogen.
In another embodiment, the biologically active oxazolidinone has Formula 1b wherein R ₁ of oxazolidinone is C (O) NR ₇ R ₈ , R ₃ , R ₄ and R ₅ are hydrogen, and R ₂ is fluorine. Is the structure.
In another embodiment, the biologically active oxazolidinone is 2-oxazolyl wherein R ₁ of the oxazolidinone contains R ₁₄ at position 4, R ₁₅ at position 5, and R ₃ , R _4, and R ₅ is hydrogen and R ₂ is fluorine.
In another embodiment, the biologically active oxazolidinone is 2-aminothiazolyl wherein R ₁ of the oxazolidinone contains R ₁₆ at position 4, R ₁₇ at position 5, and R ₃ , R ₄ and R ₅ is hydrogen and R ₂ is fluorine.
In another embodiment, the biologically active oxazolidinones are those in which R ₁ of oxazolidinone is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen and R ₈ is 5-chloropyridin-3-yl. , Thiazol-2-yl, 5 '-(5-aminopyridin-2-yl) thiopyridin-3'-yl, or pyridin-3-yl), R ₃ , R ₄ and R ₅ are hydrogen, R ₂ is fluorine and R ₆ is C (O) CH ₃ .
In another embodiment, the biologically active oxazolidinone is wherein R ₁ of oxazolidinone is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen and R ₈ is 5-chloropyridin-3-yl ), R ₃ , R ₄ and R ₅ are hydrogen, R ₂ is fluorine and R ₆ is C (O) CH ₂ SMe.
In another embodiment, the biologically active oxazolidinone is such that R ₁ of oxazolidinone is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen and R ₈ is 5-chloropyridin-3-yl. ), R ₃ , R ₄ and R ₅ are hydrogen, R ₂ is fluorine and R ₆ is C (O) CHCH (pyridin-3-yl).
In another embodiment, the biologically active oxazolidinone is a compound in which R ₁ of oxazolidinone is 5-amino-4-cyanooxazol-2-yl, R ₂ is fluorine, and R ₃ , R ₄ and R ₅ Is hydrogen and R ₆ is C (O) CH ₃ .
In another embodiment, the biologically active oxazolidinone is a compound in which R ₁ of oxazolidinone is 4-phenylthiazol-2-yl-amino, R ₂ is fluorine, and R ₃ , R ₄ and R ₅ are hydrogen. And R ₆ is C (O) CH ₃ .
In the present invention, various methods for synthesizing biologically active oxazolidinones are provided.
In one embodiment, there is provided a method for preparing an oxazolidinone, such as a compound of Formula 1b, which method comprises the steps of preparing an iminophosphoran, mixing iminophosphoran with a resin containing a carbonyl group to imine intermediate Forming an, and reducing the imine intermediate to obtain a compound bound to the resin via an amine linker. In another embodiment, the azide is reacted with phosphine to produce the iminophosphoran. In another embodiment, the amine is reacted with (trisubstituted) phosphine dihalide to produce the iminophosphoran.
In another embodiment, the resin containing the carbonyl group is a structure of formula 1c.
Where
R ₂₃ is hydrogen, alkyl, aryl, 0-alkyl or O-aryl,
R ₂₄ is hydrogen, CH ₃ O or NO ₂ ,
R ₂₅ is (CH ₂ ) _n CONH, where n is an integer ranging from 1 to about 5,
Blacked circles are polymeric supports.
In another embodiment of Formula 1c, R ₂₃ is hydrogen, R ₂₄ is CH ₃ O, R ₂₅ is (CH ₂ ) ₃ CONH, and the blackened circles are tentagel, (crosslinked) polystyrene, (Crosslinked) polyethylene glycol or polyethylene glycol-polystyrene compositions.
Also provided herein are methods for synthesizing biologically active oxazolidinones from the corresponding amines. In one embodiment, this method is for preparing an oxazolidinone, such as a compound of Formula 1b, reacting an amine with a resin containing a carbonyl group to form an imine intermediate, and reducing the imine intermediate to reduce the amine linkage group. Obtaining a compound bound to the resin through.
The present invention relates to oxazolidinones, oxazolidinones compositions, oxazolidinones combinatorial libraries, and methods for their preparation and uses.
1 shows the structure of oxazolidinone 1b.
2 is a scheme showing the synthesis of a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is C (O) R ₇ R ₈ .
3 is a scheme showing the synthesis of a series of azido oxazolidinones.
FIG. 4 is a scheme illustrating the synthesis of a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is C (O) R ₇ R ₈ , and R ₃ , R ₄ and R ₅ are hydrogen, and in FIG. 4, The N-Ac groups of 17, 18 and 19 may be NCOR ₁ , wherein R ₁ is a substituent such as H, alkyl, heteroalkyl, aryl, or heteroaryl.
FIG. 5 is a scheme showing the synthesis of a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is C (O) OR ₉ or C (O) R _10. FIG.
6 is a scheme illustrating the synthesis of a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is SR ₁₁ .
7 is a scheme showing the synthesis of a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is S (O) R ₁₁ or S (O) ₂ R ₁₁ .
8 is a scheme showing the synthesis of a series of thio substituted azido oxazolidinones.
9 is a scheme showing the synthesis of a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is NR ₁₂ R ₁₃ .
10 is a scheme showing the synthesis of a combinatorial library comprising oxazolidinone of Formula 1b wherein R ₁ is oxazole.
FIG. 11 is a scheme showing the synthesis of a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is oxazole. FIG.
12 is a scheme showing the synthesis of a combinatorial library comprising oxazolidinone of Formula 1b wherein R ₁ is aminothiazole.
FIG. 13 is a scheme showing the synthesis of a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is CH ₂ NR ₁₈ R _19. FIG.
14 is a scheme showing the synthesis of a series of azido oxazolidinones including acetals.
15 is a scheme showing a general synthesis method for preparing oxazolidinone.
16 is a scheme showing a general synthetic method for preparing azido oxazolidinone.
FIG. 17 shows a linking portion where oxazolidinone is bonded to a solid support.
18 is a scheme showing the synthesis of oxazolidinone of Formula 1b wherein R ₁ is NR ₁₂ R ₁₃ .
19 is a scheme showing the synthesis of oxazolidinones of Formula 1b wherein R ₁ is aminothiazole.
20 is a scheme showing the synthesis of oxazolidinone of Formula 1b wherein R ₁ is oxazole.
21 is a scheme showing the synthesis of oxazolidinone of Formula 1b wherein R ₁ is C (O) R ₁₀ .
22 is a scheme showing the synthesis of oxazolidinone of Formula 1b wherein R ₁ is NR ₁₂ R ₁₃ .
23 is a scheme showing a general synthesis method for preparing oxazolidinone.
24 is a scheme showing a method for producing N-[(3-phenyl-2-oxo-5-oxazolidinyl) methyl] acetamide.
Fig. 25 is a scheme showing a method for producing N-[[3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide.
FIG. 26 shows a method for preparing (S) -N-[[3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide bonded to a solid support. It is a reaction scheme.
FIG. 27 shows sulfonyl, amidyl and ureayl of (S) -N-[[3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide It is a reaction scheme showing a method for producing a derivative.
Fig. 28 shows α-thio acetamide, α, of (S) -N-[[3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide It is a reaction scheme showing a method for producing β-unsaturated acetamide and α-amino acetamide derivative.
FIG. 29 shows a non-limiting group of amines used in the preparation of sulfonyl, amidyl and ureayl oxazolidinone combinatorial libraries.
30 shows another non-limiting group of amines used in the preparation of sulfonyl, amidyl and ureayl oxazolidinone combinatorial libraries.
FIG. 31 shows another non-limiting group of amines used in the preparation of sulfonyl, amidyl and ureayl oxazolidinone combinatorial libraries.
FIG. 32 shows a method for preparing a sulfonamide, amide and urea oxazolidinone library in a manner similar to the amine bound to the solid support of formula 33a in FIG. 27 and similar to the amine of formula 32a in FIG. It represents a non-limiting group of amines used to.
FIG. 33 includes an oxazolidinone of Formula 1b wherein R ₁ is derived from the amine depicted, R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is C (O) CH ₃ It is a group of amines used for the preparation of oxazolidinone used for preparing the combinatorial library and the like.
FIG. 34 includes oxazolidinone of Formula 1b wherein R ₁ is derived from the amine depicted, R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is C (O) CH ₃ It is a group of amines used for the preparation of oxazolidinone used for preparing the combinatorial library and the like.
FIG. 35 includes an oxazolidinone of Formula 1b wherein R ₁ is derived from the amine depicted, R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is C (O) CH ₃ It is a group of amines used for the preparation of oxazolidinone used for preparing the combinatorial library and the like.
36 shows R ₁ is derived from the amine depicted, R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is C (O) CHCHC ₆ H ₄ CH (p-NOCH ₃ ) or A group of amines used for the preparation of oxazolidinone used to prepare a combinatorial library including the oxazolidinone of the formula (Ib), which is C (O) CHCHC ₆ H ₄ (p-OCH ₃ ).
FIG. 37 shows that R ₁ is derived from the amine depicted, R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is C (O) CH ₂ SCH ₃ or C (O) CHCH (3 -C ₅ H ₄ N) is a group of amines used for the preparation of oxazolidinone used to prepare a combinatorial library comprising the oxazolidinone of the formula (Ib).
FIG. 38 shows a group of biologically active oxazolidinone compounds having a MIC range of about 1.25-20 μg / ml against E. Faecium.
FIG. 39 is a scheme showing the synthesis of acylamino oxazolidinone compounds and libraries wherein R ₁ and R ₂ are substituents such as H, alkyl, heteroalkyl, aryl, heteroaryl, or alkoxy.
40 is a scheme showing the synthesis of sulfonamide oxazolidinone compounds and libraries wherein R ₁ is a substituent such as H, alkyl, heteroalkyl, aryl, heteroaryl, or alkoxy.
FIG. 41 is a scheme showing the synthesis of sulfide oxazolidinone compounds and libraries wherein R ₁ is a substituent such as H, alkyl, heteroalkyl, aryl, heteroaryl, or alkoxy.
42 and 43 show structural blocks R ₂ COOH that can be used for the synthesis of the acylamino oxazolidinone libraries and compounds shown in FIG. 39, and can also be used for further synthesis, such as the synthesis shown in FIG. 9.
44 and 45 are structural blocks R ₂ X that can be used for the synthesis of the sulfide oxazolidinone library and compounds shown in FIG. 41 and may also be used as R ₁₁ X in the synthesis shown in FIG. 6, where X is halo. ).
FIG. 46 shows a sulfonyl chloride structural block R ₂ SO ₂ Cl that can be used for the synthesis of the sulfonamide oxazolidinone libraries and compounds shown in FIG. 40 and may be used for the synthesis shown in FIG.
FIG. 47 shows an amine structure block R ₇ R ₈ NH, which can be used for the synthesis of the oxazolidinone library and compound shown in FIG. 4.
FIG. 48 shows structural blocks R ₂ R ₃ NH and R ₁ COOH, which may be used to prepare compounds of Formula 1k and libraries thereof. FIG.
49 is a general scheme showing the synthetic route of 3- (heteroaryl) oxazolidinone.
FIG. 50 is another general scheme showing the synthetic route of 3- (heteroaryl) oxazolidinone. FIG.
Justice
The terms and phrases used herein have the meanings and definitions known in the art. Some of the frequently used phrases are described in detail below.
“Combinatorial libraries” or “arrays” can be prepared synthetically and screened for biological activity in a variety of different formats (eg, libraries of soluble molecules, libraries of molecules bound to a solid support). It is a collection of different molecules. Generally, combinatorial libraries contain about 6 to 2 million compounds. In one embodiment, the combinatorial library comprises about 48 to 1 million compounds. For example, the combinatorial library may comprise about 96 to 250,000 compounds. In another embodiment, the combinatorial library may comprise about 40-100 compounds.
"Alkyl" refers to cyclic, branched or straight chain chemical groups containing only carbon and hydrogen, such as methyl, pentyl, and adamantyl. Alkyl groups may be unsubstituted or substituted with one or more substituents (eg, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl and benzyl). Alkyl groups may be saturated or unsaturated (eg, including —C═C— or —C≡C— subunits) at one or more positions. Generally, an alkyl group contains about 1 to 12 carbon atoms, for example 1 to 10, or about 1 to 8 carbon atoms.
"Heteroalkyl" means a cyclic, branched or straight chain chemical group containing carbon, hydrogen and one or more heteroatoms. Heteroatoms are usually nitrogen, oxygen or sulfur. Heteroalkyl groups may be unsubstituted or substituted with one or more substituents (eg, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl and benzyl). When the heteroalkyl group contains a nitrogen atom, the nitrogen atom may be primary, secondary, tertiary or quaternary, and may be in various forms such as amide or sulfonamide. Heteroalkyl groups may include one or more unsaturated (eg, —C═C— or —C≡C—) subunits. In general, heteroalkyl groups contain 1 to 12 atoms, for example 1 to 8, or 1 to 4 carbon atoms.
"Aryl" means a monovalent unsaturated aromatic carbocyclic group having a single ring (eg phenyl), multiple rings (eg biphenyl), or multiple condensed rings (eg naphthyl or anthryl). The aryl group may optionally be substituted or unsubstituted with amino, hydroxyl, alkyl, heteroalkyl, alkoxy, halo, mercapto and other substituents. Usually aryl groups are substituted monocyclic compounds. For example, the aryl group is a substituted phenyl ring.
"Heteroaryl" means a monovalent unsaturated aromatic carbocyclic group having a single ring (eg, pyridyl or furyl) or multiple condensed rings (eg, indolinyl or benzothienyl) and having one or more heteroatoms in these rings do. The heteroatoms in the ring are preferably nitrogen, oxygen or sulfur. Heteroaryl groups may optionally be substituted or unsubstituted with amino, hydroxyl, alkyl, heteroalkyl, alkoxy, halo, mercapto and other substituents. In one embodiment, the heteroaryl group is substituted.
"Electron attracting group" means a substituent that attracts electrons more strongly than would be expected if hydrogen atoms occupy the same position in the molecule. This definition according to the field effect is described by March, "Advanced Organic Chemistry," 3rd Edition, pp. 16-17, Wiley-Interscience, New York. This is in contrast to the definition based on the resonance effect. Examples of electron withdrawing groups are -NR ₂ , -COOH, -OR, -SR, -F, -COR, -Cl, -SH, -NO ₂ , -Br, -NH ₂ , -SO ₂ R, -I , -OH, -CN, -C = CR ₂ , wherein R is alkyl, heteroalkyl, aryl or heteroaryl.
"Chemical module" means a generic molecular type that can be introduced into a combinatorial library at individual stages in library synthesis. For example, thiols are chemical modules that can be coupled to a substrate when nucleophiles are used in the synthetic route to replace the leaving group bound to the solid support, and isocyanates are electrophiles in the synthetic route. A chemical module that can be coupled to a substrate when reacted with an amine bound to a solid support. Chemical modules can include dozens, hundreds or thousands of different individual members.
“Protecting groups” can (1) selectively react with desired functional groups in good yield to produce a protected material that is stable to the planned reactions that require protection, and (2) selectively remove from the protected material to obtain the desired functional groups (3) means a chemical group which is characterized by being able to be removed in good yield by using a reagent which can coexist with the remaining functional groups generated in this protection reaction. Examples of protecting groups are described in Greene et al., (1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York).
"Biologically active oxazolidinone compound" or "bioactive oxazolidinone compound" means an oxazolidinone compound such as Formula 1b that exhibits biological activity. For example, biologically active oxazolidinones inhibit the interaction of enzymes or receptors with their respective substrates or endogenous ligands, or inhibit cell proliferation of microorganisms by at least about 15% at solution concentrations of 10 ⁻³ M or less Can be inhibited (ie, has inhibitory activity). For example, biologically active oxazolidinone inhibits this process at a solution concentration of about 10 ⁻⁴ M or less, or 10 ⁻⁵ M or less, or for example about 10 ⁻⁶ M or less.
"Allyl amine" means a compound of the formula

Wherein R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ and R ₃₅ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
If R ₃₁ , R ₃₂ , R ₃₃ , R ₃₄ and R ₃₅ are all hydrogen, the allylic amine is allylamine.
"Phosgene equivalent" means a reagent that can add a C═O group to a molecule of interest through one or more chemical steps. Non-limiting examples of phosgene equivalents that can add C═O groups in one chemical step are carbonyldiimidazole (CDI). Non-limiting examples of phosgene equivalents that can add C═O groups in two or more chemical steps are ethyl chloroformates.
“Acyl” refers to the group — (C═O) —R, wherein R is a substituent such as H, aryl, heteroaryl, alkyl, or heteroalkyl. Examples of acyl groups include formyl, acetyl, propionyl and butyryl.
"Sulfonyl" refers to the group-(SO ₂ ) -R wherein R is a substituent such as alkyl, heteroalkyl, aryl or heteroaryl.
Oxazolidinones
The present invention provides not only oxazolidinones and combinatorial libraries thereof, but also methods of their synthesis, such as solid phase synthesis.
In one embodiment, the oxazolidinone has the structure of Formula 1a.
<Formula 1a>

Where
R ₁ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl,
R ₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₃ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₁ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, R ₃ of the oxazolidinone of Formula 1a is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl groups are aryl bonded to the amines of Table 2 and FIGS. 29, 30 and 31 and Heteroaryl group.
In another embodiment, R ₃ of oxazolidinone of Formula 1a is a heteroaryl group such as a pyridyl group, thienylphenyl group, oxazolyl group or pyrrolyl group, or is a (morpholino) fluorophenyl group.
In another embodiment, the oxazolidinone has the structure of Formula 1d.
Where
R ₁ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl,
R ₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₃ is a structure of the following formula.

Where
'X' is selected from the group consisting of hydrogen, electron withdrawing groups, alkyl, heteroalkyl, aryl and heteroaryl,
'Y' is selected from the group consisting of hydrogen, electron withdrawing groups, alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, R ₃ in oxazolidinone of formula 1d is of the structure:

In another embodiment, R ₁ of oxazolidinone of formula 1d is of the structure:

Where
R ₁₅ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₆ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, oxazolidinone is provided which is an antimicrobial compound. In one embodiment, the antimicrobial compound has a structure of Formula 1e.
Where
R ₃ is selected from the group consisting of aryl and heteroaryl,
R ₂₀ is selected from the group consisting of compounds of the formulas A, B, C, I, J and K.

Where
m is 0, 1, 2 or 3,
n is 0, 1, 2 or 3,
R ₂₁ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl,
R ₂₂ , R ₂₃ and R ₂₄ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, and heteroaryl,
R ₂₅ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₃₀ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, R ₃ of the antimicrobial compound of Formula 1e is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl groups are aryl and hetero bonded to the amines of Table 2 and FIGS. 29, 30, and 31 It is an aryl group.
In another embodiment, R ₃ of the antimicrobial compound of Formula 1e has the structure of:

Where
X and Z are each independently selected from the group consisting of hydrogen and fluorine,
Y is selected from the group consisting of compounds of the formulas D, E, F, G and H.

Wherein R ₂₆ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, Y of the antimicrobial compound of Formula 1e has the structure of Formula D:

In another embodiment, the antimicrobial compound has a structure of Formula 1f.
Where
m is 0, 1, 2 or 3,
R ₂₂ , R ₂₃ and R ₂₄ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl and heteroaryl.
In another embodiment, in the antimicrobial compound of Formula 1f, m is 0, R ₂₂ and R ₂₃ are hydrogen and R ₂₄ is an aryl group.
In another embodiment, the antimicrobial compound is of the structure

Where
R ₃₅ , R ₃₆ and R ₃₇ are independently of each other selected from the group consisting of hydrogen, an electron withdrawing group, alkyl, heteroalkyl, aryl and heteroaryl.
In another embodiment, an oxazolidinone of the structure of Formula 1b shown in FIG. 1 and a combinatorial library thereof are provided.
<Formula 1b>

In another embodiment, the substituent R of the compound of formula 1b_OneIs C (O) NR₇R₈Where R₇And R₈Are independently of each other hydrogen, alkyl, heteroalkyl, aryl or heteroaryl (non-limiting examples of amines used to prepare such a library are FIGS. 33, 34, 35, 36 and 37), C ( O) OR₉Where R₉Is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), C (O) R₁₀Where R₁₀Is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), SR₁₁(From here, R₁₁Is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), S (O)₂R₁₁Where R₁₁Is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), S (O) R₁₁Where R₁₁Is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), NR₁₂R₁₃Where R₁₂And R₁₃Are independently of each other hydrogen, acyl, sulfonyl, alkyl, heteroalkyl, aryl or heteroaryl), NR_x(C = O) R_yWhere R_xAnd R_yAre independently of each other hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), NR_x(SO₂R_yWhere R_xAnd R_yAre independently of each other hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, provided that_yIs not H), 2-oxazolyl (here, R₁₄Is at position 4, R₁₅Is at position 5, R₁₄And R₁₅Are independently of each other hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group, 2-aminothiazolyl, wherein R₁₆Is at position 4, R₁₇Is at position 5, R₁₆And R₁₇Are independently of each other hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group), and CH₂NR₁₈R₁₉Where R₁₈And R₁₉Are independently of each other hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, acyl or sulfonyl).
In one embodiment, in the substituent of the compound of formula 1b, R ₁ is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen and R ₈ is alkyl, heteroalkyl, aryl or heteroaryl , R ₂ is an electron withdrawing group, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is defined as acyl. In one embodiment, R ₁ is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen, R ₈ is aryl or heteroaryl, R ₂ is halogen, R ₃ , R ₄ and R ₅ is hydrogen and R ₆ is an acyl group of the formula C (O) (CH ₂ ) _n CH ₃ , where n is an integer ranging from 0 to about 5. In one embodiment, the substituent R ₁ is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen and R ₈ is heteroaryl, R ₂ is fluorine (F), and R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is an acyl group of the formula C (O) CH ₃ .
In another embodiment, in the substituents of the compound of formula 1b, R ₁ is C (O) OR ₉ , wherein R ₉ is alkyl, heteroalkyl, aryl or heteroaryl, and R ₂ is an electron withdrawing group R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is defined as acyl. In one embodiment, R ₁ in the substituent is C (O) OR ₉ , wherein R ₉ is alkyl or heteroalkyl, R ₂ is halogen, R ₃ , R ₄ and R ₅ are hydrogen, R ₆ is an acyl group of the formula C (O) (CH ₂ ) _n CH ₃ , wherein n is an integer ranging from 0 to about 5. For example, in a substituent, R ₁ is C (O) OR ₉ (wherein R ₉ is alkyl), R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is formula C (O) CH ₃ is an acyl group.
In another embodiment, in the substituent of the compound of formula 1b, R ₁ is C (O) R ₁₀ , wherein R ₁₀ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, and R ₂ is electron Is a trailing group, R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is defined as acyl. In one embodiment, R ₁ in the substituent is C (O) R ₁₀ , wherein R ₁₀ is alkyl or aryl, R ₂ is halogen, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is an acyl group of formula C (O) (CH ₂ ) _n CH ₃ , wherein n is an integer from 0 to about 5. For example, in the substituent, R ₁ is C (O) R ₁₀ (wherein R ₁₀ is alkyl), R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is formula C (O) CH ₃ is an acyl group.
In another embodiment, R ₁ in the substituent of the compound of formula 1b is SR ₁₁ , wherein R ₁₁ is alkyl, heteroalkyl, aryl or heteroaryl, R ₂ is an electron withdrawing group, R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is defined as acyl. In one embodiment, R ₁ in the substituent is SR ₁₁ (wherein R ₁₁ is alkyl or heteroalkyl), R ₂ is halogen, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is of the formula C (O) (CH ₂ ) _n CH ₃ is an acyl group. For example, in the substituent, R ₁ is SR ₁₁ (wherein R ₁₁ is alkyl), R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is of formula C (O) CH ₃ is acyl.
In another embodiment, in the substituent of a compound of Formula 1b, R ₁ is S (O) ₂ R ₁₁ , wherein R ₁₁ is alkyl, heteroalkyl, aryl or heteroaryl, and R ₂ attracts electrons Group, R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is defined as acyl. In one embodiment, R ₁ is S (O) ₂ R ₁₁ , wherein R ₁₁ is alkyl or heteroalkyl, R ₂ is halogen, R ₃ , R ₄ and R ₅ are hydrogen, R ₆ is an acyl group of the formula C (O) (CH ₂ ) _n CH ₃ . For example, R ₁ is S (O) ₂ R ₁₁ , wherein R ₁₁ is alkyl, R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is formula C ( O) is an acyl group of CH ₃ .
In another embodiment, in the substituents of the compound of formula 1b, R ₁ is S (O) R ₁₁ , wherein R ₁₁ is alkyl, heteroalkyl, aryl or heteroaryl, and R ₂ is an electron withdrawing group R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is defined as acyl. In one embodiment, R ₁ in the substituent is S (O) R ₁₁ , wherein R ₁₁ is alkyl or heteroalkyl, R ₂ is halogen, R ₃ , R ₄ and R ₅ are hydrogen, R ₆ is an acyl group of the formula C (O) (CH ₂ ) _n CH ₃ . For example, in the substituent, R ₁ is S (O) ₂ R ₁₁ , wherein R ₁₁ is alkyl, R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is a chemical formula It is an acyl group of C (O) CH ₃ .
In another embodiment, in the substituent of a compound of Formula 1b, R ₁ is NR ₁₂ R ₁₃ , wherein R ₁₂ is hydrogen and R ₁₃ is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, acyl or sulfonyl ), R ₂ is an electron withdrawing group, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is defined as acyl. In one embodiment, R ₁ in the substituent is NR ₁₂ R ₁₃ , wherein R ₁₂ is hydrogen, R ₁₃ is acyl or sulfonyl, R ₂ is halogen, and R ₃ , R ₄ and R ₅ are Hydrogen and R ₆ is an acyl group of the formula C (O) (CH ₂ ) _n CH ₃ , wherein n is an integer ranging from 0 to about 5. For example, R ₁ in the substituents is NR ₁₂ R ₁₃ (wherein R ₁₂ is hydrogen and R ₁₃ is acyl), R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is an acyl group of the formula C (O) CH ₃ .
In another embodiment, in the substituent of the compound of formula 1b, R ₁ is 2-oxazolyl, wherein R ₁₄ is position 4, R ₁₅ is position 5, and R ₁₄ and R ₁₅ are independently of each other , Hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group, R ₂ is an electron withdrawing group, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is acyl. In one embodiment, R ₁ in the substituents is 2-oxazolyl, wherein R ₁₄ is at position 4, R ₁₅ is at position 5, and R ₁₄ and R ₁₅ are groups that attract electrons independently of each other; , R ₂ is halogen, R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is an acyl group of the formula C (O) (CH ₂ ) _n CH ₃ . For example, R ₁ in the substituents is 2-oxazolyl, wherein R ₁₄ is at position 4, R ₁₅ is at position 5, and R ₁₄ and R ₁₅ are groups that independently draw electrons from each other, and R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is an acyl group of the formula C (O) CH ₃ .
In another embodiment, in the substituent of the compound of formula 1b, R ₁ is 2-aminothiazolyl, wherein R ₁₆ is position 4, R ₁₇ is position 5, and R ₁₆ and R ₁₇ are independent of each other Hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group, R ₂ is an electron withdrawing group, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is acyl. In one embodiment, R ₁ in the substituent is 2-aminothiazolyl, wherein R ₁₆ is at position 4, R ₁₇ is at position 5, and R ₁₆ and R ₁₇ are, independently of one another, an electron withdrawing group ), R ₂ is halogen, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is of formula C (O) (CH ₂ ) _n CH ₃ , wherein n is an integer from 0 to about 5 You know it. For example, R ₁ is 2-aminothiazolyl, wherein R ₁₆ is at position 4, R ₁₇ is at position 5, and R ₁₆ and R ₁₇ are independently of each other, an electron withdrawing group, and R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is an acyl group of the formula C (O) CH ₃ .
In another embodiment, in the substituent of a compound of Formula 1b, R ₁ is CH ₂ NR ₁₈ R ₁₉ , wherein R ₁₈ is hydrogen and R ₁₉ is alkyl, heteroalkyl, aryl, heteroaryl, acyl or sulfonyl ), R ₂ is an electron withdrawing group, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is defined as acyl. In one embodiment, R ₁ in the substituent is CH ₂ NR ₁₈ R ₁₉ , wherein R ₁₈ is hydrogen, R ₁₉ is acyl or sulfonyl, R ₂ is halogen, R ₃ , R ₄ and R ₅ is hydrogen and R ₆ is an acyl group of the formula C (O) (CH ₂ ) _n CH ₃ . For example, in the substituent, R ₁ is CH ₂ NR ₁₈ R ₁₉ (wherein R ₁₈ is hydrogen and R ₁₉ is acyl), R ₂ is fluorine, and R ₃ , R ₄ and R ₅ are hydrogen , R ₆ is an acyl group of formula C (O) CH ₃ .
Synthesis of Combinatorial Library of Oxazolidinones of Formula 1b
The present invention provides a method of preparing a combinatorial library comprising an oxazolidinone such as Formula 1b (see US Pat. No. 5,549,974 for a general discussion of combinatorial library synthesis, the entire contents of which are incorporated herein) ). In one embodiment, the method includes coupling an aryl oxazolidinone to the solid support, functionalizing the position 4 of the aryl group, and removing the oxazolidinone from the solid support.
FIG. 2 shows a method for preparing a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is C (O) NR ₇ R ₈ . Various azides (Formula 2) are reacted with phosphines to convert to the corresponding iminophosphoran. This imide is mixed with various solid phase supports containing carbonyl functional groups to produce various imines. This imine is reduced with NaBH ₃ CN or the like to obtain various amines (Formula 3). Deprotection of the ester groups of the amines of formula 3 yields various acids (Formula 4). This amine is acylated and the acid of formula 4 is activated to give various, activated esters (Formula 5). The activated ester is reacted with R ₇ R ₈ NH amine units to give various amides (Formula 6). Using the appropriate reagent (eg TFA), the amide (Formula 6) bound to the solid support is removed from the solid support to obtain various amides (Formula 7) in solution.
Various azides (Formula 2) are prepared starting from a series of substituted methylnitrobenzenes (FIG. 3, Formula 8). The methyl group of the compound of formula 8 is oxidized to give the corresponding carboxylic acid (formula 9). This acid is esterified to give a nitro ester series (Formula 10). The nitro group of the compound of formula 10 is reduced to give a series of amines (formula 11). Acylating the compound of formula 11 yields a protected amine series (formula 12). The amine (Formula 12) is reacted with a substituted epoxide to give a series of amino alcohols, which are cyclized to give a series of oxazolidinones (Formula 13). Azide (Formula 2) is obtained by replacing the primary alcohol of the compound of Formula 13.
4 is R_OneThis C (O) NR₇R₈(From here, R₇Is hydrogen, R₈Is alkyl, heteroalkyl, aryl, or heteroaryl), R₂Is fluorine and R₃, R₄And R₅Is hydrogen and R₆This chemical formula C (O) CH₃An exemplary method for producing a combinatorial library comprising an oxazolidinone of formula (Ib) which is an acyl group of is shown. Various azides (Formula 14) are converted to the corresponding iminophosphoran using triphenylphosphine. This iminophosphoran is mixed with various 5-formyldimethoxyphenoxybutyric acid resin beads (BAL resin beads, manufactured by Novabiochem) to prepare various imines. NaBH immigration₃Reduction with CN affords various amines (Formula 15). Trimethylsilylchloride (TMSCl) is used to deprotect the ester group of the amine of formula 15 to give various acids (Formula 16). Amine Ac₂Acylating with O and acid PfpOCOCF₃Activated to obtain various, activated esters (Formula 17). Activated Ester R₇R₈Reaction with NH units gives various amides (Formula 18). TFA is used to separate the amide (Formula 18) bound to the solid support from the solid support to obtain various amides (Formula 19) in solution. FIG. 47 is an amine structure block R that can be used for the synthesis of oxazolidinone libraries and compounds as shown in FIG.₇R₈NH is shown.
FIG. 5 shows an exemplary method of making a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is C (O) OR ₉ or C (O) R ₁₀ . The acid (Formula 4) bound to the various, solid support is converted to the activated acid (Formula 20). To prepare an oxazolidinone library wherein R ₁ is C (O) OR ₉ , the activated acid (Formula 20) is reacted with R ₉ OH units to obtain various esters (Formula 21). Treatment with the appropriate reagent removes this ester from the solid support to give various amides (Formula 22) in solution. To prepare an oxazolidinone library in which R ₁ is C (O) R ₁₀ , the activated acid (Formula 20) is reacted with an amine to obtain various Weinreb amides (Formula 23). Wainrepe amide is reacted with organometallic units (eg LiAlH ₄ or MeMgBr) to obtain various ketones (Formula 24). Treatment with the appropriate reagent removes this ketone (Formula 24) from the solid support to obtain various ketones (Formula 25) in solution.
6 shows an exemplary method of making a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is SR ₁₁ . Various azides (Formula 26) are reacted with phosphines to convert to the corresponding iminophosphoran. This iminophosphoran is mixed with various solid phase supports containing carbonyl functional groups to obtain various imines. This imine is reduced to give various amines (Formula 27). This amine is acylated and the deprotection of the sulfide of formula 27 yields various thiols (formula 28). The compound of formula 28 is alkylated using an electrophile to obtain various sulfides (formula 29). Using a suitable reagent, the sulfide (Formula 29) bound to the solid support is removed from the solid support to obtain various sulfides (Formula 30) in solution. Another embodiment is shown in FIG. 41. 44 and 45 are structural blocks R ₂ X that can be used to synthesize the sulfide oxazolidinone libraries and compounds shown in FIG. 41 and may also be used as R ₁₁ X in the synthesis shown in FIG. 6, where X is halo. Im).
FIG. 7 shows an exemplary method of making a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is S (O) R ₁₁ or S (O) ₂ R ₁₁ . To prepare an oxazolidinone library in which R ₁ is S (O) R ₁₁ , sulfides (Formula 29) bound to various, solid supports are converted to various sulfoxides (Formula 31). Treatment with the appropriate reagents removes the sulfoxide from the solid support to obtain various sulfoxides (Formula 32) in solution. To prepare an oxazolidinone library wherein R ₁ is S (O) ₂ R ₁₁ , sulfides (Formula 29) bound to various, solid supports are converted to various sulfones (Formula 33). Treatment with the appropriate reagents removes the sulfone from the solid support to obtain various sulfones (Formula 34) in solution.
Various azides (formula 26) are prepared starting from a series of substituted anilines (formula 35). Electrophilic aromatic substitution of position 4 of the aniline gives an isothiocyanate series (formula 36). The amine portion of the compound of formula 36 is protected to give the compound of formula 37. The isothiocyanate group of the compound of formula 37 is reacted with sodium sulfide and trityl bromide to obtain a protected sulfide series (formula 38). The protected aniline of formula 38 is reacted with a substituted epoxide and cyclized to give an oxazolidinone series (formula 39). The primary alcohol of the compound of formula 39 is converted to an azide to give an azide series (formula 26) (see FIG. 8).
9 shows an exemplary method of preparing a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is NR ₁₂ R ₁₃ . Azides (Formula 5) bound to various, solid supports, containing activated ester groups, are converted to various Acyl Azides (Formula 40). Reaction with acyl azide is carried out to obtain various protected anilines (formula 41). Deprotection of the compound of formula 41 yields various anilines (formula 42), which are reacted with electrophilic units R ₁₂ X and R ₁₃ X to give various substituted anilines (formula 43). Using a suitable reagent, the substituted aniline (Formula 43) bound to the solid support is removed from the solid support to obtain various substituted anilines (Formula 44) in solution. Another embodiment is shown in FIG. 39, which is a scheme showing the synthesis of acylamino oxazolidinone compounds and libraries wherein R ₁ and R ₂ are substituents such as H, alkyl, heteroalkyl, aryl, heteroaryl, or alkoxy. . 42 and 43 illustrate structural blocks R ₂ COOH that can be used for the synthesis of acylamino oxazolidinone libraries and compounds as shown in FIG. 39 and can also be used for other synthesis, such as the synthesis shown in FIG. 9.
FIG. 10 shows an exemplary method for preparing a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is 2-oxazolyl having a cyano group at position 4 and an amino group at position 5. Various azides (Formula 2) are reacted with phosphines to convert to the corresponding iminophosphoran. This lide is mixed with various solid phase supports containing carbonyl functional groups to obtain various amines (Formula 3). Deprotection of the ester groups of the compounds of formula 3 yields various carboxylic acids. Acylating the amine and activating the carboxylic acid yields various esters (Formula 5). The compound of formula 5 is reacted with amino malonitrile to give various oxazoles (formula 45). Using the appropriate reagent, the oxazole bound to the solid support is removed from the solid support to obtain various oxazoles (Formula 46) in solution.
Of Figure 11 is R ₁ is R ₁₄ is located in the 4-position, or 2-oxazolyl that R ₁₅ in the 5-position furnace cyano at the 4-position, and, R ₁₅ is 2-oxazolyl 5-position in the formula An exemplary method of making a combinatorial library comprising the oxazolidinone of 1b is shown. R ₁ is and R ₁₄ is in position 4, to produce a 2-oxazolyl the oxazolidinone library with R ₁₅ in the 5-position, different, the oxazole (Formula 45) coupled to a solid support, 4 A variety of oxazole compounds (Formula 47) are obtained by reacting a cyano group at position 1 with a reagent that can be converted to another functional group (eg, hydrolyzed to an acid). The amino substituent at position 5 of the compound of formula 47 is alkylated or acylated to give various compounds (Formula 48). Using a suitable reagent, the oxazole (Formula 48) bound to the solid support is removed from the solid support to obtain various R ₁₄ , R ₁₅ -substituted oxazoles (Formula 49) in solution. To prepare an oxazolidinone library wherein R ₁ is cyano at position 4 and 2-oxazolyl having R ₁₅ at position 5, the amino substituent at position 5 of the compound of formula 45 is alkylated or acylated. To obtain various compounds (Formula 50). Using appropriate reagents, the oxazole (Formula 50) bound to the solid support is removed from the solid support to obtain various cyano, R ₁₅ substituted oxazoles (Formula 51) in solution.
Figure 12 is R ₁ is R ₁₆ is located in position 4, illustrates an exemplary method of manufacturing a combinatorial library containing a 2-amino-thiazolyl of the oxazolidinone of Formula 1b with R ₁₇ in the 5-position. A variety of protected thiocarbamates (Formula 52) are obtained by reacting various anilines (Formula 42) with protected isothiocyanates. Decarbohydrate this carbamate to obtain various carbamate (Formula 53). The compound of formula 53 is reacted with a-halo ketone to give various aminothiazoles (Formula 54). Using appropriate reagents, the aminothiazole bound to the solid support is removed from the solid support to obtain various aminothiazoles (55) as a solution.
FIG. 13 shows an exemplary method for preparing a combinatorial library comprising an oxazolidinone of Formula 1b wherein R ₁ is CH ₂ NR ₁₈ R ₁₉ . Various azides (Formula 56) are reacted with phosphines to convert to the corresponding iminophosphoran. This iminophosphoran is mixed with various solid phase supports to produce various imines. The imine is reduced and acylated to give a variety of acetals (Formula 57). Acetal is removed to obtain various aldehydes (Formula 58). Reductive amination of the aldehyde yields various amines (Formula 59). Using the appropriate reagent, the amine bound to the solid support is removed from the solid support to obtain various amines (Formula 60) in solution.
Various azides (Formula 67) are prepared starting from a substituted methylnitrobenzene series (FIG. 14, Formula 61). The methyl group of the compound of formula 61 is oxidized to give acetal (Formula 62). Acetal exchange reaction of the compound of formula 62 yields a dimethyl acetal series (Formula 63). The nitro group of the compound of formula 63 is reduced to yield the aniline of formula 64, which is a protected compound of formula 65. The protected aniline is reacted with a substituted epoxide and the amino alcohol obtained is cyclized to give an oxazolidinone series (Formula 66). The primary alcohol of the compound of formula 66 is replaced with an azide to give the compound of formula 67.
Embodiments of Biologically Active Oxazolidinone Compounds
In one embodiment, there are provided oxazolidinones that are biologically active, for example antibiotic activity, such as oxazolidinones of Formula 1b.
<Formula 1b>

In one embodiment, the substituents of the compound of Formula 1b are as follows: The substituents R ₁ of the compound of Formula 1b are C (O) NR ₇ R ₈ , wherein R ₇ and R ₈ are independently of each other hydrogen, Alkyl, heteroalkyl, aryl or heteroaryl), C (O) OR ₉ (wherein R ₉ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), C (O) R ₁₀ (where R ₁₀ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, SR ₁₁ (herein R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), S (O) ₂ R ₁₁ (here, R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, S (O) R ₁₁ , wherein R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, NR ₁₂ R ₁₃ (here R ₁₂ and R ₁₃ are each independently hydrogen, acyl, sulfonyl, alkyl, heteroalkyl, aryl or heteroaryl, 2-oxazolyl, wherein R ₁₄ is in position 4 and R ₁₅ Is at position 5, R ₁₄ and R ₁₅ are, independently from each other, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or an electron withdrawing group, 2-aminothiazolyl, wherein R ₁₆ is position 4 R ₁₇ is in position 5, R ₁₆ and R ₁₇ are, independently of each other, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or an electron withdrawing group, and CH ₂ NR ₁₈ R ₁₉ , wherein , R ₁₈ and R ₁₉ are, independently from each other, one of the functional groups of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, acyl or sulfonyl. Substituents R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group and R ₆ is acyl or sulfonyl.
In one embodiment, the biologically active oxazolidinone of Formula 1b is substituted as follows: R ₁ is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen, R ₈ is alkyl, Heteroalkyl, aryl or heteroaryl), R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is an acyl group of formula C (O) CH ₃ . In one embodiment, the oxazolidinone is substituted as follows: R ₁ is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen and R ₈ is aryl or heteroaryl, and R _Di is fluorine, R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is an acyl group of the formula C (O) CH ₃ . In another embodiment, the oxazolidinone is substituted as follows: R ₁ is C (O) NR ₇ R ₈ , wherein R ₇ is hydrogen and R ₈ is heteroaryl, and R ₂ is Fluorine, R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is an acyl group of the formula C (O) CH ₃ .
In another embodiment, the biologically active oxazolidinone of Formula 1b is substituted as follows: R ₁ has a cyano group at position 4 of the oxazole and an amino group at position 5 of the oxazole -Oxazolyl, R ₂ and R ₄ are, independently of one another, hydrogen or electron withdrawing groups, R ₃ and R ₅ are hydrogen, and R ₆ is acyl or sulfonyl. For example, oxazolidinone is substituted as follows: R ₁ is 2-oxazolyl having a cyano group at position 4 of oxazole, an amino group at position 5 of oxazole, and R ₂ is halogen R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is an acyl group. In another embodiment, the oxazolidinone is substituted as follows: R ₁ is 2-oxazolyl having a cyano group at position 4 of the oxazole, an amino group at position 5 of the oxazole, and R ₂ Is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is an acyl group of the formula C (O) CH ₃ .
In another embodiment, the biologically active oxazolidinone of Formula 1b is substituted as follows: R ₁ is 2-aminothiazolyl, wherein R ₁₆ is at position 4 of the thiazole and is number 5 R _17, and the on position, R ₁₆ and R ₁₇ are independently of each other, hydrogen, alkyl, aryl, or heteroaryl), R ₂ and R ₄ are independently from each other, and withdrawing group hydrogen or an electron, R ₃ And R ₅ is hydrogen and R ₆ is acyl. For example, oxazolidinone is substituted as follows: R ₁ is 2-aminothiazolyl, wherein R ₁₆ is at position 4 of the thiazole, R ₁₇ is at position 5, and R ₁₆ And R ₁₇ are, independently of each other, hydrogen, alkyl or aryl), R ₂ is halogen, R ₃ , R ₄ and R ₅ are hydrogen and R ₆ is an acyl group of formula C (O) CH ₃ . In another embodiment, the oxazolidinone is substituted as follows: R ₁ is 2-aminothiazolyl, wherein R ₁₆ is at position 4 of the thiazole and R ₁₇ is located at position 5, R ₁₆ and R ₁₇ are, independently of each other, hydrogen or aryl), R ₂ is fluorine, R ₃ , R ₄ and R ₅ are hydrogen, and R ₆ is an acyl group of formula C (O) CH ₃ .
Synthesis of Biologically Active Oxazolidinone Compound (Formula 1b)
Exemplary methods of solid phase synthesis of biologically active oxazolidinones having structures such as Formula 1b are provided herein. This method comprises the steps of preparing an iminophosphoran, mixing iminophosphoran with a resin containing a carbonyl group to form an imine intermediate, and reducing the imine intermediate to obtain a compound bound to the resin via an amine linker. It includes.
15 shows solid phase synthesis of a typical oxazolidinone compound. Oxazolidinone (Formula 68) in which R ₂₀ is (4-R ₁ ) -aryl (Formula 1) is treated with two routes, namely 1) an azide of formula 68 with phosphine (R ₂₁ is alkyl or aryl) To prepare iminophosphorane (Formula 69) and react it with a resin containing carbonyl, or 2) reduce the azide of formula 68 to an amine (Formula 70), Reaction to convert to imine (Formula 71). Reduction of imine (Formula 71) using an appropriate reducing agent (eg, NaBH ₃ CN) affords the compound (Formula 72) bound to the resin via an amine linker.
16 shows the general synthesis of compounds of formula 68. The epoxide (formula 73) is subjected to a nucleophilic attack with R ₂₀ NH ₂ to obtain an amino alcohol. This amino alcohol is cyclized to give oxazolidinone (Formula 74). The ester protecting group of formula 74 is removed to give the primary alcohol (formula 75). This primary alcohol is replaced with an azide to give a compound of formula 68.
Resin containing carbonyl is shown in FIG. 15. Substituent R ₂₃ is hydrogen, alkyl, aryl, O-alkyl or O-aryl. Polymeric supports (blacked out circles) include, but are not limited to, tenagel, (crosslinked) polystyrene, (crosslinked) polyethyleneglycol, poly-ethyleneglycol-polystyrene compositions, and polyacrylates . The substituent R ₂₂ is shown in FIG. 17, wherein R ₂₄ is hydrogen, CH ₃ O or NO ₂ , and R ₂₅ is (CH ₂ ) _n CONH where n is an integer ranging from 1 to about 5.
18 illustrates one embodiment of a solid phase synthesis method. Azide (Formula 14) is converted to iminophosphoran by treatment with triphenylphosphine. Iminophosphorane is reacted with BAL resin to obtain imine, which is reduced with NaBH ₃ CN to give an amine (Formula 15). The compound of Formula 15 is reacted with TMSCl to remove the ester group (Formula 16). The amine of formula 16 is acylated and the carboxylic acid is converted to an activated ester (formula 17). Treatment of activated esters with Bu ₄ NN ₃ or TMSN ₃ gives acyl azide (Formula 77). The reaction is carried out to an acyl azide (Formula 77) to obtain a protected aniline (Formula 78). The Fmoc protecting group is removed (Formula 79) and the resulting aniline is sulfonated with pO ₂ NC ₆ H ₄ SO ₂ Cl (Formula 80). The sulfonated aniline (formula 80) is reacted with TFA to separate from the solid phase support to afford the compound of formula 81. Another embodiment is shown in FIG. 40. FIG. 46 depicts sulfonyl chloride structural blocks R ₂ SO ₂ Cl that can be used in the preparation of the sulfonamide oxazolidinone libraries and compounds shown in FIG. 40, and can also be used in the synthesis shown in FIG.
19 shows another embodiment of a solid phase synthesis method. Aniline (Formula 79) is reacted with Fmoc-N = C = S to afford protected thiourea (Formula 82). This protected thiourea is treated with piperidine to obtain deprotected thiocarbamate (Formula 83). The compound of formula 83 is reacted with 2-bromoacetophenone to give thiazole (Formula 84). The compound of formula 84 is treated with TFA to separate the thiazole from the solid support to obtain the compound of formula 85.
20 shows another embodiment of a solid phase synthesis method. Azide (Formula 4) is converted to iminophosphoran by treatment with triphenylphosphine. Iminophosphorane is reacted with BAL resin to prepare imine. This imine is reduced with NaBH ₃ CN to give the amine (Formula 15) bound to the solid phase support. The ester of the compound of formula 15 is deprotected using TMSCl to give a carboxylic acid, the amine is then acylated by reaction with Ac ₂ O, and the acid is activated using PfpOCOCF ₃ to obtain the compound of formula 17. The compound of formula 17 is reacted with aminomalonitrile to give oxazole (formula 86). The compound of formula 86 is treated with TFA to separate the oxazole from the solid phase support to afford the compound of formula 87.
21 shows two embodiments of a solid phase synthesis method. The compound of formula 17 is treated with HN (OCH ₃ ) CH ₃ to obtain wainleb amide (Formula 88). The amide (Formula 88) is reduced with LiAlH ₄ to obtain an aldehyde (Formula 89) or by reacting with Grignard reagent MeMgI to obtain a ketone (Formula 91). Aldehyde (formula 89) or ketone (formula 91) is treated with TFA, respectively, to obtain the separated products of formula 90 and 92.
22 illustrates two embodiments of a solid phase synthesis method. Treatment of the compound of formula 79 with dialdehyde gives morpholine (Formula 93), or with diacetal to give pyrrole (Formula 95). Morpholine (Formula 93) or pyrrole (Formula 95) is treated with TFA, respectively, to obtain isolated products of formula 94 and 96.
FIG. 48 shows structural blocks R ₂ R ₃ NH and R ₁ COOH that can be used to prepare exemplary oxazolidinone compounds of Formula 1k and libraries thereof. FIG.
Synthesis of Oxazolidinone Compound (Formula 1a)
Oxazolidinone compounds (formula 1a) and precursors thereof can be prepared by various methods as described herein.
An embodiment of a solid phase synthesis process for preparing amino alcohols wherein R ₁ is alkyl is shown in FIG. 23. An olefin group is bonded to the surface of the solid support (Formula 5a) to prepare a functionalized resin (Formula 6a). This olefin has "m" of 0, 1 or 2, "n" of 0, 1 or 2, and R ₁₀ , R ₁₁ , R ₁₂ , R ₂ and R ₃ are independently of each other hydrogen, alkyl, heteroalkyl , Aryl or heteroaryl. This olefin is chemically modified to obtain an epoxide (Formula 7a). Substituted amines are added to the terminal carbon of the immobilized epoxide (Formula 7a) to obtain amino alcohols (Formula 8a) bound to the solid phase support. The alcohol bound to the solid support (Formula 8a) is treated with a phosgene equivalent to give oxazolidinone (Formula 15a), which is separated under standard conditions to give free oxazolidinone (Formula 16a). Acylating the compound of Formula 16a affords oxazolidinone (Formula 16b).
Another embodiment of a solid phase synthesis process for preparing oxazolidinone is shown in FIG. 24. The immobilized epoxide (Formula 12a) is treated with aniline in the presence of lithium triflate to afford amino alcohol (19a), which is bound to a solid support. The compound of formula 19a is reacted with CDI to give oxazolidinone (formula 20a). Alternatively, the compound of formula 20a was prepared directly by treating the epoxide (Formula 12a) with the lithium salt of aniline benzylcarbamate. TFA is added to oxazolidinone (Formula 20a) to give free oxazolidinone (Formula 21a), which is acetylated to give acetamide (Formula 22a).
Another embodiment of a solid phase synthesis process for preparing oxazolidinone is shown in FIG. 25. PNP Wang resin (Formula 23a) was reacted with allyl amine to give carbamate (Formula 24a). Terminal olefins of carbamate (Formula 24a) are oxidized using mCPBA to obtain immobilized epoxide (Formula 12a). 3-Fluoro-4-morpholinoaniline is added to the compound of formula 12a to inhibit the amino alcohol (Formula 25a), which is treated with CDI to cyclize to give oxazolidinone (Formula 26a). The compound of formula 26a is reacted with TFA to give the free amine (Formula 27a). Acetyl chloride is added to the compound of formula 27a to obtain acetamide (Formula 28a).
Synthesis of Combinatorial Library Containing Oxazolidinone of Formula 1a
In one embodiment, there is provided a method of synthesizing a combinatorial library comprising oxazolidinone of Formula 1a and a composition formed by the method. In one embodiment, oxazolidinone (Formula 1a) has a structure of Formula 1a.
<Formula 1a>

Where
R ₁ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl,
R ₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₃ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₁ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
An embodiment of a solid phase process for preparing an oxazolidinone library wherein R ₁ is an alkyl group is described with reference to FIG. 23. Olefin groups are bonded to the surfaces of various solid phase supports (Formula 5a) to obtain functionalized resins (Formula 6a). This olefin group has "m" of 0, 1 or 2, "n" of 0, 1 or 2, and R ₂ , R ₃ , R ₁₀ , R ₁₁ and R ₁₂ are independently of each other hydrogen, alkyl, heteroalkyl , Aryl or heteroaryl. Each olefin group is chemically modified to give an epoxide (Formula 7a). Another amine unit is added to the terminal carbon of the epoxide (Formula 7a) to obtain various amino alcohols (Formula 8a).
The amino alcohols (Formula 8a) bound to the various solid phase supports are treated with phosgene equivalents to obtain various oxazolidinones (Formula 15a), which are separated under standard conditions to give free oxazolidinones (Formula 16a).
Another embodiment of a solid phase process for preparing an oxazolidinone library is shown in FIGS. 26 and 27. The carboxylic acid (Formula 30a) is bonded to the amine resin (Formula 29a) to give the amide (Formula 31a). Reductive amination of the compound of Formula 31a using an amine (Formula 32a) yields a functionalized amine (Formula 33a), which is placed in a separate reaction chamber arrangement. Sulfonyl chloride units are added to various amines (Formula 33a) to obtain sulfonamides (Formula 34a). Sulfonamides are separated from the solid phase support under standard conditions to obtain various free sulfonamides (formula 35a). Carboxylic acid or carboxylic acid derivative units are added to various amines (Formula 33a) to give amides (Formula 36a). The amide (Formula 36a) is separated from the solid support under standard conditions to obtain various free amides (Formula 37a). Isocyanate units are added to amine (Formula 33a) to obtain urea (Formula 38a). Urea (Formula 38a) is separated from the solid phase support under standard conditions to obtain various free ureas (Formula 39a).
Another embodiment of a solid phase method of making an oxazolidinone library is shown in FIG. 28. Coupling α-bromo acetic acid with an amine (Formula 33a) yields an amide (Formula 40a), which is divided into separate reaction chamber arrangements. Nucleophilic addition of thiol units to various amides (Formula 40a) affords α-thioamides (Formula 41a), which are treated with TFA to separate from the solid phase support to obtain various free α-thioamides (Formula 42a). Nucleophilic addition of triphenylphosphine to various amides (Formula 40a) yielded the Wittig reagent bound to the solid phase support, which was then coupled with aldehyde units to give various α, β-unsaturated amides (Formula 43a). The amide was treated with TFA to separate it from the solid support to obtain various free α, β-unsaturated amides (Formula 44a). Nucleophilic addition of various amides (Formula 40a) with amines gave α-amino amides (Formula 45a), which were treated with TFA to separate from the solid phase support to give various free α-amino amides (Formula 46a).
3- (multi-substituted) oxazolidinones
Optionally, various 3- (multisubstituted) oxazolidinones having biological activity such as antimicrobial activity are provided.
In one embodiment, there is provided a combinatorial library comprising this compound as well as 3- (multiply substituted) oxazolidinone (Formula 2c).
In one embodiment of the above formula,
R ₆ is acyl or sulfonyl,
R ₇ is aryl or heteroaryl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, NRC (= 0), C (= 0), C (= 0) O, OC (= 0), S ( = O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ', or (CH ₂ ) _n O, where n is 0 to 6 and R and R' are independently of each other, H, or C _1- Alkyl such as C ₇ alkyl, or a substituent such as heteroalkyl, aryl or heteroaryl,
R ₉ is hydrogen, OH, alkyl, aryl, heteroalkyl, or heteroaryl.
In another embodiment, 3- [4- (heteroaryl) aminocarbonylaryl] oxazolidinone and 3- [4- (N-oxide heteroaryl) aminocarbonylaryl] oxazolidinone are provided.
In one embodiment of Formula 2c,
R ₆ is C (═O) R, wherein R is H or alkyl of C ₁ -C ₇ alkyl such as methyl or ethyl, or a substituent such as heteroalkyl, aryl or heteroaryl,
R ₇ is aryl,
R ₈ is an amide group such as NH (C═O) or NR ′ (C═O), wherein R ′ is alkyl such as H, heteroalkyl, aryl, heteroaryl or C ₁ -C ₇ such as methyl ,
R ₉ is a heteroaryl group such as hydrogen or a substituted or unsubstituted heteroaryl group, and heteroaryl groups include pyridinyl, thiazolyl, benzothiazolyl, isothiazolyl, quinolinyl, 1,3,4-triazolyl Or 1,3,4-thiadiazolyl.
For example, a compound of Formula 2d is provided.
Where
R ₉ is hydrogen or a heteroaryl group such as pyridinyl, thiazolyl, benzothiazolyl, quinolinyl, 1,3,4-triazolyl or 1,3,4-thiadiazolyl, substituted or unsubstituted,
R and R 'are, independently of each other, H, or alkyl of C ₁ -C ₇ alkyl such as methyl, or heteroalkyl, aryl or heteroaryl.
Exemplary compounds are shown below.
In one embodiment, standard whole cell assays described herein are used to provide the following nine preferred compounds having a MIC for S. aureus of about 0.5-1 μg / mL.


The following nine preferred compounds are also provided having a MIC of about 2-4 μg / mL for S. aureus using standard whole cell assays described herein.


In addition, the following compounds are also provided.

Another exemplary oxazolidinone compound falling within the scope of the present invention is shown below.


R ₆ is also an acyl group, such as C (═O) R, wherein R is H, or alkyl such as C ₁ -C ₇ alkyl, including methyl, or heteroalkyl, aryl, or heteroaryl. ₇ is aryl, R ₈ is NH (C═O), and R ₉ is hydrogen or OH to provide 3- (aminocarbonyl) oxazolidinone of formula 2c.
Exemplary compounds are shown below.


In one embodiment, the standard whole cell assay described herein provides the following compounds having a MIC of about 0.5 μg / mL for S. aureus.

3-[(substituted) aryl] oxazolidinones
Optionally, 3-[(substituted) aryl] oxazolidinone is provided as biologically active, for example as an antimicrobial compound.
In one embodiment, there is provided a combinatorial library comprising an oxazolidinone of Formula 3c and a compound of Formula 3c.
In one embodiment of the above formula,
R ₂ , R ₃ , R ₅ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, NRC (= 0), C (= 0), C (= 0) O, OC (= 0), S ( = O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ', or (CH ₂ ) _n O, where n is 0 to 6 and R and R' are independently of each other, H, or C _1- Alkyl, such as C ₇ alkyl, or heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroaryl or heteroaryl.
In another embodiment, 3- [4- (alkylthio) aryl] oxazolidinone is provided. For example, provided is a compound of Formula 3c, wherein
R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl, such as C (═O) CH ₃ ,
R ₇ is an aryl group,
R ₈ is the same thio group as S
R ₉ is a heteroalkyl group.
In another embodiment, a compound of Formula 3d is provided.
Where
R ₉ is alkyl, aryl, heteroalkyl, or heteroaryl,
R 'is a substituent such as H, or alkyl, heteroalkyl, aryl or heteroaryl, such as C ₁ -C ₇ alkyl.
Exemplary compounds are shown below.
In one preferred embodiment, the following three compounds are provided having a MIC of about 2 μg / mL for S. aureus using standard whole cell assays described herein.

In another embodiment, the following four compounds are provided having a MIC of about 8 μg / mL for S. aureus using standard whole cell assays described herein.


In addition, the following compounds are provided.

In another embodiment, 3- [4- (ester group) aryl] oxazolidinones useful as antibacterial agents are provided. For example, provided is a compound of Formula 3c, wherein
R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is an acyl group, such as C (═O) CH ₃ ,
R ₈ is an ester such as OC (═O),
R ₉ is an alkyl group such as a C ₁ -C ₇ alkyl group.
In one embodiment, a compound of Formula 3e is provided.
Where
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl,
R 'is H, or an alkyl such as C ₁ -C ₇ alkyl, or a substituent such as heteroalkyl, aryl or heteroaryl.
Exemplary compounds have the following structure.

3-[(substituted) heteroaryl] oxazolidinones
In another embodiment, various 3-[(substituted) heteroaryl] oxazolidinones are optionally provided that are biologically active as antimicrobial compounds.
In one embodiment, a compound of Formula 4c and a combinatorial library thereof are provided.
In one embodiment of 4c,
R ₆ is acyl or sulfonyl,
Het ₁ is a heterocyclic group such as a substituted or unsubstituted heteroaryl such as thienylphenyl, thiazolyl, 1,3,4-thiadiazole, pyridinyl, or pyrimidinyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, or alkyl, such as C ₁ -C ₇ alkyl, or heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl.
In formula (4c), the substituents on the heteroaryl group Het ₁ are independently of each other hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OH, OR " , SR ", S (= O) R", SO ₂ R ", C (= O) R", C (= O) OR ", OC (= O) R", C (= O) NR "R"', N (R ") C (= O) R"' , or an N- oxide group Het ₁ in the nucleus, R "and R"'are, independently, H, or C ₁ -C ₇ alkyl, such as one another Alkyl, or heteroalkyl, aryl or heteroaryl.
3- [4- (linked heteroaryl) aryl] oxazolidinone
In another embodiment, there is optionally provided a biologically active 3- [4- (linked heteroaryl) aryl] oxazolidinone as an antimicrobial compound.
For example, a compound of Formula 5c and a combinatorial library thereof are provided.
In one embodiment of the above formula,
R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, NRC (= 0), C (= 0) NOR, C (= 0) O, OC (= 0), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, or C ₁ − Alkyl, such as C ₇ alkyl, or heteroalkyl, aryl or heteroaryl,
Het ₂ is oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, thienylphenyl, thiazolyl, isothiazolyl , 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4- Heterocyclic groups such as substituted or unsubstituted heterocyclic groups such as triazinyl, 1,3,5-triazinyl or 1,2,4,5-tetrazinyl,
Substituents on the heteroaryl group Het ₂ are independently of each other hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OH, OR ", SR", S (= O) R ", SO ₂ R", C (= O) R ", C (= O) OR", OC (= O) R ", C (= O) NR" R "', N ( R ″) C (═O) R ″ ′ or an N-oxide group in the Het ₂ nucleus, wherein R ″ and R ″ ′ are independently of each other, H, or alkyl such as C ₁ -C ₇ alkyl, Or heteroalkyl, aryl or heteroaryl substituents.
In another embodiment, there is provided 3- [4- (linked heteroaryl) aryl] oxazolidinone of Formula 5c, optionally with antimicrobial activity, wherein
R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl, such as C (═O) CH ₃ ,
R ₇ is an aryl group,
R ₈ is the same thio group as S
Het ₂ is a substituted or unsubstituted thienylphenyl or thiazolyl heteroaryl group.
Also provided is a compound of formula 5d.
Where
Het ₂ is a substituted or unsubstituted thienylphenyl or thiazolyl heteroaryl group,
R ′ is H, or alkyl such as C ₁ -C ₇ alkyl, or heteroalkyl, aryl, or heteroaryl.
Exemplary compounds are shown below.


In another embodiment, optionally provided is an antibacterial compound, 3- [4- (triazinylamino) aryl] oxazolidinone. For example, R ₂ , R ₃ , R ₄ and R ₅ are independently of each other hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl, such as C (═O) CH ₃ ,
R ₈ is an amino group such as NH,
Het ₂ provides a compound of Formula 5c which is 1,3,5-triazinyl.
Also provided is a compound of formula 5e.
Where
Het ₂ is substituted or unsubstituted 1,3,5-triazinyl,
R 'is H, or alkyl such as C ₁ -C ₇ alkyl, or heteroalkyl, aryl or heteroaryl.
Exemplary compounds are shown below.


3- [4- (linked heteroaryl) heteroaryl] oxazolidinone
In another embodiment, there is optionally provided a biologically active 3- [4- (bonded heteroaryl) heteroaryl] oxazolidinone as an antimicrobial compound.
For example, the following compounds of Formula 6c and their combinatorial libraries are provided.
In one embodiment of the above formula,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, NRC (= 0), C (= 0) NOR, C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, or alkyl, such as C ₁ -C ₇ alkyl, or a substituent of heteroalkyl, aryl or heteroaryl,
Het ₁ is a heterocyclic group such as a substituted or unsubstituted heterocyclic group such as thienylphenyl, thiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, phenyl or fluorophenyl,
Substituents on the heteroaryl group Het ₁ are independently of each other hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S ( = O) R ", SO ₂ R", C (= O) R ", C (= O) OR", OC (= O) R ", C (= O) NR" R "', N (R" ) C (= O) R "', or an N- oxide group Het ₁ in the nucleus, R" and R "' are independently of each other, alkyl, such as H, or C ₁ -C ₇ alkyl, or heteroalkyl , Aryl or heteroaryl.
Het ₂ is oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, thienylphenyl, thiazolyl, isothiazolyl , 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4- Substituted or unsubstituted heterocyclic preferred hetero aryl groups such as triazinyl, 1,3,5-triazinyl or 1,2,4,5-tetrazinyl,
Substituents on the heteroaryl group Het ₂ independently of one another are hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing groups, F, Cl, CN, NO ₂ , NR _x R _y , OH, OR _x , SR _x , S (= O) R _x , SO ₂ R _x , C (= O) R _x , C (= O) OR _x , OC (= O) R _x , C (= O) NR _x R _y , N (R _x ) C (= 0) R _y or an N-oxide group in the Het ₂ nucleus, wherein R _x and R _y are, independently from each other, alkyl such as H, or C ₁ -C ₇ alkyl, or heteroalkyl, Substituents of aryl or heteroaryl.
3- (substituted pyridyl) oxazolidinones
It also optionally provides a biologically active 3- (substituted pyridyl) oxazolidinone as an antimicrobial compound.
In one embodiment, there is provided a compound of Formula 7c or 8c and a combinatorial library thereof.
In one embodiment of the above formula,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, or alkyl, such as C ₁ -C ₇ alkyl, or a substituent of heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl, or heteroaryl,
R ₁₀ , R ₁₁ and R ₁₂ independently of one another are hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing groups, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S ( = O) R ", SO ₂ R", C (= O) R ", C (= O) OR", OC (= O) R ", C (= O) NR" R "', N (R" ) C (= O) R "' is a group or pyridine-N- oxide in the nucleus, R" and R "' are independently of each other, H, or C ₁ -C ₇ alkyl, such as alkyl, or heterocyclic alkyl, aryl Or a heteroaryl substituent.
3- (substituted pyrimidinyl) oxazolidinones
Optionally, various 3- (substituted pyrimidinyl) oxazolidinones are also provided that have biological activity such as antimicrobial activity.
In one embodiment, there are provided compounds of Formulas 9c and 10c, and combination libraries thereof.

In one embodiment of the above formula,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, or alkyl, such as C ₁ -C ₇ alkyl, or heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl, or heteroaryl,
R ₁₀ and R ₁₁ are independently of each other hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S (= 0) R ", SO ₂ R", C (= O) R ", C (= O) OR", OC (= O) R ", C (= O) NR" R "', N (R") C ( ═O) R ″ ′ or an N-oxide group in the pyrimidine nucleus, R ″ and R ″ ′ independently of each other, H, or alkyl, such as C ₁ -C ₇ alkyl, or heteroalkyl, aryl or hetero It is a substituent of aryl.
3- (thienyl) oxazolidinone
Optionally, various 3- (thienyl) oxazolidinones are provided that have biological activity such as antimicrobial activity.
In one embodiment, there are provided compounds of Formulas 11c, 12c, and 13c, and combination libraries thereof.

In one embodiment of the above formulas,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, or alkyl, such as C ₁ -C ₇ alkyl, or heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl,
R ₁₀ and R ₁₁ are independently of each other hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S (= 0) R ", SO ₂ R", C (= 0) R ", C (= 0) OR", OC (= 0) R ", C (= 0) NR" R "'or N (R") C ( = O) R "', and where R" and R "' are independently of each other, H, or C ₁ -C substituent of alkyl or heteroalkyl, aryl or heteroaryl, such as a _7-alkyl.
3- (thiazolyl) oxazolidinone
Optionally, various 3- (thiazolyl) oxazolidinones are provided that have biological activity, such as antimicrobial activity.
In one embodiment, there are provided compounds of Formulas 14c, 15c, and 16c, and combination libraries thereof.

In one embodiment of the above formulas,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, or alkyl, such as C ₁ -C ₇ alkyl, or a substituent of heteroalkyl, aryl or heteroaryl,
R ₉ is an alkyl, aryl, heteroalkyl or heteroaryl group,
R ₁₀ is hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S (= O) R ", SO ₂ R" , C (= 0) R ", C (= 0) OR", OC (= 0) R ", C (= 0) NR" R "'or N (R") C (= 0) R "' , Wherein R ″ and R ″ ′, independently of one another, are substituents of H, or alkyl, such as C ₁ -C ₇ alkyl, or heteroalkyl, aryl or heteroaryl.
3- (1,3,4-thiadiazolyl) oxazolidinone
Optionally, various 3- (1,3,4-thiadiazolyl) oxazolidinones are provided that have biological activity such as antimicrobial activity.
In one embodiment, there is provided a compound of Formula 17c and a combinatorial library thereof.
In one embodiment of the above formula,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, or alkyl, such as C ₁ -C ₇ alkyl, or heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl, or heteroaryl.
Synthesis of 3- (heteroaryl) oxazolidinone
3- (heteroaryl) oxazolidinones and other oxazolidinones can be synthesized through various routes described herein. In one embodiment, this synthesis comprises the steps of reacting a suitable heteroaryl halide with 3-aminopropane-1,2-diol, as described in FIG. 49, and ringing the (heteroaryl) aminodiol obtained with a phosgene or equivalent thereof. And a step of converting 5- (R) -hydroxymethyl-3-heteroaryloxazolidinone to 5- (S) -aminomethyl-3-heteroaryl oxazolidinone immobilized on the resin. It can be performed according to. Further reaction of this reagent yields the desired oxazolidinone.
In another embodiment, 5- (S) -azidomethyl-3-hetero in the presence of a base from a suitable heteroaryl halide and 5- (S) -azidomethyloxazolidinone or its equivalent as shown in FIG. 50. Prepare an aryloxazolidinone reagent. The azide or amine intermediate obtained is then immobilized on the BAL linker resin. Further reaction of the X and / or amine groups bound to the solid phase yields the desired 3-heteroaryloxazolidinone configuration.
Based on the teachings herein, those skilled in the art will appreciate that the oxazolidinones described herein can be readily synthesized using the reactions described herein and other reactions.
Combination Library Synthesis
Combination library synthesis is generally performed on solid phase supports [Lam et al., (1991) Nature 354: 82-84; and Houghten et al., (1991) Nature 354: 84-86. There are two general techniques for producing a combinatorial library: "mix and split" techniques and "multiple parallel synthesis" techniques.
In the "mixing and splitting" technique, a number of beads or particles are dispersed in a suitable carrier (e.g. solvent) contained in the parent container. For example, the beads are provided with functionalized moieties that bind with chemical modules. The beads are then divided and placed in several separate reactors. The first chemical module is bound to the beads to obtain a variety of differently substituted solid phase supports. If the first chemical module contains three different members, the resulting substituted beads can be represented by A ₁ , A ₂ and A ₃ .
The beads are washed to remove excess reagent and then remixed in the mother vessel. The bead mixture is subdivided and placed in several separate reactors. Couple the second chemical module to the first chemical module. If the second chemical module comprises three different members, ie B ₁ , B ₂ and B ₃ , nine differently substituted beads, ie A ₁ B ₁ , A ₁ B ₂ , A ₁ B ₃ , A ₂ B ₁ , A ₂ B ₂ , A ₂ B ₃ , A ₃ B ₁ , A ₃ B ₂ , and A ₃ B ₃ are obtained. Each bead has only a single type of molecule bound to its surface.
The synthesis process of remixing / redistribution is repeated so that different chemical modules are all introduced into the molecules bound to the solid phase support. In this way, a large number of individual compounds can be easily and efficiently synthesized. For example, if there are four different chemical modules and each chemical module contains 20 members, 160,000 beads can be prepared that are substituted with different molecular units.
Synthesis of combinatorial libraries using the "mix and split" technique can be done manually or through an automated process. When manually preparing combinatorial libraries, scientists perform several chemical treatments. When a combinatorial library is manufactured through an automated process, several chemical treatments are generally mechanically performed (see, eg, US Pat. No. 5,463,564).
For the "multiple parallel synthesis" technique, the beads or particles are dispersed in a suitable carrier (eg solvent) in the reaction chamber arrangement. This bead or particle provides a functionalized moiety that binds to a chemical module. Different members of the chemical module are added to separate reaction chambers to obtain different functionalized bead arrangements. If there are 96 separate reaction chambers and 96 different chemical module sources, a combinatorial library of 96 compounds is formed. These compounds can be analyzed on a solid support, separated on a solid support, or added another chemical module.
Synthesis of combinatorial libraries using the "multiple parallel synthesis" technique can be done manually or through an automated process. When manually preparing combinatorial libraries, scientists perform several chemical treatments. When a combinatorial library is manufactured through an automated process, several chemical treatments are usually mechanically performed.
Solid support
In one embodiment, solid phase synthesis of the compositions provided herein is performed on a solid support. "Solid support" includes insoluble materials suitably derived such that the chemical module can be bound to the material surface through standard chemical methods. Solid phase supports include, but are not limited to, beads and particles such as peptide synthetic resins [Merrifield (1963) J. Am. Chem. Soc. 85: 2149-2154; U.S. Patent 4,631,211; and Geysen et al. (1984) Proc. Natl. Acad. Sci. USA 81: 3998-4002].
Solid phase supports may consist of a variety of materials, but are primarily limited by the capacity of the materials that can be functionalized through synthetic methods. Examples of such materials include, but are not limited to, polymers, plastics, resins, polysaccharides, silicon or silica based materials, carbon, metals, inorganic glasses and membranes. Preferred resins include Sasrin resin (polystyrene resin, commercially available from Bachem Bioscience, Switzerland), Wang resin or p-nitrophenylcarbonate king resin (PNP resin, Novabiochem ( From Novabiochem, and TentaGel S AC, Tentagel PHB, or Tentagel S NH ₂ resin (Rapp Polymere, Tubingen, Germany, or Perseptive, Boston) Commercially available polystyrene-polyethylene glycol copolymer resin).
Solid phase supports are commercially available with suitable functional groups already present so that chemical modules can be bound to the surface of the support (eg Novabiochem, Biochem, Lab Polymer). Alternatively, solid phase supports can be chemically modified such that chemical modules can be bound to the surface of the support [Grant (1992) Synthetic Peptides, A User's Guide, W. H. Freeman and Co .; and Hermkens et al. (1996) Tetrahedron 52: 4527-4554. One skilled in the art knows that the choice of functional group used to bind a molecule to a solid support depends on the nature of the compound to be synthesized and the type of solid support. Examples of functional groups present on solid supports that can be used to bond chemical modules include alkyl or alkyl halides, aldehydes, alcohols, carbonates, ketones, amines, sulfides, carboxyl groups, aldehyde groups and sulfonyl groups, and the like. It is not limited.
Examples of functional groups on the solid support to bond chemical modules include alcohol, amine, aldehyde, carbonate, or diol groups [Gordon et al. (1994) J. Med. Chem. 37: 1385-1401; and Hermkens et al. (1996) Tetrahedron 52: 4527-4554.
To prepare some combinatorial libraries, it is possible to purchase a solid support in which the protected chemical module is already bound and present. An example of such a support is FmocGly Sasrin, available from Bachem. Generally, however, the first step in synthesizing combinatorial libraries is to couple chemical modules to solid support via functional groups present on the surface of the support. Examples of chemical reactions that can be used to bond chemical modules to a support include nucleophilic substitution of halides or other leaving groups, etherification of alcohols, esterification of alcohols, amidation of amines, carbamateization of amines, carbonyls Reductive amination of compounds, acetalization of aldehydes and ketalization of ketones, and the like, but are not limited to this [Hermkens et al. (1996) Tetrahedron 52: 4527-4554.
Reactions used to bind chemical modules to solid phase supports include, for example, carbamateization of amines, reductive amination of carbonyl compounds, or nucleophilic substitution of halides or other leaving groups [Hermkens et al. (1996)].
In bonding some chemical modules to the solid phase support, it may be necessary to mask functional groups that are not involved in the binding process but are not compatible with the mode of binding. Non-limiting examples of this type of process include the esterification of alcohol functionalized solid support with hydroxyl-substituted carboxylic acids as coupling partners. Prior to the esterification reaction, the hydroxyl group of the carboxylic acid is "protected" via alkylation, silication, acetylation, or another method known to those skilled in the art. Schemes using masking or protecting groups are known in the art as described in Greene, (1985) Protecting Groups in Organic Synthesis, Wiley.
Method for Separating Compounds from Solid Supports
Separation of the oxazolidinone from the solid support to obtain the corresponding "free" compound can be carried out using various methods. For example, photolytically, Wang et al. (1976), J. Org. Chem. 41: 3258; Rich et al. (1975) J. Am. Chem. Soc. 97: 1575-1579, nucleophilic attack [US Pat. No. 5,549,974], or hydrolysis [Hutchins et al., (1994) Tetrahedron Lett. 35: 4055-4058 can be used to separate compounds from solid support. The method of obtaining a soluble compound by separating a compound from a solid support is performed using hydrolysis conditions, such as adding trifluoroacetic acid, for example.
Screening
Libraries of the invention can be used to screen for one or more bioactive molecules. Preferably, the bioactive molecule is active against cellular targets including but not limited to enzymes and receptors, or microorganisms. Target cell redids or microorganisms are those known or believed to be important for the pathogenesis or progression of the disease. Examples of disease states that amino alcohol, thio alcohol, oxazolidinone, and sulfone libraries can be screened include, but are not limited to inflammation, infection, hypertension, central nervous system disorders, and cardiovascular disease.
Several methods of screening libraries of compounds to identify bioactive molecules have been developed in recent years. Methods of isolating library compound species having desirable affinity for a receptor or enzyme are known in the art.
For example, under conditions favorable for enzyme-ligand binding, the enzyme solution can be mixed with a solution of a compound of a particular combinatorial library [Bush et al. (1993) Antimicrobial Agents and Chemotherapy 37: 851-858; and Daub et al. (1989) Biochemistry 27: 3701-3708. Specific binding of the library compounds to enzymes can be detected, for example, by any of a number of enzyme inhibition assays known in the art. Compounds that bind to enzymes are readily separated from compounds that remain free in solution by adding the solution to a suitable separation material, such as a Sephadex G-25 gel filtration column. Free enzymes and enzyme-ligand complexes pass quickly through the column, while free library compounds delay the progress through the column. The mixture of enzyme-ligand complex and free enzyme is then treated with a suitable denaturing reagent such as guanidinium hydrochloride or urea to release the ligand from the enzyme. This solution is then injected into an HPLC column (e.g., a Vydac C-4 reversed phase column, eluted with acetonitrile mixture of water and acetonitrile with acetonitrile varying in proportion from 0% to 80%). The diode array is measured to identify combinatorial library compounds from enzymes. The compound peaks are then collected and confirmed by mass spectroscopy.
Another way to identify compounds that inhibit enzymes is to divide the library into separate sub-libraries in which one step of synthesis is unique to each sub-library. To prepare a combinatorial library, the reactants are mixed together during one step to produce a mixture of several compounds. However, at certain stages of the synthesis, the resin containing the synthetic intermediate is divided into several parts and then each part undergoes a unique modification. The resin parts are then (separately) subjected to the remaining synthesis step in the combinatorial synthesis method. Thus, individual resin parts constitute separate sub libraries. When testing a compound, if a given sublibrary is more active than the rest of the sublibrary, a unique step in this sublibrary is fixed. This sublibrary then becomes a new library with this fixed step, forming the basis for another sub library synthesis that optimizes another step in the synthesis process. This process is carried out at each step until the final compound is reached. The method described above generalizes the method described in WO 86/00991 by Geysen to determine the "mimotopes" of peptides for the synthetic method of the present invention.
Finding compounds that inhibit enzymes is most easily done using free compounds in solution. The compounds may be screened while bound to the resins used for synthesis, and in some cases this may be the preferred method of finding compounds with desirable properties. For example, if a compound that binds to a particular antibody is desired, the library of compound bound to the resin is contacted with the antibody solution under conditions that promote the formation of stable antibody-compound-resin complexes. Then, a second antibody labeled with fluorescence that binds to a constant region of the first antibody is contacted with this antibody-compound-resin complex. By doing this, it is confirmed whether the specific beads carry the compound recognized by the first antibody binding site. The beads are then physically separated from the resin mixture and subjected to mass spectrometry. When the synthesis is done in such a way that only one compound is synthesized on a particular bead, the binding compound is identified. If a large number of compounds are present on a single bead after synthesis, the information obtained from its analysis can be used to narrow down the choice of synthetic objects for the synthesis and identification of subsequent processes.
The enzyme, antibody, or receptor target need not be a solution. The antibody or enzyme can be immobilized on the column. After a library of compounds is passed through the column, the compounds that bind strongly on the column after washing the compounds that bind weakly and those that do not bind are delayed. The column is then washed under conditions that break down the protein-ligand bonds to initially remove the remaining compound. These compounds are analyzed and synthesized quantitatively separately for the next test. Similarly, cells containing surface receptors are contacted with a solution of the library compound. Cells containing bound compounds are easily separated from solutions containing unbound compounds. The cells are then washed with a solution that degrades this bound ligand from the cell surface receptor. Again, these cells are separated from the solution and analyzed for this solution.
Pharmaceutical composition
The present invention also provides a pharmaceutical composition comprising a bioactive oxazolidinone compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compositions of the present invention include those in a form suitable for oral, topical or parenteral use, and can be used for the treatment of bacterial infections in mammals, including humans.
Antibiotic compounds referred to herein as antimicrobial compounds may, according to the invention, be formulated in dosage forms for use in humans or veterinary drugs in any conventional manner, similar to other antibiotics. Such methods are well known in the art and thus are not described in detail herein.
The compositions of the present invention can be formulated by any route known in the art, for example for subcutaneous, inhalation, oral, topical or parenteral administration. The composition may be in any form known in the art and includes, but is not limited to, tablets, capsules, powders, granules, lozenges, creams, or liquid formulations such as oral or sterile parenteral solutions or suspensions. .
Topical formulations of the invention may be, for example, ointments, creams or lotions, eye ointments and eye drops or ear drops, incorporated bandages and aerosols, preservatives, solvents to assist drug penetration, and ointments and creams Suitable conventional additives such as emollients of
The formulations may also include conventionally compatible carriers such as cream or ointment bases and ethanol or oleyl alcohols for lotions. Such carriers may be present, for example, from about 1% to about 98% of the formulation. For example, such a carrier may comprise up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dosage form and may include binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Tableting lubricants such as magnesium stearate, talc, polyethylene glycol or silica; Disintegrants such as potato starch; Or conventional excipients such as acceptable wetting agents, such as sodium lauryl sulfate. Tablets may be coated according to methods known in conventional pharmaceutical practice.
Oral liquid preparations may be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be present as a dry product that is remanufactured with water or other suitable vehicle before use. Such liquid preparations include suspending agents such as sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; Emulsifiers such as lecithin, sorbitan monooleate, or acacia; Non-aqueous vehicles (which may include edible oils) such as almond oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid, and conventional additives such as conventional flavoring or coloring agents, if desired.
For parenteral administration, the flowable unit dosage form is prepared using a compound of the invention and a sterile vehicle, preferably water. The compounds of the present invention may be suspended or dissolved in vehicle or other suitable solvent, depending on the vehicle and concentration used. In preparing solutions, the compounds of the present invention can be dissolved in water for injection, sterile filtered and sealed in appropriate vials or ampoules. Advantageously, drugs such as local anesthetic preservatives and buffers can be dissolved in the vehicle. To improve stability, the composition can be placed in a vial and frozen, and the water removed in vacuo. To seal and inject the lyophilized powder into the vial, the liquid may be remanufactured in a separate vial of water prior to use. Parenteral suspensions are prepared in much the same way except that the compounds of the present invention are suspended in a vehicle instead of dissolved, and sterilization cannot be accomplished through filtration. Compounds of the invention are sterilized by exposure to ethylene oxide and suspended in sterile vehicles. Advantageously, surfactants or wetting agents are included in the composition to facilitate uniform dispersion of the compound.
The composition of the present invention may comprise at least about 0.1% by weight, for example about 10 to 60% by weight, depending on the method of administration. If the composition comprises dosage units, each unit contains about 50 to 500 mg of the active ingredient. Dosages used in the treatment of adults range from about 100 to 3000 mg per day, for example 1500 mg per day, depending on the route and frequency of administration. Such dosages correspond to about 1.5 to 50 mg per kg body weight per day. Appropriate dosages are about 5 to 20 mg per kg body weight per day.
Pharmaceutical use
The oxazolidinones described herein can be used in a variety of pharmaceutical applications.
Compounds of the invention include, for example, peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, synoptic sites, nerve effector junctions, endocrine and hormonal systems, immune systems, reproductive systems, skeletal systems It can be used as a pharmaceutical active agent acting on otacoid system, digestion and excretion system, hydramine system and central nervous system as well as other biological systems. Thus, the compounds of the present invention may be used as sedatives, psychoexciters, neurostables, anticonvulsants, muscle relaxants, anti-Parkinson's, analgesics, anti-inflammatory agents, local anesthetics, muscle contractants, antibiotics, antiviral agents, antiretrovirals, antimalarials, diuretics It can be used as lipid modulator, anti-male hormone, antiparasitic, neoplastic, anti-neoplastic and chemotherapy. The compounds of the present invention can also be used to treat cardiovascular diseases, central nervous system diseases, cancer, metabolic disorders, infections and skin diseases as well as other biological diseases and infections. The compounds of the present invention can also be used as monoamine oxidase inhibitors.
In one embodiment, the compounds of the present invention can be used as antibacterial agents to treat infectious diseases caused by bacterial substances such as bacteria.
In one embodiment, there is provided a composition comprising a pharmaceutically acceptable carrier in combination with an oxazolidinone compound described herein for treating or preventing an infectious disease.
In another embodiment, a dose of oxazolidinone as described herein is provided in an amount effective for treating, preventing or alleviating a disease, such as an infectious disease.
Oxazolidinone can be screened for activity against various bacterial substances, and the appropriate dosage can be determined through methods known in the art. Advantageously, a large amount of oxazolidinone can be prepared by a method of making a combinatorial library as described herein, and can be screened for a variety of different fungal materials to easily isolate oxazolidinone effective for a particular target microorganism. . This method can also be used to determine new oxazolidinones for use later or in the event of bacterial resistance.
The compounds of the present invention can be used to treat subjects who are required to treat, prevent or lessen the extent of infection. The subject includes surfaces such as animals, plants, blood substances, cultures, and medicines or research equipment such as glass, needles, and test tubes.
In one embodiment, a method of treating or preventing an infectious disease in a subject, such as a human or other animal subject, is provided by administering to the subject an effective amount of oxazolidinone, as described herein. In one embodiment, the compounds of the present invention are administered in a pharmaceutically acceptable dosage form, optionally in a pharmaceutically acceptable carrier. As used herein, the term “infectious disease” is any disease characterized by a microbial infection, such as a bacterial infection. Such infectious diseases include, for example, central nervous system infection, external ear infection, middle ear infections such as acute otitis media, infections of the dural vein, eye infections, oral infections such as infections of the teeth, gums and mucous membranes, upper respiratory tract infections, lower respiratory tract infections, Immunosuppressed, such as genital infections, gastrointestinal infections, maternal infections, sepsis, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prevention of surgery, and cancer chemotherapy or organ transplant patients Antimicrobial prevention in patients. The compounds of the present invention and compositions comprising them can be administered by local, topical or systemic routes. Systemic administration includes any method of administering a compound of the invention into tissue of the body, such as intradural, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral administration. The specific dosage and duration of treatment of the antimicrobial to be administered can be adjusted as needed.
The compounds of the present invention can be used for the treatment or prevention of infectious diseases caused by various bacterial organisms. Examples include Staphylcocci, such as Staphylococcus aureus; Enterococci, such as E. faecalis; Streptococci, such as S. pneumoniae; Haemophilus, such as H. influenza; Moraxella (Moraxella), such as the catarrhalis Morax (M. catarrhalis); Gram-positive and Gram-negative aerobic and anaerobic bacteria, including fungi (Escherichia), such as E. coli. Another example is Mycobacteria, such as M. tuberculosis; Intercellular bacteria such as Chlamydia and Rickettsiae; And Mycoplasma, such as M. pneumoniae.
The following examples are provided to illustrate but not limit the invention.
Abbreviation: ACN, acetonitrile; CDI, carbonyldiimidazole; DIEA, diethylisopropylamine; DCM, dichloromethane; DIC, diisopropyldiimide; DMF, dimethylformamide; HATU, O- (7-azabenzotriazol-1-yl) -1,1,3,3-bis (tetramethylene) uronium hexafluorophosphate; NMM, N-methyl morpholine; mCPBA, m-chloroperoxybenzoic acid; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TMOF, trimethylorthoformate.
Normal
The reagents include Aldrich, St. Louis, Missouri, Sigma, St. Louis, Missouri, Bachem Bioscience, Rapp Polymere, Perseptive ) And Novabiochem and used without further purification. After workup, the solution was concentrated using reduced pressure rotary evaporation or using a SpeedVac instrument from Savant. The reaction with a moisture sensitive reagent was carried out under a nitrogen atmosphere.
Mass spectra were obtained using ESI technology. HTLC analysis and purification was done using Beckman System Gold R® and detected at 220 nm. Analytical EPLC was performed over 6 minutes in a solvent with a rate change from YMC 5 micron C18 (4.6 mm × 50 mm) reversed phase column (0.1% TFA 100% aqueous to 0.1% TFA 100% in MECN, effluent rate 2.0 mL / min )). Purified TLC was performed using EM silica gel 60 F ₂₅₄ plates (20 × 20 cm, thickness 2 mm).
NMR spectra were obtained using CDCl ₃ as solvent on a Varian Gemini 300 MHz instrument unless otherwise noted. ^The terms used in the ¹ H NMR spectrum are chemical shifts for tetramethylsilane (0.00 ppm), multiplicity (s = single peak, d = double peak, t = triple peak, q = quad peak, m = multi peak, b = Broad peak), coupling and integral.
2-fluoro-4-nitrobenzoic acid
Concentrated sulfuric acid (32 ml) was carefully added to a solution of 2-fluoro-4-nitrotoluene (16.5 g, 0.106 mol) in acetic acid (200 ml) with stirring. The mixture was warmed to 95 ° C. and a solution of chromium trioxide (37.1 g, 0.371 mol) in water (32 ml) was added dropwise over 2 hours with stirring. The mixture was heated for another 30 minutes with stirring, cooled to room temperature and poured into water (1000 ml). The product was extracted with diethyl ether (3 x 200 ml). The combined ether layers were washed with water and evaporated to dryness. The residue was dissolved in 10% aqueous potassium carbonate solution and washed with ether. The aqueous layer was acidified with concentrated HCl and the white precipitate obtained was filtered and dried (16.3 g, 83%), mp 174-177 ° C. ¹ H NMR.
Tert-Butyl 2-fluoro-4-nitrobenzoate
Thionyl chloride (45 ml, 0.62 mol) was added to 2-fluoro-4-nitrobenzoic acid (23.0 g, 0.124 mol) and the mixture was refluxed with stirring for 2 hours. The solvent was removed in vacuo and the residue was dried completely in vacuo to give crystalline acid chloride (25.2 g, 99%). Acid chloride was dissolved in tetrahydrofuran (150 ml) under a nitrogen atmosphere and 1 M lithium tert-butoxide (136 ml, 0.136 mol) in tetrahydrofuran was added dropwise at room temperature with stirring. The mixture was stirred overnight, diluted with water (300 ml) and extracted with ether. The ether layer was washed with saturated aqueous sodium hydrogen carbonate solution, brine and dried over MgSO ₄ . The solvent was removed in vacuo to give the product as a white crystalline solid (24.2 g, 81%), mp 81-82 ° C. ¹ H NMR.
tert-butyl-2-fluoro-4-aminobenzoate
High temperature (95 ° C.) of ammonium chloride (53.5 g, 1.00 mol) in which tert-butyl 2-fluoro-4-nitrobenzoate (24.2 g, 0.100 mol) was dissolved in ethanol (300 ml) and water (150 ml) Was added to the solution. Iron powder (325 mesh, 16.8 g, 0.300 mol) was added in portions over approximately 1 hour with stirring. The reaction mixture was stirred and further heated at 95 ° C. for 30 minutes and then filtered at high temperature. The filtered solid was washed thoroughly with excess ethanol. The filtrate and washings were diluted with water (1 L) and extracted with ether (3 x 150 ml).
The combined ether extracts were washed with water and brine, dried over MgSO ₄ and evaporated to afford the product as an off-white solid (21.1 g, 98%), mp 100-101 ° C. ¹ H NMR.
O-benzyl-N- (3-fluoro-4-butoxycarbonylphenyl) carbamate
Benzyl chloroformate (15.9 ml, 0.112 mol) of tert-butyl-2-fluoro-4-aminobenzoate (21.5 g, 0.102 mol) and pyridine (16.5 ml, 0.204 mol) in dichloromethane (200 ml) To the mixture was added dropwise with stirring at 0 ° C. The reaction mixture was stirred for 30 minutes at 0 ° C., warmed to room temperature and poured into water (approximately 300 ml). The organic layer was separated, washed with water, brine and dried over MgSO ₄ . Evaporation gave a white solid which was washed with hexane and dried in vacuo to give the product (32.8 g, 93%), mp 117-118 ° C. ¹ H NMR.
5- (R) -hydroxymethyl-3- [4'-tert-butoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
1 M lithium bis (trimethylsilyl) amide (104 ml, 0.104 mol) in tetrahydrofuran was added O-benzyl-N- (3-fluoro-4-butoxycarbonylphenyl) carbohydrate in tetrahydrofuran (150 ml) To a solution of barmate (32.8 g, 0.0948 mol) was added dropwise with stirring at -78 ° C. The mixture was stirred at −78 ° C. for 1 h and then added dropwise with stirring (R) -glycidyl butyrate (15.0 g, 0.104 mol). The mixture was allowed to warm to room temperature overnight and then quenched with saturated aqueous ammonium chloride solution (100 ml). The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (eluent: 30% ethyl acetate in hexane) to give the product as a white solid (20.0 g, 68%), mp 148-149 ° C. ¹ H NMR.
5- (S) -azidomethyl-3- [4'-tert-butoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
Methanesulfonyl chloride (2.61 ml, 0.0337 mol) was added 5- (R) -hydroxymethyl-3- [4'-tert-butoxycarbonyl-3'-fluorophenyl] oxa in dichloromethane (150 ml). To a solution of zolidin-2-one (10.0 g, 0.0321 mol) and triethylamine (6.71 ml, 0.0482 mol) was added dropwise over approximately 15 minutes with stirring at 0 ° C. The reaction mixture was allowed to warm to room temperature and then poured into water. The organic layer was separated, washed with water, saturated aqueous NaHCO ₃ , brine and dried over MgSO ₄ . The solvent was removed in vacuo to give mesylate intermediate as an oil (11.6 g, 99%). A mixture of mesylate (13.4 g, 0.0370 mol) and sodium azide (12.0 g, 0.185 mol) in DMF (130 ml) was heated at 75 ° C. for 12 hours with stirring. The reaction mixture was cooled to rt, diluted with water (300 ml) and extracted with ethyl acetate (3 × 100 ml). The combined organic layers were washed with water and brine, dried over MgSO ₄ and evaporated. The residue was washed with diethyl ether to give pure azide as a white solid (9.76 g, 90.5%), mp 91-92 ° C. ¹ H NMR.
S- (S) -azidomethyl-3- [4'-N-methyl-N-methoxyamido-3'-fluorophenyl] oxazolidin-2-one
5- (S) -azidomethyl-3- [4'-tert-butoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (3.36 g, 0.01 mol) was diluted with dichloromethane (approx. 100 ml) and trifluoroacetic acid (50 ml) was added with stirring. The mixture was left at room temperature for 3-4 hours, the solvent was removed in vacuo, and the residue was washed with diethyl ether-hexane (1: 3, approximately 20 ml) to give an intermediate acid. This acid (1.40 g, 0.005 mol) was dissolved in dichloromethane (100 ml) and dimethylformamide (50 ml), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.96 g, 0.005 mole) was added. The mixture was stirred for approximately 2 hours, N-methyl-N-methoxyamine hydrochloride (0.48 g, 0.005 mmol) was added and triethylamine (1.5 ml, 0.015 mmol) was added. The mixture was stirred at room temperature for 3-4 hours, poured into water (approximately 200 ml) and then extracted with ethyl acetate (3 × 150 ml). The combined organic layers were washed with water (4 × 250 ml), brine and dried over MgSO ₄ . The solvent was removed in vacuo to yield Waynerep amide.
2-fluoro-4-nitrobenzylidene diacetate
2-fluoro-4-nitrotoluene (21.65 g, 0.140 mol) was dissolved in acetic anhydride (145 ml) and concentrated sulfuric acid (30 ml) was added slowly with stirring. The mixture was cooled to 0 ° C. and a solution of chromium trioxide (42.0 g, 0.420 mol) in acetic anhydride (200 ml) was added at a rate such that the temperature did not exceed 10 ° C. The reaction mixture was stirred for additional 2 h at 0 ° C. and then poured into ice water (1000 ml). The precipitate obtained was filtered off, washed with water and dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate solution, brine and dried over MgSO ₄ . The solvent was removed in vacuo to give the product as a white crystalline solid (37.9 g, 70%), mp 116-117 ° C. ¹ H NMR.
2-fluoro-4-nitrobenzaldehyde dimethyl acetal
2-fluoro-4-nitrobenzylidene diacetate (9.30 g, 0.0343 mol) was dissolved in methanol (200 ml) and potassium carbonate (4.74 g, 0.0343 mol) was added in one portion. The mixture was stirred at rt for 2 h and then evaporated to dryness. The residue was dissolved in diethyl ether, washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo to give an aldehyde intermediate (5.68 g, 98%). Aldehyde (6.00 g, 0.0355 mol) was dissolved in a mixture of methanol (4.5 ml) and trimethyl orthoformate (4.27 ml, 0.0390 mol). Ammonium chloride (0.10 g, 0.00178 mol) was added and the mixture was refluxed for 2 hours. The solvent was removed in vacuo and the residue was washed with diethyl ether. The ether solution obtained was washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo to yield the product as a colorless oil. Yield 7.60 g (99%). ¹ H NMR.
4-amino-3-fluorobenzaldehyde dimethyl acetal
2-Fluoro-4-nitrobenzaldehyde dimethyl acetal (0.59 g, 2.74 mmol) was dissolved in methanol (20 ml) and palladium on 5% carbon (0.059 g) was added. This flask was filled with hydrogen gas and the mixture was stirred at rt for 20 h. The catalyst was filtered through celite and the solvent removed in vacuo to yield the product. Yield 0.40 g (78%). ¹ H NMR.
O-benzyl-N- [3-fluoro-4- (dimethoxymethyl) phenyl] carbamate
Benzyl chloroformate (0.34 ml, 2.38 mmol) was added to a solution of 4-amino-3-fluorobenzaldehyde dimethyl acetal (0.40 g, 2.16 mmol) and pyridine (0.26 ml, 3.24 mmol) in dichloromethane (10 ml). It was added dropwise while stirring at ℃. The reaction mixture was allowed to warm to room temperature, then washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo to afford the desired product as a white solid. Yield 0.56 g (81%). ¹ H NMR.
S- (R) -hydroxymethyl-3- [4'-dimethoxymethyl-3'-fluorophenyl] oxazolidin-2-one
1 M lithium bis (trimethylsilyl) amide (0.86 ml, 0.941 mmol) in tetrahydrofuran was added O-benzyl-N- [3-fluoro-4- (dimethoxymethyl) phenyl] in tetrahydrofuran (5 ml). Carbamate (0.273 g, 0.855 mmol) was added dropwise with stirring at -78 ° C. The mixture was stirred at −78 ° C. for 1 hour and then (R) -glycidyl butyrate (0.145 ml, 1.03 mmol) was added dropwise with stirring. The mixture was allowed to warm to room temperature overnight and then quenched with saturated aqueous ammonium chloride solution (5 ml). The mixture was extracted with ethyl acetate and the product was washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (eluent: 30% ethyl acetate in hexanes) to afford alcohol as an oil. Yield 0.24 g (99%). ¹ H NMR.
5- (S) -azidomethyl-3- [4'-dimethoxymethyl-3'-fluorophenyl] oxazolidin-2-one
Methanesulfonyl chloride (0.0664 ml, 0.858 mmol) was added S- (R) -hydroxymethyl-3- [4'-dimethoxymethyl-3 -'- fluorophenyl] oxazolidine in dichloromethane (10 ml). To a solution of 2-one (0.233 g, 0.817 mmol) and triethylamine (0.228 ml, 1.63 mmol) was added with stirring at 0 ° C. The reaction mixture is allowed to warm to room temperature and then poured into water. The organic layer was separated, washed with water, saturated aqueous NaHCO ₃ , brine and dried over MgSO ₄ . The solvent was removed in vacuo to give mesylate intermediate as an oil (0.246 g, 83%). A mixture of mesylate (0.189 g, 0.520 mmol) and sodium azide (0.170 g, 2.60 mmol) in DMF (5 ml) was heated at 75 ° C. for 12 h. The reaction mixture was cooled to rt, diluted with water (50 ml) and extracted with ethyl acetate (3 × 30 ml). The combined organic layers were washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (eluent: 50% ethyl acetate in hexanes) to afford the desired product as a colorless oil (0.154 g, 95%). MS (m / z): 311 [M + H] ⁺ . ¹ H NMR.
3-fluoro-4-thiocyanoaniline
N-bromosuccinimide (1.76 g, 9.89 mmol) and potassium thiocyanate (1.75 g, 18.0 mmol) in methanol (30 ml) were stirred at room temperature for 15 minutes. The reaction mixture was cooled to 0 ° C. and 3-fluoroaniline (1.00 g, 9.0 mmol) was added dropwise. The mixture was stirred at 0 ° C for 2 h. The solvent was removed in vacuo and the residue was washed with dichloromethane. The mixture was filtered to remove succinimide byproduct, and the solution was washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo to afford the desired product as a colorless oil. Yield 1.45 g (96%). ¹ H NMR.
O-benzyl-N- [3-fluoro-4- (thiocyano) phenyl] carbamate
Benzyl chloroformate (1.87 ml, 13.1 mmol) was added to a mixture of 3-fluoro-4-thiocyanoaniline (2.00 g, 11.9 mmol) and pyridine (2.12 ml, 26.2 mmol) in dichloromethane (30 ml). It was added at ℃. The mixture was stirred at 0 ° C. for 30 minutes and allowed to warm to room temperature and then poured into water. The organic layer was separated, washed with brine and dried over MgSO ₄ . The solvent was removed in vacuo. The crude product was washed with ether-hexane and dried in vacuo to afford the desired product. Yield 3.64 g (92%), mp. 74-75 ° C. ¹ H NMR.
O-benzyl-N- [3-fluoro-4- (triphenylmethylthio) phenyl] carbamate
Sodium sulfide nonahydrate (0.794 g, 3.31 mmol) in water (3 ml) was added to O-benzyl-N- [3-fluoro-4- (thiocyano) phenyl] carbamate in ethanol (10 ml). (1.00 g, 3.31 mmol) was added dropwise at room temperature. The reaction mixture was stirred at rt for 30 min and then triphenylmethyl bromide (1.07 g, 3.31 mmol) in 1,4-dioxane (5 ml) was added dropwise. The reaction mixture was stirred overnight. The organic solvent was removed in vacuo and the residue was treated with ethyl acetate. The solution was washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (eluent: 10% ethyl acetate in hexanes) to afford the desired compound as a white solid. Yield 1.10 g (64%). mp 152-153 ° C. ¹ H NMR.
5- (R) -hydroxymethyl-3- [4'-triphenylmethylthio-3'-fluorophenyl] oxazolidin-2-one
1 M lithium bis (trimethylsilyl) amide (54 ml, 69.9 mmol) in tetrahydrofuran was converted to O-benzyl-N- [3-fluoro-4- (triphenylmethylthio) phenyl in tetrahydrofuran (250 ml). ] To a solution of carbamate (33.0 g, 63.5 mmol) was added dropwise with stirring at -78 ° C. The mixture was stirred at −78 ° C. for 1 h and then added dropwise with stirring (R) -glycidyl butyrate (11.0 g, 76.2 mmol). The mixture was allowed to warm to room temperature overnight and then quenched with saturated aqueous ammonium chloride solution (125 ml). The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate with ratio change from 30% to 75% in hexane) to give the product. TLC: Rt 0.2 (ethyl acetate-hexane 1: 1). MS 486 [M + H] ⁺ . ¹ H NMR.
5- (S) -azidomethyl-3- [4'-triphenylmethylthio-3'-fluorophenyl] oxazolidin-2-one
Methanesulfonyl chloride (3.91 ml, 50.6 mmol) was added 5- (R) -hydroxymethyl-3- [4'-triphenylmethylthio-3'-fluorophenyl] oxazolidine in dichloromethane (200 ml). To a solution of 2-one (23.4 g, 48.2 mmol) and triethylamine (10.1 ml, 73.8 mmol) was added dropwise with stirring at 0 ° C. over about 10 minutes. The reaction mixture was allowed to warm to room temperature and then poured into water. The organic layer was separated, washed with water, saturated aqueous NaHCO ₃ , brine and dried over MgSO ₄ . The solvent was removed in vacuo to give mesylate intermediate as an oil (27.2 g, 99%). Mesylate (27.2 g, 48.2 mmol) and sodium azide (15.7 g, 241.0 mmol) in DMF (150 ml) were heated with stirring at 70 ° C. for 12 h. The reaction mixture was cooled to rt, diluted with water (750 ml) and extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (eluent: 30% ethyl acetate in hexanes) to give the azide product as a white solid. Yield 18.1 g (73%). mp 77-79 ° C. [a] ^D = -114 ° (c = 1, methanol). ¹ H NMR.
5-benzyloxycarbonylaminoindazole
Benzyl chloroformate (9.9 ml, approximately 66 mmol) in tetrahydrofuran (66 ml) was added 5-aminoindazole (4.44 g, 33 mmol) in tetrahydrofuran (150 ml) and pyridine (12.0 ml, 150 mmol). Was added dropwise with stirring at -5 ° C. The mixture was warmed to room temperature, then stirred for 4 hours and concentrated in vacuo. Ethyl acetate (100 ml) and water (150 ml) were added and the aqueous layer was extracted with ethyl acetate (2 × 100 ml). The combined organic layers were washed with 0.3 N aqueous HCl solution (2 × 100 ml), water, brine and dried over MgSO ₄ . The solvent was removed in vacuo to afford the crude product as a mixture of two positional regioisomers. MS (m / z): 402.1 [M + H] ⁺ . 0.3 M lithium hydroxide monohydrate (250 ml, approximately 75 mmol) in methanol was added. The mixture was stirred at room temperature for 45 minutes and then acidified carefully with 6N aqueous HCl solution until the pH of the solution reached 2. The product obtained was filtered, washed with water and dried in vacuo to afford the desired compound. R _t 4.2 min. MS (m / z): 268.1 [M + H] ⁺ . ¹ H NMR.
5-benzyloxycarbonylamino-1-triphenylmethylindazole
5-benzyloxycarbonylaminoindazole (0.534 g, 2 mmol) was converted to trityl chloride (0.556 g, 2 mmol) and tetrabutylammonium in tetrahydrofuran (5 ml) and triethylamine (0.42 ml, 3 mmol). Stir with iodide (0.074 g, 0.2 mmol) at room temperature for 3 days. The solvent was removed in vacuo and the solid residue was treated with methanol (3 ml). The solid was washed with a methanol-water mixture (5: 1, approximately 15 ml) and dried in vacuo to afford the desired product. Yield 0.73 g (72%). ¹ H NMR.
5- [5- (R) -hydroxymethyloxazolidin-2-one-3-yl] -1-triphenylmethylindazole
1 M lithium bis (trimethylsilyl) amide (1.1 ml, 1.1 mmol) in tetrahydrofuran was converted to 5-benzyloxycarbonylamino-1-trityindazole (0.510 g, 1 mmol) in tetrahydrofuran (10 ml). Was added dropwise while stirring at -78 ° C under a nitrogen atmosphere. The mixture was stirred at -78 ° C for 1.5 h. (R) -glycidyl butyrate (0.160 ml, 1.2 mmol) was added dropwise with stirring. This mixture was allowed to warm to room temperature overnight. Saturated aqueous NH ₄ Cl solution (10 ml) was added and the mixture was extracted with EtOAc (2 × 20 ml). The combined organic layers were washed with water (10 ml), brine (10 ml) and dried over MgSO ₄ . The solvent was evaporated to 3 ml and the residue was treated with hexane (50 ml). The white crystalline product was filtered off, washed with hexanes and dried in vacuo. Yield 0.440 g (93%). MS (m / z): 232.1 [M-Trt] ^- . ¹ H NMR.
5- [5- (S) -azidomethyloxazolidin-2-one-3-yl] -1-triphenylmethylindazole
Methanesulfonyl chloride (0.066 ml, 0.85 mmol) is 5- [5- (R) -hydroxymethyloxazolidin-2-one-3-yl] -1-triphenylmethyl in dichloromethane (7.0 ml) To a solution of sol (0.300 g, 0.63 mmol) and triethylamine (0.18 ml, 1.3 mmol) was added dropwise over 5 minutes with stirring at -30 ° C. The reaction mixture was stirred at 5 ° C. for 2 hours and quenched with water (15 ml). Ethyl acetate (20 ml) was added and the organic layer was washed with water, brine and dried over MgSO ₄ . Solvent was removed in vacuo to give mesylate intermediate. Mesylate and sodium azide (0.205 g, 3.15 mmol) in DMF (4 ml) were heated with stirring at 75 ° C. for 4 hours. The reaction mixture was cooled to rt, diluted with water (approximately 10 ml) and extracted with ethyl acetate (2 × 15 ml). The combined organic layers were washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo to afford the desired product as off white crystals. Yield 0.31 g (95%). MS (m / z): 257.1 [M-Trt] ^- . ¹ H NMR.
BAL aldehyde resin
4- (4-formyl-3,5-dimethoxyphenoxy) butyric acid (9.33 g, 34.8 mmol), pyridine (15 ml), and diisopropylcarbodiimide (3.00 ml, in dichloromethane (135 ml) 19.1 mmol) was stirred at rt for 1 h. Tentagel S-NH, a resin (0.29 mmol / g, 8.7 mmol) from Rapp Polymere, was added, and the mixture was stirred at room temperature overnight. The resin was filtered off, washed thoroughly with MeOH and dichloromethane and dried in vacuo.
5- [5- (S) -acetamidomethyloxazolidin-2-one-3-yl] -1-indazol
Tetrahydrofuran (1.0 ml) was added to 5- [5- (S) -azidomethyloxazolidin-2-one-3-yl] -1-triphenylmethylindazole (0.065 g, 0.13 mmol, in a resin reagent. To approximately 3 equivalents), triphenylphosphine (0.034 g, 0.13 mmol), and BAL aldehyde resin (150 mg, approximately 0.044 mmol). The mixture was stirred at rt for 2 h. The rubber septum was replaced with a Teflon coated lid and the mixture was stirred at 75 ° C. for approximately 10 hours. Tetrahydrofuran-triethylorthoformate mixture (1: 1, 1 ml) was added to the obtained imine resin and 0.5 M NaBH ₃ CN (0.5 ml, 0.25 mmol) was added. The mixture was stirred at rt for 3 h. The obtained amine resin was sufficiently washed with MeOH and dichloromethane and dried in vacuo. Acetic anhydride-pyridine-dichloromethane solution (1: 1.5: 3, 4 ml) was added and the mixture was stirred for 2 hours (until the negative ninhydrin test indicated that acylation was complete). Trityl protecting group was removed by treatment with 1% TFA in DCM (2 × 4 ml, 15 minutes) and the product was separated over 60 hours with 60% TFA in DCM (2 ml). HPLC purity of the isolated product was 90% (Rt 2.95 min). The solvent was removed in vacuo and the product was purified by purified silica gel TLC (eluent: dichloromethane-MeOH 5: 1). Yield 7.0 mg (58%). R _t 2.9 min (shown below). MS (m / z): 275.1 [M + H] ⁺ . ¹ H NMR.
BAL resin immobilized 5- (S) -aminomethyl-3- [4'-dimethoxymethyl-3'-fluorophenyl] oxazolidin-2-one
Triphenylphosphine (0.130 g, 0.496 mmol) was mixed with BAL aldehyde resin (0.57 g, 0.165 mmol) in THF (3 ml) and 5- (S) -azidomethyl-3- [4'-dimethoxymethyl-3 To a mixture of '-fluorophenyl] oxazolidin-2-one (0.154 g, 0.496 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours and then at 75 ° C. for 16 hours. The mixture was cooled to room temperature and 1 M sodium cyanoborohydride (0.99 ml, 0.992 mmol) in THF was added in one portion. The reaction mixture was stirred for 8 hours. The obtained amine resin was sufficiently washed with methanol and dichloromethane and dried in vacuo.
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4'-dimethoxymethyl-3'-fluorophenyl] oxazolidin-2-one
Acetic anhydride-pyridine-dichloromethane solution (1: 1.5: 3, 4 ml) was added BAL resin fixed 5- (S) -aminomethyl-3- [4'-dimethoxymethyl-3'-fluorophenyl] oxa Zolidin-2-one was added and the mixture was stirred for approximately 2 hours (until the negative ninhydrin test indicated that acylation was complete). The resin was filtered off, washed thoroughly with methanol and dichloromethane and dried in vacuo.
5- (S) -acetamidomethyl-3- [4'-formyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4'-dimethoxymethyl-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.029 mmol) in dichloromethane Suspended in 60% trifluoroacetic acid (2 ml) at room temperature for 2 hours. This mixture was filtered and the supernatant was evaporated in vacuo to afford the crude product. The crude product was purified by purified HPLC to give the desired product as an oil. Yield 4.9 mg (60%). R _t 3.0 min. MS (m / z): 281.1 [M + H] ⁺ . ¹ H NMR.
BAL resin immobilized 5- (S) -aminomethyl-3- [4'-tert-butoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
Triphenylphosphine (7.61 g, 29.0 mmol) was added 5- (S) -azidomethyl-3- [4'-tert-part with BAL aldehyde resin (33.3 g, 9.67 mmol) in tetrahydrofuran (170 ml). To a mixture of oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (9.76 g, 29.0 mmol) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and then at 75 ° C. for 16 hours. The mixture was cooled to rt and 1 M sodium cyanoborohydride (58.0 ml, 58.0 mmol) in THF was added in one portion. The reaction mixture was stirred for 8 hours. The obtained amine resin was filtered, washed sufficiently with methanol and dichloromethane and dried in vacuo.
BAL resin immobilized 5- (S) -aminomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one
A mixture of 1 M chlorotrimethylsilane (290 ml, 0.29 mmol) in dichloromethane and 1 M phenol (290 ml, 0.29 mmol) in dichloromethane was added to BAL resin fixed 5- (S) -aminomethyl-3- [4 '. -tert-butoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one was added and the reaction mixture was stirred for 36 hours at room temperature. The obtained acid resin was filtered, washed sufficiently with methanol and dichloromethane and dried in vacuo.
General method for synthesizing immobilized 5- (S) -acylaminomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one
Selected carboxylic acid (18.0 mmol), pyridine (1.46 ml, 18.0 n-tmol) and diisopropylcarbodiimide (1.35 ml, 9.90 mmol) in a mixture of dimethylformamide-dichloromethane (4: 1, 8 ml) Was stirred at room temperature for 1 hour. Appropriate BAL resin immobilized 5- (S) -aminomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one (1.80 mmol) is added and the mixture is stirred for 16 hours at room temperature. Stir for a while (or until the ninhydrin test indicates that acylation is complete). The resin was filtered off, washed well with dimethylformamide, MeOH, dichloromethane and dried in vacuo.
5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one
Acetic anhydride-pyridine-dichloromethane solution (1: 1.5: 3, 200 ml) was fixed 5- (S) -acylaminomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidine- To 2-one (33.3 g, 9.67 mmol) was added and the mixture was stirred overnight. The resin was filtered off, washed well with methanol and dichloromethane and dried in vacuo. Acylated resin (0.100 g, 0.029 mmol) was suspended in 60% trifluoroacetic acid in dichloromethane for 2 hours at room temperature. The mixture was filtered and the supernatant was evaporated in vacuo to give a white solid which was washed with ether and dried in vacuo. Yield 7.6 mg (88%); mp 252-253 ° C. ¹ H NMR.
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
Pentafluorophenyl trifluoroacetate (7.10 ml, 41.3 mmol) was added BAL resin fixed 5- (S) -acetamidomethyl-3- [4 in N-methylpyrrolidin-2-one (35 ml). '-Carboxy-3'-fluorophenyl] oxazolidin-2-one (20.4 g, 5.90 mmol) and pyridine (8 ml) were added to the mixture. The reaction mixture was stirred at rt for 16 h. The resin was filtered off, washed with N-methylpyrrolidin-2-one and dichloromethane and dried in vacuo. The resin was separated and analyzed using 60% trifluoroacetic acid in dichloromethane (2 ml / 0.100 g, 0.029 mmol of resin, 2 hours). The supernatant obtained was evaporated in vacuo to give the pentafluorophenyl ester released as a white solid. This solid was purified by purified TLC (eluent: 10% MeOH in dichloromethane). Yield 8.0 mg (60%), mp 172-173 ° C. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(4 "-morpholinophenylamino) carbonyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.029 mmol) was stirred with 4-morpholinoaniline (0.155 mg, 0.87 mmol) in 10% pyridine (2 ml) in dimethylformamide for 24 hours. The resin was filtered off, washed well with dimethylformamide, MeOH, DCM and dried in vacuo. The dry resin was separated with 60% trifluoroacetic acid (2 ml) in dichloromethane at room temperature for 2 hours. The supernatant was evaporated in vacuo and the crude product was purified by TLC (eluent: 10% methanol in dichloromethane) to afford the product as a white solid. Yield 6.6 mg (50%). MS (m / s): 457.2 [M + H] ⁺ . ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(3 "-pyridylamino) carbonyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.029 mmol) was stirred for 24 h with 3-aminopyridine (0.082 mg, 0.87 mmol) in 10% pyridine (2 ml) in dimethylformamide. The resin was filtered off, washed well with dimethylformamide, MeOH, DCM and dried in vacuo. The dry resin was separated with 60% trifluoroacetic acid (2 ml) in dichloromethane at room temperature for 2 hours. The supernatant was evaporated in vacuo and the crude product was purified by purified TLC (eluent: 10% methanol in dichloromethane) to afford the product as a white solid. Yield 4.3 mg (40%). MS (m / z): 373.1 [M + H] ⁺ . ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(4 "-morpholino) carbonyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.029 mmol) was stirred with morpholine (0.10 ml, 0.116 mmol) in N-methylpyrrolidin-2-one (2 ml) for 16 h. The resin was filtered, washed sufficiently with N-methylpyrrolidin-2-one, MeOH, dichloromethane and dried in vacuo. The dry resin was separated with 60% trifluoroacetic acid (2 ml) in dichloromethane at room temperature for 2 hours. The resin was filtered off, the filtrate was evaporated in vacuo and the crude product was purified by purified TLC (eluent: 10% MeOH in dichloromethane) to afford the product as a white solid. Yield 5.6 mg (53%), mp 210-211 ° C. ¹ H NMR.
BAL resin immobilized wainreb amide: 5- (S) -acetamidomethyl-3- [4'-N-methoxy-N-methylaminocarbonyl-3'-fluorophenyl] oxazolidine-2- On
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (1.00 g, 0.29 mmol) with N-methoxy-N-methylamine hydrochloride (0.59 g, 6.0 mmol) and triethylamine (0.84 ml, 6.0 mmol) in N-methylpyrrolidin-2-one for 16 hours at room temperature. Stirred. The resin was filtered off, washed well with N-methylpyrrolidin-2-one, MeOH, dichloromethane and dried in vacuo. A portion of the resin (approximately 10 mg) was separated with 60% trifluoroacetic acid (0.20 ml) in dichloromethane for 2 hours at room temperature. The supernatant was concentrated in vacuo to give the separated Wainrep amide as an oil. R _t 2.8 min. MS (m / z): 340.1 [M + H] ⁺ . ¹ H NMR.
BAL resin immobilized aldehyde 5- (S) -acetamidomethyl-3- [4'-formyl-3'-fluorophenyl] oxazolidin-2-one
0.1 M lithium aluminum hydride (0.52 ml) in tetrahydrofuran was added BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-N-methoxy-N in tetrahydrofuran (2 ml) -Methylaminocarbonyl-3'-fluorophenyl] oxazolidin-2-one (0.150 g, 0.044 mmol) was added dropwise with stirring at -78 ° C. The mixture was stirred at -78 ° C for 4-6 h. Then it was allowed to warm to room temperature overnight. The resin was filtered off, washed well with tetrahydrofuran, MeOH, dichloromethane and dried in vacuo. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4'-formyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4'-formyl-3'-fluorophenyl] oxazolidin-2-one (0.150 g, 0.0435 mol) in 60 in dichloromethane Separated with% trifluoroacetic acid (2 ml) at room temperature for 2 hours. The supernatant was evaporated in vacuo to afford the crude product as an oil. MS (m / z): 281.1 [M + H] ⁺ . ¹ H NMR.
5- (S) -acetamidomethyl-3- [4'-acetyl-3'-fluorophenyl] oxazolidin-2-one
3.0 M methylmagnesium iodide (0.022 ml, 0.066 mmol) in diethyl ether was added BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-N- in tetrahydrofuran (2 ml). To methoxy-N-methylaminocarbonyl-3'-fluorophenyl] oxazolidin-2-one (0.150 g, 0.044 mmol) was added dropwise with stirring at -78 ° C. The mixture was stirred at −78 ° C. for 5-10 hours and allowed to warm to room temperature overnight. The resin was filtered off, washed well with tetrahydrofuran, MeOH, dichloromethane and dried in vacuo. The resulting ketone resin was separated with 60% trifluoroacetic acid (2 ml) in dichloromethane at room temperature for 2 hours. The supernatant was evaporated in vacuo to afford the desired product.
BAL resin immobilized acyl azide 5- (S) -acetamidomethyl-3- [4'-azidocarbonyl-3'-fluorophenyl] oxazolidin-2-one
Method A: Using azidotrimethylsilane and tetrabutylammonium fluoride. 1 M tetrabutylammonium fluoride (0.609 ml, 0.609 mmol) in tetrahydrofuran was added to azidotrimethylsilane (0.34 ml, 2.6 mmol) in tetrahydrofuran (3.5 ml) and the mixture was left at room temperature for 0.5 hours. . The obtained solution was added to BAL resin fixed 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one The mixture was stirred at room temperature for 4-5 hours. Acyl azide resin was filtered off and washed with dichloromethane and acetone. IR (cm- ¹ ): 2136 (N ₃ ). The resin was analyzed by separation with 60% trifluoroacetic acid (2 ml / 0.100 g, 0.029 mmol of resin, 2 hours) in dichloromethane. The supernatant obtained was evaporated in vacuo to give the released acyl azide product. R _t 3.3 min. IR (cm- ¹ ): 2138 (N ₃ ). MS (m / z): 278.1 [MN ₂ + H] ⁺ . ¹ H NMR.
Method B: Use tetrabutylammonium azide. BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (tentagel HL NH ₂ resin, 1.00 g, approximately 0.40 mmol / g) was stirred with tetrabutylammonium azide (0.797 g, 2.8 mmol) in tetrahydrofuran (10 ml) at room temperature for 5 hours. The resin was filtered off, washed well with dichloromethane and acetone and dried in vacuo.
BAL resin immobilized protected amine 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidine-2- On
BAL resin immobilized acyl azide 5- (S) -acetamidomethyl-3- [4'-azidocarbonyl-3'-fluorophenyl] oxazolidine-2- in tetrahydrofuran (7.0 ml) Warm (0.75 g, 0.22 mmol) and (9-fluorenyl) methanol (1.18 g, 6.0 mmol) were stirred at 80 ° C. for 4 h. The resulting Fmoc-protected amine resin was washed with tetrahydrofuran, MeOH, dichloromethane and dried in vacuo.
5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one
Method A. BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidine-2- Warm (0.200 g) was separated for 2 h with 60% trifluoroacetic acid (2 ml) in dichloromethane The supernatant obtained was evaporated in vacuo to give the released Fmoc carbamate product, R _t 4.3 min. (m / z):. 490.2 [M + H] + 1 H NMR.
Method B. 9-Fluorenylmethyl chloroformate (0.039 g, 0.15 mmol) in dichloromethane (0.300 ml) and pyridine (0.05 ml, 0.62 mmol) was added BAL resin fixed 5- (S) -acetamidomethyl 3-3- [4'-amino-3'-fluorophenyl] oxazolidin-2-one was added and the mixture was stirred at room temperature for 2 hours. The obtained resin was worked up and separated as described in Method A above. R _t 4.3 min. MS (m / z): 490.2 [M + H] ⁺ . ¹ H NMR.
BAL resin immobilized amine 5- (S) -acetamidomethyl-3- [4'-amino-3'-fluorophenyl] oxazolidin-2-one.
Method A. BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidine-2- Warm (approximately 0.200 g) was deprotected with 20% piperidine (2 ml) in dimethylformamide for 20 minutes The resulting amine resin was washed thoroughly with MeOH, dichloromethane and dried in vacuo. . 60% trifluoroacetic acid and analyzed by separating the acetic acid (2 ml, 2 times) and the resulting supernatant was evaporated in vacuo to give the emitted amine product MS (m / z):. . 268.1 [M + H] + 1 H NMR.
Method B. BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 ′-(pentafluorophenyl) oxycarbonyl-3′-fluorophenyl] oxa in tetrahydrofuran (5 ml) Zolidin-2-one (0.200 mg), azidotrimethylsilane (0.240 mg, 1.74 mmol) and a catalytic amount of tetrabutylammonium fluoride (0.05 ml, 0.05 mmol) were stirred at 80 ° C. for 4 hours. The obtained amine resin was sufficiently washed with MeOH and dichloromethane. It was dried in vacuo and analyzed as described in Method A above. MS (m / z): 268.1 [M + H] ⁺ . ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(p-nitrobenzene) sulfonamido-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4'-amino-3'-fluorophenyl] oxazolidin-2-one (0.200 g) in p in dichloromethane (2.0 ml) -Nitrobenzenesulfonyl chloride (0.108 g, 0.50 mmol) and N-methylmorpholine (0.200 ml) were stirred at room temperature for 14 hours. The obtained sulfonamide resin was filtered, washed sufficiently with dimethylformamide, MeOH and dichloromethane and dried in vacuo. The dry resin was separated by 60% trifluoroacetic acid (2 ml, 2 hours) in dichloromethane. The supernatant obtained was evaporated in vacuo to give the sulfonamide product. MS (m / z): 453.1 [M + H] ⁺ . ¹ H NMR.
N ^1- (9-fluorenylmethoxycarbonyl) -N ^2- [4 '-(5 "-(S) -acetamidomethyloxazolidin-2-one-3" -yl) -3'- Fluorophenyl] thiourea
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4'-amino-3'-fluorophenyl] oxazolidin-2-one (0.200 g) in 9 in dichloromethane (2.0 ml) It was stirred with fluorenylmethoxycarbonylisocyanate (0.140 g, 0.50 mmol) at room temperature for 14 hours. The obtained thiourea resin was filtered, washed sufficiently with dimethylformamide, MeOH and dichloromethane and dried in vacuo. The dry resin was separated by 60% trifluoroacetic acid (2 ml, 2 hours) in dichloromethane. The supernatant obtained was evaporated in vacuo to give the sulfonamide product. R _t 4.5 min. MS (m / z): 549.1 [M + H] ⁺ . ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(4 "-phenylthiazol-2" -yl) amino-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized N ^1- (9-fluorenylmethoxycarbonyl) -N ^2- [4 '-(5 "-(S) -acetamidomethyloxazolidin-2-one-3" -yl) -3'-fluorophenyl] thiourea was deprotected with 20% piperidine (2 ml) in dimethylformamide for 40 minutes, filtered, washed well with MeOH, dichloromethane and dried in vacuo. 2-bromoacetophenone (0.100 g, 0.50 mmol) in tetrahydrofuran (2.0 ml) was added and the mixture was stirred at rt for 2 h. The obtained thiazole resin was sufficiently washed with MeOH and dichloromethane and dried in vacuo. The dry resin was separated by 60% trifluoroacetic acid (2 ml, 2 hours) in dichloromethane. The supernatant obtained was evaporated in vacuo to afford the thiazole product. R _t 3.9 min. MS (m / z): 427.1 [M + H] ⁺ . ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(5 "-amino-4" -cyanooxazol-2 "-yl) -3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (0.100 g) Stirred with aminomalonitrile tosylate (0.253 g, 1 mmol) in a mixture of anhydrous pyridine and N-methylpyrrolidin-2-one (1: 1, 2.0 ml) for 8-10 hours at 60 ° C. The obtained aminooxazole resin was sufficiently washed with MeOH and dichloromethane and dried in vacuo. The dry resin was separated by 60% trifluoroacetic acid (2 ml, 2 hours) in dichloromethane. The supernatant obtained was evaporated in vacuo to afford the oxazole product. R _t 3.2 min. MS (m / z): 360.1 [M + H] ⁺ . ¹ H NMR.
5- (S) -acetamidomethyl-3- [4'-triphenylmethylthio-3'-fluorophenyl] oxazolidin-2-one
Triphenylphosphine (2.82 g, 10.8 mmol) was added 5- (S) -azidomethyl-3- [4'-triphenylmethylthio-3'-fluorophenyl] oxazolidine- in THF (40 ml). To the solution of 2-one (5.00 g, 9.79 mmol) was added in several portions and the mixture was stirred at room temperature for 2 hours. Water (1.41 ml, 78.3 mmol) was added and the mixture was heated at 40 ° C. overnight. The solvent was removed in vacuo and the oily residue was dissolved in dichloromethane (50 ml). Acetic anhydride (4.62 ml, 49.0 mmol) and pyridine (7.92 ml, 97.9 mmol) were added and the mixture was stirred at rt for 8 h. The solvent was removed in vacuo and the crude product was purified by silica gel flash column chromatography (eluent: 30% ethyl acetate in hexanes) to give the product as a foam (4.98 g, 97%). MS: 527 [M + H] ⁺ . ¹ H NMR.
BAL resin immobilized 5- (S) -aminomethyl-3- [4'-triphenylmethylthio-3'-fluorophenyl] oxazolidin-2-one
Diisopropylcarbodiimide (4.24 ml, 27.0 mmol) was added 4- (4-formyl-3,5-dimethoxyphenoxy) butyric acid (13.19 g, 49.2 mmol) and pyridine (20 in dichloromethane (190 ml). ml), and the mixture was stirred at room temperature for 1 hour. Tentagel S-NH ₂ resin (30.0 g, 12.3 mmol, manufactured by Rapp Polymere) was added, and the mixture was stirred at room temperature overnight. The obtained BAL resin was filtered, washed sufficiently with methanol and dichloromethane and dried in vacuo. Triphenylphosphine (7.97 g, 0.0304 mol) was added to the BAL aldehyde resin (50.9 g, 0.0209 mol) and 5- (S) -azidomethyl-3- [4'-triphenylmethylthio in THF (200 ml). To a mixture of -3'-fluorophenyl] oxazolidin-2-one (15.5 g, 30.4 mmol) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and then heated at 75 ° C. for 16 hours. The mixture was cooled to rt and 1 M sodium cyanoborohydride (62.7 ml, 62.7 mmol) in THF was added. The mixture was stirred at rt for 8 h. The resin was filtered off, washed thoroughly with methanol and dichloromethane and dried in vacuo.
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -aminomethyl-3- [4'-triphenylmethylthio-3'-fluorophenyl] oxazolidin-2-one (5.00 g, 2.05 mmol) in 5 dichloromethane Suspended in% trifluoroacetic acid and 2.5% triisopropylsilane (50 ml) and the mixture was stirred for 1 hour. The resin was filtered off and the process was repeated for an additional 30 minutes with 5% trifluoroacetic acid and 2.5% triisopropylsilane (50 ml) in fresh dichloromethane. The resin was filtered off and washed well with dichloromethane. The thiol resin obtained was immediately suspended in a mixture of acetic anhydride (20 ml) and pyridine (30 ml) in DCM (50 ml) and the mixture was stirred at rt overnight. The resin was filtered off, washed well with dichloromethane and dried in vacuo.
5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidin-2-one (0.15 g, 0.041 mmol) in 60 in dichloromethane It was suspended in% trifluoroacetic acid at room temperature for 2 hours. The supernatant was evaporated in vacuo and the crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 8.7 mg (67%). MS: 327 [M + H] ⁺ . ¹ H NMR.
Ester oxazolidinone derivatives
General method for preparing 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluoromethyl] oxazolidin-2-one
Method A. 4.37 M sodium methoxide (0.0927 ml, 0.405 mmol) in methanol was added with an appropriate BAL resin fixed 5- () in a polar aprotic solvent (preferably N-methylpyrrolidin-2-one, 1.5 ml). S) -amidomethyl-3- [4'-acylthio-3'-fluorophenyl] oxazolidin-2-one (prepared as described above, 0.15 g, 0.041 mmol) and The mixture is stirred for 5-25 minutes (acetylated compound is usually completed within 5 minutes). In some cases, an organic base (eg, tetramethylguanidine or alkylamine) was used in place of sodium methoxide. Appropriate alkylation or (hetero) arylation reagents (0.8-1.6 mmol) were added and the mixture was stirred at room temperature for 12-36 hours (usually completed overnight). The resin was washed thoroughly with N-methylpyrrolidin-2-one, dichloromethane and methanol. The resin was suspended in 60% trifluoroacetic acid in dichloromethane and stirred at room temperature for 2 hours. The supernatant was evaporated in vacuo and the crude product was purified by TLC (eluent: methanol-dichloromethane mixture).
Method B. 5% trifluoroacetic acid and 2.5% triisopropylsilane (2.0 ml) in dichloromethane were added to 5- (S) -acetamidomethyl-3- [4'-triphenylmethylthio-3'-fluoro Rophenyl] oxazolidin-2-one (0.10 g, 0.19 mmol) was added and the mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the residue was dissolved in methanol (3 ml). Appropriate alkylation or (hetero) arylation reagents (19-0.38 mmol) were added and 4.37 M sodium methoxide (0.087 ml, 0.380 mmol) in methanol was added dropwise. In some cases, an organic base (eg, tetramethylguanidine or alkylamine) was used in place of sodium methoxide. The mixture was stirred at 20-70 ° C. for 2-24 hours (usually 2 hours at room temperature). The solvent was removed in vacuo and the crude product was purified by TLC (eluent: methanol-dichloromethane mixture).
5- (S) -acetamidomethyl-3- [4 '-(6 "-chloropyridazin-3" -yl) thio-3'-fluorophenyl] oxazolidin-2-one
BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluoro from 2-one with 3,6-dichloropyridazine (0.12 g, 0.81 mmol) Prepared according to Method A of the general method for preparing rophenyl] oxazolidin-2-one. Synthesis was performed overnight at room temperature, and the isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 3.9 mg (24%). MS: 397 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(4 ", 6" -dimethoxy-1 ", 3", 5 "-triazine-2" -yl) thio-3'-fluoro Lophenyl] oxazolidin-2-one
BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 from 2-one and 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.1 g, 0.81 mmol) Prepared according to Method A of the general method for preparing '-(substituted) thio-3'-fluorophenyl] oxazolidin-2-one. Synthesis was performed overnight at room temperature, and the isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 6.1 mg (36%). MS: 424 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(5 "-nitropyridin-2" -yl) thio-3'-fluorophenyl] oxazolidin-2-one
BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluoro from 2-one and 2-chloro-5-nitropyridine (0.13 g, 0.81 mmol) Prepared according to Method A of the general method for preparing rophenyl] oxazolidin-2-one. Synthesis was performed overnight at room temperature, and the isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 7.0 mg (44%). MS: 407 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- (4 '-[2 "-(4"'-morpholino) ethyl] thio-3'-fluorophenyl) oxazolidin-2-one
BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio- from 2-one and 4- (2-chloroethyl) morpholine hydrochloride (0.28 g, 0.81 mmol) Prepared according to Method A of the general method for preparing 3'-fluorophenyl] oxazolidin-2-one. Synthesis was performed overnight at room temperature, and the isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 2.4 mg (15%). MS: 398 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(pyridin-3 "-yl) methylthio-3'-fluorophenyl) oxazolidin-2-one
BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'- from 2-one and 3- (chloromethyl) pyridine hydrochloride (0.13 g, 0.81 mmol) Prepared according to Method A of the general method for preparing fluorophenyl] oxazolidin-2-ones. Synthesis was performed overnight at room temperature, and the isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 3.6 mg (24%). MS: 376 [M + H] ⁺ _.
5- (S) -acetamidomethyl-3- (4'-methylthio-3'-fluorophenyl) oxazolidin-2-one
BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluorophenyl] oxa from 2-one and methyl iodide (0.05 ml, 0.81 mmol) Prepared according to Method A of the general method for preparing zolidin-2-one. Synthesis was performed overnight at room temperature, and the isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 6.3 mg (52%). MS: 299 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(2 "-methylthiazol-4" -yl) methylthio-3'-fluorophenyl] oxazolidin-2-one
BAL resin fixed 5- (S) -acetamidomethyl-3- [4'-acetylthio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio- from 2-one and 4-chloromethyl-2-methylthiazole hydrochloride (0.15 g, 0.81 mmol) Prepared according to Method A of the general method for preparing 3'-fluorophenyl] oxazolidin-2-one. Synthesis was performed overnight at room temperature, and the isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 6.9 mg (43%). MS: 396 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(1 ", 2", 4 "-oxadiazol-3" -yl) methylthiazol-4 "-yl) methylthio-3' -Fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) from 2-one and 3-chloromethyl-1,2,4-oxadiazole (0.045 g, 0.38 mmol) Prepared according to Method B of the general method for preparing thio-3'-fluorophenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.043 g (62%). MS: 367 [M + H] ⁺ _.
5- (S) -acetamidomethyl-3- [4 '-(methoxycarbonyl) methylthio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluorophenyl] oxa from 2-one and methyl bromoacetate (0.058 g, 0.38 mmol) Prepared according to Method B of the general method for preparing zolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.056 g (83%). mp 119-120 ° C. MS: 357 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(2 "-methoxyethyl) thio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluorophenyl from 2-one and 2-chloroethyl methyl ether (0.036 g, 0.38 mmol) ] Produced according to Method B of the general method for preparing oxazolidin-2-ones. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.034 g (52%). MS (m / z): 343 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(3 "-nitrothien-2" -yl) thio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'- from 2-one and 2-chloro-3-nitrothiophene (0.062 g, 0.38 mmol) Prepared according to Method B of the general method for preparing fluorophenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.066 g (85%). mp 149-195 ° C. MS (m / z): 412 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(acetylmethyl) thio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluorophenyl] oxazolidine from 2-one and chloroacetone (0.062 g, 0.38 mmol) Prepared according to Method B of the general method for preparing the 2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.039 g (61%). MS (m / z): 341 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(2 "-hydroxyethyl) thio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluorophenyl] from 2-one and 2-bromoethanol (0.048 g, 0.38 mmol) Prepared according to Method B of the general method for preparing oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.045 g (72%). MS (m / z): 329 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(5 "-carboxypyridin-3" -yl) thio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'- from 2-one and t-butyl 2-chloronicotinate (0.081 g, 0.38 mmol) Prepared according to Method B of the general method for preparing fluorophenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The intermediate t-butyl ester of the product was deprotected with 20% trifluoroacetic acid (1 ml, 2 hours at room temperature) in dichloromethane. The solvent was evaporated in vacuo and the crude product was washed with diethyl ether. Yield 0.050 g (65%). MS (m / z): 406 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- (4'-cyclopropylmethylthio-3'-fluorophenyl) oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluorophenyl] oxa from 2-one and chloromethyl cyclopropane (0.051 g, 0.38 mmol) Prepared according to Method B of the general method for preparing zolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.053 g (82%). MS (m / z): 339 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(3 "-cyanoethyl) thio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluoro from 2-one and 3-bromopropionitrile (0.051 g, 0.38 mmol) Prepared according to Method B of the general method for preparing phenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.032 g (50%). MS (m / z): 338 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(5 "-nitrothiazol-2" -yl) thio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3' from 2-one and 2-bromo-5-nitrothiazole (0.079 g, 0.38 mmol) Prepared according to Method B of the general method for preparing -fluorophenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.061 g (78%). MS (m / z): 413 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(5 "-phenyl-1", 2 ", 4" -oxazol-3 "-yl) methylthio-3'-fluorophenyl] Oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4'- from 2-one and 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (0.074 g, 0.38 mmol) Prepared according to Method B of the general method for preparing (substituted) thio-3'-fluorophenyl] oxazolidin-2-ones. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.040 g (47%). MS (m / z): 443 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(3 "-methoxycarbonylpropane-2" -one-1 "-yl) thio-3'-fluorophenyl] oxazolidine- 2-on
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluorophenyl from 2-one and methyl 4-chloroacetoacetate (0.057 g, 0.38 mmol) ] Produced according to Method B of the general method for preparing oxazolidin-2-ones. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.027 g (35%). MS (m / z): 399 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(2 "-chloroethyl) thio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'- from 2-one and 1-bromo-2-chloroethane (0.055 g, 0.38 mmol) Prepared according to Method B of the general method for preparing fluorophenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.047 g (72%). MS (m / z): 347 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(1 "-ethoxycarbonyl-1", 1 "-dimethyl) methylthio-3'-fluorophenyl] oxazolidine-2- On
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluoro from 2-one and ethyl 2-bromoisobutyrate (0.074 g, 0.38 mmol) Prepared according to Method B of the general method for preparing phenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.061 g (80%). MS (m / z): 399 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(2 "-diethoxyphosphinoyl) ethylthio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio- from 2-one and diethyl (2-bromoethyl) phosphonate (0.093 g, 0.38 mmol) Prepared according to Method B of the general method for preparing 3'-fluorophenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.043 g (50%). MS (m / z): 449 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(thiocyano) methylthio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) thio-3'-fluorophenyl] from 2-one with chloromethyl thiocyanate (0.041 g, 0.38 mmol) Prepared according to Method B of the general method for preparing oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.022 g (35%). MS (m / z): 324 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(3 "-methyltetrahydrofuran-2" -one-3 "-yl) thio-3'-fluorophenyl] oxazolidine-2 -On
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(substituted) from 2-one and α-bromo-α-methyl-γ-butyrolactone (0.068 g, 0.38 mmol) Prepared according to Method B of the general method for preparing thio-3'-fluorophenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.035 g (48%). MS (m / z): 383 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(2 "-diethylamino) ethylthio-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(triphenylmethyl) thio-3'-fluorophenyl] oxazolidine- in N-methylpyrrolidin-2-one (1 ml) 5- (S)-(N-acylaminomethyl) from 2-one and 2- (diethylamino) ethyl chloride hydrochloride (0.065 g, 0.38 mmol) and 4.37 M of sodium methoxide (0.174 ml, 0.760 mmol) Prepared according to Method B of the general method for preparing -3- [4 '-(substituted) thio-3'-fluorophenyl] oxazolidin-2-one. Synthesis was performed at room temperature for 2 hours. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.011 g (15%). MS (m / z): 383 [M + H] ⁺ _. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(2 "-hydroxyethyl) sulfinyl-3'-fluorophenyl] oxazolidin-2-one
Sodium periodate (0.014 g, 0.065 mmol) in water (0.5 ml) was added 5- (S) -acetamidomethyl-3- [4 '-(2 "-hydroxyethyl) thio in methanol (1 ml). -3'-fluorophenyl] oxazolidin-2-one (0.020 g, 0.061 mmol) was added and the mixture was stirred at rt overnight The solvent was removed in vacuo and the residue was ethyl acetate (approximately 5 ml). The resulting solution was washed with water, brine and dried over MgSO _{4. The} solvent was removed in vacuo and the crude product was purified by TLC (eluent: 10% methanol in dichloromethane), yield 0.018 g ( 86%) MS (m / z ):.. 345 [M + H] + 1 H NMR.
5- (S) -acetamidomethyl-3- [4 '-(2 "-hydroxyethyl) sulfonyl-3'-fluorophenyl] oxazolidin-2-one
30% hydrogen peroxide (0.023 ml, 0.244 mmol) was added 5- (S) -acetamidomethyl-3- [4 '-(2 "-hydroxyethyl) thio-3'-fluorophenyl in acetic acid (1 ml). ] Oxazolidin-2-one (0.020 g, 0.061 mmol) was added and the mixture was stirred overnight at 60 ° C. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (approximately 5 ml). The solution was washed with water, brine and dried over MgSO _{4. The} solvent was removed in vacuo and the crude product was purified by TLC (eluent: 10% methanol in dichloromethane) yield 0.017 g (77%). Mp 162 -163 ℃ MS (m / z) :.. 361 [M + H] + 1 H NMR.
Ester oxazolidinone derivatives
5- (S)-(N-acetylaminomethyl) -3- [4 '-(tert-butoxy) carbonyl-3'-fluorophenyl] oxazolidin-2-one
Triphenylphosphine (0.521 g, 1.99 mmol) was added 5- (S)-(N-azidomethyl) -3- [4 '-(tert-butoxy) carbonyl-3'- in THF (10 ml). To the solution of fluorophenyl] oxazolidin-2-one (0.607 g, 1.80 mmol) was added in several portions and the mixture was stirred at room temperature for 2 hours. Water (0.259 ml, 14.4 mmol) was added and the mixture was heated at 40 ° C. overnight. The solvent was removed in vacuo. The oily residue was dissolved in a mixture of acetic anhydride (0.849 ml, 9.00 mmol) and pyridine (0.146 ml, 18.0 mmol) in dichloromethane (10 ml) and stirred for 4 hours. The solvent was removed in vacuo and the crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.62 g (98%). MS (m / z): 353 [M + H] ⁺ . ¹ H NMR.
5- (S)-(N-acetylaminomethyl) -3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one
5- (S)-(N-acetylaminomethyl) -3- [4 '-(4 "-(tert-butoxy) carbonyl-3'-fluorophenyl] oxazolidin-2-one (6.20 g , 17.5 mmol) was dissolved in 20% trifluoroacetic acid in dichloromethane and the mixture was stirred at rt overnight The solvent was removed in vacuo and the residue was treated with ether to give the product as a white solid. yield 5.20 g (99%) mp 252-253 ℃ MS:... 297 [M + H] + 1 H NMR.
Prepare 5- (S)-(N-acylaminomethyl) -3- [4 '-[alkyl [or (hetero) aryl] oxy] carbonyl-3'-fluorophenyl] oxazolidin-2-one Common way to
Method A. Suitable 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(pentafluorophenyl) oxycarbonyl-3'-fluoro of the same type as in formula (5) Phenyl] oxazolidin-2-one resin (0.1 mmol, prepared as described above by two-step acylation of the resin of formula 4 with the appropriate N-acylation reagent, followed by Pfp-activation) Selected alcohol reagent (1 to 3 mmol, usually 1 to 1) in an aprotic solvent (N, N-dimethylformamide, dichloromethane or dimethylsulfoxide; preferably N, N-dimethylformamide, 4 to 6 ml) 2 mmol) and 4-dimethylaminopyridine (0.2-1 mmol, usually 1 mmol) The mixture was stirred at 20-70 ° C. for 6-48 hours (usually overnight at room temperature). Washed thoroughly with N, N-dimethylformamide, dichloromethane, methanol, dried in vacuo, and then dried in 60% dichloromethane. It was isolated by acid (5 ml, 2 times) fluoro. Evaporation of the resulting supernatant in vacuo The crude product was purified by HPLC or TLC.
Method B. Appropriate alkylation reagent (0.35 to 1.2 mmol; preferably 1 mmol) was added 5- (S)-(N-acetamidomethyl) -3- [4 in N, N-dimethylformamide (2 ml). To '-(pentafluorophenyloxy) carbonyl-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.34 mmol) and potassium carbonate (0.187 g, 1.35 mmol) and add the mixture to 20 Stir at 6-24 h (usually overnight at room temperature) at -80 ° C. Water (approximately 10-15 ml) was added and the mixture was extracted with ethyl acetate (approximately 3 × 20 ml). The combined organic solvents were washed with water, brine and dried over MgSO ₄ . The solvent was evaporated in vacuo and the crude product was purified by HPLC or TLC.
5- (S)-(N-acetylaminomethyl) -3- [4'-cyclopropylmethoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin 5- (S)-(N-acylaminomethyl) -3- [4 '-(pentafluorophenyl) with 4-dimethylaminopyridine (1 mmol) in N, N-dimethylformamide (4 ml) 5- (S)-(N-acylaminomethyl) from oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol) and hydroxymethylcyclopropane (0.144 g, 2 mmol) Prepared according to Method A of the general method for preparing -3- [4 '-[alkyl [or (hetero) aryl] oxy] carbonyl-3'-fluorophenyl] oxazolidin-2-one. The reaction was carried out overnight at room temperature. The isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). MS (m / z): 350 [M + H] ⁺ .
Alternatively, 5- (S)-(N-acetamidomethyl) -3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.34 mmol) and (bro This compound was prepared according to Method B of the aforementioned general method from the mother methyl) cyclopropane (0.098 ml, 1 mmol). The reaction was performed at 70 ° C. overnight. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.100 g (85%). MS (m / z): 350 [M + H] ⁺ . ¹ H NMR.
5- (S)-(N-acetamidomethyl) -3- [4'-methoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S)-(N-acetamidomethyl) -3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.34 mmol) and methyl iodide ( 0.063 ml, 1 mmol) from 5- (S)-(N-acylaminomethyl) -3- [4 '-[alkyl [or (hetero) aryl] oxy] carbonyl-3'-fluorophenyl] oxazoli Prepared according to Method B of the general method for preparing din-2-one. The reaction was carried out overnight at room temperature. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 104 mg (99%). MS (m / z): 311 [M + H] ⁺ . ¹ H NMR.
5- (S)-(N-acetamidomethyl) -3- [4'-isopropoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S)-(N-acetamidomethyl) -3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.34 mmol) and 2-bromopropane 5- (S)-(N-acylaminomethyl) -3- [4 '-[alkyl [or (hetero) aryl] oxy] carbonyl-3'-fluorophenyl] oxa from (0.095 ml, 1 mmol) Prepared according to Method B of the general method for preparing zolidin-2-one. The reaction was performed at 70 ° C. overnight. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 105 mg (92%). MS (m / z): 339 [M + H] ⁺ . ¹ H NMR.
5- (S)-(N-acetamidomethyl) -3- [4'-ethoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S)-(N-acetamidomethyl) -3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one (0.100 g, 0.34 mmol) and ethyl iodide ( 0.081 ml, 1 mmol) from 5- (S)-(N-acylaminomethyl) -3- [4 '-[alkyl [or (hetero) aryl] oxy] carbonyl-3'-fluorophenyl] oxazoli Prepared according to Method B of the general method for preparing din-2-one. The reaction was carried out overnight at room temperature. The crude product was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 107 mg (98%). MS (m / z): 325 [M + H] ⁺ . ¹ H NMR.
5- (S)-(N-acetamidomethyl) -3- [4 '-[(CN-isopropylidene) imino] oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S)-(N-acetamidomethyl) -3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one in N, N-dimethylformamide (2 ml) 0.100 g, 0.34 mmol), 4- (dimethylamino) pyridine (0.041 g, 0.34 mmol), a mixture of diisopropylcarbodiimide (0.053 ml, 0.34 mmol) and acetone oxime (0.025 g, 0.34 mmol) at room temperature Stir overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO ₄ . The solvent was removed in vacuo and the residue was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.098 g (83%). MS (m / z): 352 [M + H] ⁺ . ¹ H NMR.
5- (S)-(N-acetamidomethyl) -3- [4 '-(pyridin-3 "-yl) methoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S)-(N-acetamidomethyl) -3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one in N, N-dimethylformamide (2 ml) 0.100 g, 0.34 mmol), 4- (dimethylamino) pyridine (0.041 g, 0.34 mmol), diisopropylcarbodiimide (0.053 ml, 0.34 mmol) and 3-pyridylcarbinol (0.033 g, 0.34 mmol) The mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO ₄ . The solvent was removed in vacuo and the residue was purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.094 g (72%). MS (m / z): 388 [M + H] ⁺ . ¹ H NMR.
Amide oxazolidinone derivative
5- (S)-(N-acylaminomethyl) -3- [4 '-[(non) substituted amino] carbonyl-3'-fluorophenyl] oxazolidin-2-one (Formula 7) General method of manufacturing
Method A. Suitable 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(pentafluorophenyl) oxycarbonyl-3'-fluoro of the same type as in formula (5) Phenyl] oxazolidin-2-one resin (0.029 mmol, BAL resin immobilized 5- (S) -aminomethyl-3- [4'-carboxy, using appropriate N-acylation reagents as described above Prepared by two-step acylation of -3'-fluorophenyl] oxazolidin-2-one (Formula 4) followed by Pfp-activation) to a selected amine compound (0.1 to 0.2 mmol; preferably 0.116 mmol) With 10-20% by volume of organic base (pyridine, 2,6-lutidine or diisopropylethylamine), stirring at 25-70 ° C. for 16-48 hours (preferably overnight at 60 ° C.) In some cases, for low soluble amine reagents, dimethyl sulfoxide (0.5 to 1 ml) is added, and in some cases functionalized amines (e.g. amino acids or amino acids). No alcohol) was previously dissolved by adding a silylating reagent (e.g., bis-trimethylsilylacetamide, 0.2 to 0.6 mmol), and then a resin was added, and the reaction was performed under an inert gas (nitrogen) atmosphere. Wash thoroughly with N-methylpyrrolidin-2-one, MeOH, dichloromethane and dry in vacuo The dry resin was separated for 2 hours at room temperature using 60% trifluoroacetic acid (2 ml) in dichloromethane. The resin was filtered off, the filtrate was evaporated in vacuo and the crude product was purified by purified TLC (eluent: MeOH-dichloromethane) or reverse phase HPLC.
Method B. 60% trifluoroacetic acid (5 ml) in dichloromethane was added to 5- (S) -azidomethyl-3- [4'-tert-butoxycarbonyl-3'-fluorophenyl] oxazolidine 2-one (0.336 g, 1 mmol) was added and the solution was left at room temperature for 1 hour. The solvent was removed in vacuo to afford 5- (S) -azidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one (0.280 g, 99%) as dry. . N-trimethylsilyl-N, N-dimethylamine (0.23 ml, 1.2 mmol) was added to the product in anhydrous dichloromethane (3 ml) under a nitrogen atmosphere and the solution was stirred for 15 minutes. Solvent and excess reagent were removed in vacuo and the residue was dissolved in dichloromethane (4 ml). The solution was cooled to approximately 0 ° C. and oxalyl chloride (1.5 mmol, 0.13 ml) was added dropwise followed by the addition of a catalytic amount of N, N-dimethylformamide (approximately 0.01 ml). The mixture was allowed to warm to room temperature and then stirred at room temperature for an additional 2 hours. The solvent was removed in vacuo and the resulting 5- (S) -azidomethyl-3- [4'-chlorocarbonyl-3'-fluorophenyl] oxazolidin-2-one was dried with anhydrous aprotic solvent (preferably Preferably, tetrahydrofuran, pyridine or acetonitrile, 3 to 10 ml). The resulting solution (0.8 ml, approximately 0.2 mmol) is subjected to an aprotic solvent (preferably acetonitrile or pyridine, 1 to 5 ml), optionally comprising an organic base (preferably pyridine, 0.5 to 2 ml) To the appropriate amine reagent (1 mmol). The mixture was stirred at room temperature for 1-5 hours. The solvent was removed in vacuo and the resulting 5- (S) -azidomethyl-3- [4 '-(substituted) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one usually with water Washed and dried in vacuo. Triphenylphosphine (0.262 g, 1.0 mmol) in tetrahydrofuran di (10 ml) was added to the azide intermediate and the mixture was stirred at 45-55 ° C. for 2 hours. Water (0.5 ml) was added and the mixture was stirred at 50-60 ° C. overnight. The solvent was removed in vacuo and the crude crude amine intermediate obtained was usually washed with excess diethyl ether. After adding aprotic solvent (preferably tetrahydrofuran, 5 to 15 ml) and pyridine (0.25 to 0.5 ml) and acetic anhydride (0.2 to 0.5 ml), the mixture is allowed to stand at room temperature for 0.5 to 2 hours ( Usually 1 hour). The solvent was removed in vacuo and the product obtained was usually washed with excess diethyl ether and dried in vacuo.
Method C. Polar aprotic solvents such as N, N-diisopropyl-N-ethylamine (0.34 ml, 2 mmol), N, N-dimethylformamide (3 ml) and tetrahydrofuran (2 ml) 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one (0.296 g, 1 mmol) and coupling reagent in [referably O -(7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU)] and the solution was left at room temperature for 20 minutes. Appropriate amine (1 mmol) is added and an organic base (preferably N, N-diisopropyl-N-ethylamine, 0.17 ml, 1 mmol) is added and the mixture is then heated at 20-60 ° C. for 1-24 h Was stirred (usually 1-2 hours at room temperature). Additional base (usually 1 mmol) was added when the amine salt was added. In some cases, when acylating a less reactive amine, a catalytic amount of 4-dimethylaminopyridine (0.05 to 0.2 mmol) was added. Volatile organic solvents were removed in vacuo. The product was usually isolated by precipitation in excess water (5 to 60 ml) or by extraction in aqueous solution with ethyl acetate (20 to 40 ml). In the latter case, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water, 3% citric acid solution, water, brine, and dried over MgSO ₄ . The organic solvent is removed in vacuo and the product is further purified by washing with excess diethyl ether or crystallizing in a suitable solvent (usually methanol or ethanol).
Method D. N-ethyl-N '-(3-diethylaminopropyl) carbodiimide (0.92 g, 4.8 mmol) was added 5- (S) -acetamido in N, N-dimethylformamide (50 ml). To methyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one (1.18 g, 4.0 mmol) and pentafluorophenol (0.81 g, 4.4 mmol), add this solution to room temperature Stirred for 24 h. Most of the solvent was removed in vacuo and the residue was dissolved in acetonitrile (approx. 40 ml) and the solution was added dropwise with stirring to 3% aqueous citric acid solution (approx. 150 ml). Precipitated 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one was filtered, washed with water and vacuum Dried (yield 1.30 g (70%). Mp 172-173 ° C. Rt 5.2 min). The resulting ester (1 mmol) was dissolved in a polar solvent (preferably tetrahydrofuran or acetonitrile, 10 ml) and the appropriate amine (1-5 mmol) was added. The mixture was stirred at room temperature for 1 to 10 hours (usually 1 to 2 hours). Solvent and excess reagents were removed in vacuo and the product purified by chromatography or crystallized in appropriate solvent.
5- (S) -acetamidomethyl-3- [4 '-(6 "-chloropyridin-3" -yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
Method A. BAL resin in 10% pyridine in N-methylpyrrolidin-2-one Fixed 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(ratio) from' -fluorophenyl] oxazolidin-2-one and 2-chloro-5-aminopyridine Prepared according to Method A of the general method for preparing substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one (70 ° C., 48 h) MS: 407 [M + H] ^+. in order to obtain the hydrochloride form of the compound, dissolved in the material (41 mg, approximately 0.1 mmol) in methanol containing 2 M HCl (5 ml) in 1,4-dioxane for (10 ml). obtained The solution is filtered, the solvent is removed in vacuo and the crude salt is washed with excess diethyl ether.
Method B. 5- (S) -azidomethyl-3- [4'-chlorocarbonyl-3'-fluorophenyl] oxazolidin-2-one and 2-chloro-5- in pyridine (3 ml) 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxa by amide coupling the aminopyridine Prepared according to Method B of the general method for preparing zolidin-2-one (room temperature, 1 hour) The solvent is removed in vacuo and the resulting 5- (S) -azidomethyl-3- [4 '-( 6 "-Chloropyridin-3" -yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one was washed with water (5 x 3 ml) and dried in vacuo. Triphenylphosphine (0.262 g, 1.0 mmol) in 10 ml) was added to the azide intermediate and the mixture was stirred for 2 hours at 45 ° C. Water (0.5 ml) was added and the mixture was stirred at 50 ° C. overnight. The solvent is removed in vacuo and the resulting crude amine intermediate is removed in excess of di Washed with ethyl ether tetrahydrofuran (15 ml) was added, pyridine (0.25 ml) and acetic anhydride (0.2 ml) were added and the mixture was stirred for 1 h at rt The solvent was removed in vacuo and the resulting the product was washed with excess diethyl ether, MS:.. 407 [M + H] + 1 H NMR.
5- (S) -acetamidomethyl-3- [4 '-(thiazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
Method A. BAL resin in 10% pyridine in N-methylpyrrolidin-2-one Fixed 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted from' -fluorophenyl] oxazolidin-2-one and 2-aminothiazole Prepared according to general method A for preparing amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one (room temperature, 24 hours), MS: 379 [M + H] ⁺ Rt 3.8 min. To obtain the hydrochloride form of this compound, the material (38 mg, approximately 0.1 mmol) is dissolved in methanol (10 ml) containing 2 M HCl (5 ml) in 1,4-dioxane, filtered, The solvent was removed in vacuo and the residue was washed with excess diethyl ether.
Method B. From 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 2-aminothiazole (0.10 g, 1 mmol) , 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one Prepared according to the general method of preparation according to Method C. This synthesis was carried out overnight at room temperature The tetrahydrofuran was removed in vacuo and the residue was added to water (60 ml) The resulting suspension was stirred at room temperature for 1 hour. After filtration, the product was washed with excess water and dried in vacuo.
5- (S) -acetamidomethyl-3- [4 '-(4,5-dimethylthiazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
Method A. BAL resin in 10% pyridine in N-methylpyrrolidin-2-one Fixed 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 ") from' -fluorophenyl] oxazolidin-2-one and 2-amino-4,5-dimethylthiazole Prepared according to Method A of the general method for preparing-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one (room temperature, 24 hours) MS: 407 [M &lt; + &gt; H] ⁺ Rt 4.1 min ¹ H NMR.
Method B. From 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 2-amino-4,5-dimethylthiazole, Prepare 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one Prepared according to the general method Method C. Synthesis was carried out for 3 hours at room temperature: MS: 407 [M + H] ⁺ Rt 4.1 min, ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(pyrimidin-4 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
Method A. BAL resin in 10% pyridine in N-methylpyrrolidin-2-one Fixed 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted from' -fluorophenyl] oxazolidin-2-one and 4-aminopyrimidine Prepared according to Method A of the general method for preparing amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one (70 ° C., 48 h) MS: 374 [M + H] ⁺ .Rt 3.4 min. ¹ H NMR.
Method B. 5- (S)-(from 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 4-aminopyrimidine In method C of the general method for preparing N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one . according to prepare synthesis was carried out for 24 hours at room temperature water was added (15 ml), the mixture was allowed to crystallize by placing the product at room temperature for 3 days MS:... 374 [M + H] + Rt 3.4 ^minutes, H NMR.
5- (S) -acetamidomethyl-3- [4 '-(thiazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
Method A. BAL resin in 10% pyridine in N-methylpyrrolidin-2-one Fixed 5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3 From '-fluorophenyl] oxazolidin-2-one and 5-chloro-2-aminothiazole, 5- (S)-(N-acylaminomethyl) -3- [4'-(4 "-( B) Prepared according to the general procedure for preparing substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-ones (70 ° C., 48 h) MS: 413 [M + H] ^{+ 1} H NMR.
Method B. 5- (S) -azidomethyl-3- [4'-chlorocarbonyl-3'- in tetrahydrofuran (approximately 4 ml) and acetonitrile (2.5 ml) comprising pyridine (0.5 ml) By amide coupling fluorophenyl] oxazolidin-2-one and 5-chloro-2-aminothiazole hydrochloride, 5- (S)-(N-acylaminomethyl) -3- [4 '-( Prepared according to Method B of the general method for preparing 4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one. The mixture is stirred at room temperature for 2 hours and Methanol (approximately 7 ml) was added The resulting 5- (S) -azidomethyl-3- [4 '-(thiazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxadia A precipitate of zolidin-2-one was filtered off, washed with methanol (8 ml), diethyl ether and dried in vacuo. Triphenylphosphine (0.31 g, 1.2 mmol) in N-methylpyrrolidin-2-one (1.25 ml) and tetrahydrofuran (1.25 ml) was added to the azide intermediate and the mixture was allowed to stand at room temperature for 2 hours. Stirred. Water (1.0 ml) was added and the mixture was stirred at 50 ° C. overnight. The solvent was removed in vacuo and the resulting crude-amine intermediate was washed with excess diethyl ether. Tetrahydrofuran (8 ml) was added, pyridine (0.5 ml) and acetic anhydride (0.5 ml) were added and the mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the product obtained was washed with excess diethyl ether, water (2 × 3 ml), diethyl ether and dried in vacuo. MS: 413 [M + H] ⁺ . ¹ H NMR.
5- (S)-(methylthio) acetamidomethyl-3- [4 '-(6 "-chloropyridin-3" -yl) aminocarbonyl-3'-fluorophenyl] oxazolidine-2- On
BAL resin immobilized 5- (S)-(methylthio) acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one and 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl from 2-chloro-5-aminopyridine ] Oxazolidin-2-one was prepared according to Method A of the general method for preparing MS: 453 [M + H] ⁺ .To obtain the hydrochloride form of this compound, the above material (45 mg, approximately 0.1 mmol) ) Was dissolved in methanol (10 ml) containing 2 M HCl (5 ml) in 1,4-dioxane, filtered, the solvent was removed in vacuo and the residue was washed with excess diethyl ether.
5- (S) _acetamidomethyl-3- [4 '-(benzothiazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S)-(N from 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 2-aminobenzothiazole According to Method C of the general method for preparing acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one Synthesis was carried out over 3 hours at room temperature MS: 429 [M + H] ⁺ Rt 4.6 min, ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(6 "-methoxybenzothiazol-2" -yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
From 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 6-methoxy-2-aminobenzothiazole, S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one Prepared according to Method C. Synthesis was carried out over 3 hours at room temperature MS: 459 [M + H] ⁺ Rt 4.7 min. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(6 "-methoxybenzothiazol-2" -yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S) from 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 5-methylthio-3-aminopyridine Method of general method for preparing-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one Prepared according to C. Synthesis was carried out overnight at room temperature MS: 419 [M + H] ⁺ Rt 3.8 min, ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(4 "-amino-5" -phenylthiazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidine- 2-on
From 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 2,4-diamino-5-phenylthiazole hydrobromide, Prepare 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one Prepared according to the general method Method C. Synthesis was carried out overnight at room temperature MS: 470 [M + H] ⁺ Rt 4.5 min. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(5 "-ethylthio-1,3,4-thiadiazol-2" -yl) aminocarbonyl-3'-fluorophenyl] Oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 5-ethylthio-2-amino-1,3,4-thia 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidine-2 from diazole Prepared according to Method C of the general method for preparing -one MS: 440 [M + H] ⁺ Rt 4.4 min. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(1,3,4-thiadiazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidine-2- On
5- from 5- (S) -acetamidomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one and 2-amino-1,3,4-thiadiazole General Preparation of (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-ones Prepared according to Method C. MS: 380 [M + H] ⁺ Rt 3.6 min. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(imidazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S)-(methylthio) acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one ( 0.400 g, approximately 0.1 mmol) and 2-aminoimidazole sulfate (0.234 g, 2 mmol), 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(ratio) Prepared according to Method A of the general method for preparing substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-ones. The amine reagent was prepared in 10-N-methylpyrrolidin-2-ones. 70 ° C. in a mixture of% pyridine (4 ml), bis- (trimethylsilyl) acetamide (0.5 ml) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.15 ml, 1 mmol) in was pre-dissolved over 2 hours, coupling with the resin reagents were carried out over 48 hours at room temperature and then separated from the resin and purified the crude product by reverse phase HPLC MS:.... 362 [M + H] + 1 H NMR.
5- (S) -acetamidomethyl-3- [4 '-(1,3,4-thiazol-2 "-yl) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S)-(methylthio) acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one ( 0.400 g, approximately 0.1 mmol) and 2- (l)-(N-acylaminomethyl) -3- [4 '-() from 2-amino-1,3,4-thiazole (0.168 g, 2 mmol). Prepared according to Method A of the general method for preparing 4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one. The amine reagent is prepared in N-methylpyrrolidin- Pre-dissolved in a mixture of 10% pyridine (4 ml), bis- (trimethylsilyl) acetamide (0.5 ml) in 2-one over 2 hours at 70 ° C. Coupling with the resin reagent was 48 hours at 60 ° C. on was carried over from the resin was separated and purified the crude product by reverse phase HPLC MS:.... 363 [M + H] + Rt 3.1 bun ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(pyridin-3 "-yl-1" -oxide) aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
30% hydrogen peroxide solution (0.05 ml) in 5- (S) -acetamidomethyl-3- [4 '-(3 "-pyridylamino) carbide in N-methylpyrrolidin-2-one (0.15 ml) To carbonyl-3'-fluorophenyl] oxazolidin-2-one (7 mg, approximately 0.02 mmol) and methylenium trioxide (MTO, 0.9 mg) The mixture was stirred at room temperature for 30 minutes and the solvent removed in vacuo (0.1 torr, room temperature) and the crude product was washed with methanol (0.5 ml) and diethyl ether, MS:.... 389 [ M + H] + R t 3.3 bun ¹ H NMR.
5- (S) -acetamidomethyl-3- [4'-hydroxyaminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one in tetrahydrofuran (1 ml) 0.046 g, 0.1 mmol) and O-trimethylsilylhydroxylamine (0.052 ml, approximately 0.5 mmol), 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(ratio Prepared according to method D of the general method for preparing substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one Synthesis was carried out for 2 hours at room temperature Diethyl ether (4 ml) was added and the precipitated product was washed with diethyl ether, tetrahydrofuran (2 × 0.5 ml), excess ether and dried in vacuo MS: 312 [M + H] ⁺ .R _t 2.8 min. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4'-methylaminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acetamidomethyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxazolidin-2-one (0.046 g, 0.1 mmol) and tetra 5- (S)-(N-acylaminomethyl) -3- [4 '-(4 "-(non) substituted amino) carbonyl from 2M methylamine (1 ml, approximately 2 mmol) in hydrofuran Prepared according to method D of the general method for preparing -3'-fluorophenyl] oxazolidin-2-one Synthesis was carried out for 45 minutes at room temperature Diethyl ether (4 ml) was added and precipitated The product was washed with diethyl ether, tetrahydrofuran (2 × 0.5 ml), excess ether and dried in vacuo MS: 310 [M + H] ⁺ .Rt 3.2 min. ¹ H NMR.
5- (S) -trans- [4 "-(methoxyimino) cinnamoyl] methyl-3- [4'-aminocarbonyl-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S)-[trans- (4 "-methoxyimino) cinnamoyl] methyl-3- [4 '-(pentafluorophenyl) oxycarbonyl-3'-fluorophenyl] oxa 5- (S)-(N-acylaminomethyl) -3 from zolidin-2-one (0.400 g, approximately 0.1 mmol) and 2 M ammonia (5 ml, approximately 10 mmol) in 1,4-dioxane Prepared according to Method C of the general method for preparing-[4 '-(4 "-(non) substituted amino) carbonyl-3'-fluorophenyl] oxazolidin-2-one. Synthesis was done overnight at room temperature. After separation from the resin, the crude product was purified by reverse phase HPLC. MS: 441 [M + H] ⁺ . ¹ H NMR.
5- (S) -amidomethyl-3- [4 '-[(non) substituted 1 ", 3", 5 "-triazin-2" -yl] amino-3'-fluorophenyl] oxazoli General preparation method of din-2-one
Suitable BAL resin immobilized 5- (S) -acylaminomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.06 To 0.1 mmol) was deprotected by stirring with 20% piperidine (4 ml) in DMF for 45 minutes The resulting aniline resin was washed sufficiently with N, N-dimethylformamide, dichloromethane, methanol and in vacuo. A suitable halogen-substituted triazine reagent (preferably chloro) in an aprotic solvent (preferably N-methylpyrrolidin-2-one, dichloromethane, 1,4-dioxane or acetonitrile) Triazine derivative, 1 to 3 mmol) and a solution of an organic base (preferably N, N-diisopropyl-N-ethylamine or 2,6-di-t-butylpyridine, 3 to 6 mmol), are added, The mixture was stirred at 0-80 ° C. for 12-36 hours (usually overnight at 0-40 ° C.). Washed sufficiently with N, N-dimethylformamide, dichloromethane, methanol and dried in vacuo If the triazine oxazolidinone contains one or more halogen substituents, the reaction optionally uses an amine, thiol or alcohol reagent Repeat as described above (40-80 ° C., 12-36 hours) Washed and dried resin was separated by 60% trifluoroacetic acid (5 ml, 2 hours) in dichloromethane. Was evaporated in vacuo and the crude product was purified by HPLC or TLC.
5- (S) -acetamidomethyl-3- [4 '-(4 "-chloro-6" -1 ", 2", 3 "-triazine-2" -yl) amino-3'-fluoro Phenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.06 mmol) was deprotected by stirring with 20% piperidine (4 ml) in DMF for 45 minutes The resulting aniline resin was sufficiently washed with N, N-dimethylformamide, dichloromethane, methanol and dried in vacuo. A solution of cyanuric trichloride (0.194 g, 1.0 mmol) and 2,6-di-t-butylpyridine (0.36 ml, 1.5 mmol) in dichloromethane (4 ml) is added and the mixture is allowed to stand at room temperature for 24 hours. The resulting aniline resin was sufficiently washed with N, N-dimethylformamide, dichloromethane, methanol and dried in vacuo 0.5 M ammonia (5 ml, 2.5 mmol) in 1,4-dioxane was added and the mixture The mixture was stirred at room temperature for 24 hours The resin was filled with N, N-dimethylformamide, dichloromethane and methanol. Wash gently, dry in vacuo and separate with 60% trifluoroacetic acid in dichloromethane (5 ml, 2 h) The supernatant obtained was evaporated in vacuo and the crude product was purified TLC (eluent: methanol-dichloromethane 1 : 10) MS: 396 [M + H] ⁺ .Rt 3.6 min. ¹ H NMR.
5- (S) -acetamidomethyl-3- [4 '-(4 ", 6" -dimethoxy-1 ", 3", 5 "-triazine-2" -yl) amino-3'-fluor Lophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.06 mmol) and 2-chloro-4,6-dimethoxytriazine (0.275 g, 1.5 mmol) from 5- (S) -amidomethyl-3- [4 '-[(non) substituted triazinyl]- Prepared according to the general method for preparing 3'-fluorophenyl] oxazolidin-2-one The reaction of immobilized aniline with triazine reagents is a mixture of N-methylpyrrolidin-2-one and dichloromethane ( 1: from 1, 4 ml), was repeated twice at room temperature overnight the isolated crude product was purified TLC (eluent: methanol - was purified by dichloromethane 1:10) MS: 407 [M + H] + 1 H NMR.
Acylamino oxazolidinone derivative
General method for preparing 5- (S)-(N-acylaminomethyl) -3- [4'-acylamino-3'-fluorophenyl] oxazolidin-2-one
Suitable BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one ( 0.1 mmol) was deprotected by stirring with 20% piperidine (4 ml) in DMF for 45 minutes The resulting aniline resin was sufficiently washed with N, N-dimethylformamide, dichloromethane, methanol and dried in vacuo. Separately, N, N-diisopropyl-N-ethylamine (3-6 mmol, usually 3 mmol) was selected in a polar aprotic solvent (7-10 ml) such as N, N-dimethylformamide. Carboxylic acid (1-2 mmol, usually 1 mmol) and coupling reagent [referably O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluro To hexafluorophosphate or diisopropylcarbodiimide, 3 to 6 mmol, usually 3 mmol), and the mixture was stirred at room temperature for 20 to 30 minutes. The resulting solution of the oxidized acid reagent was added to the aniline resin and the mixture was stirred for 6-24 hours (usually overnight at room temperature) at 20-60 ° C. The resin was treated with N, N-dimethylformamide, dichloromethane, After washing sufficiently with methanol and drying in vacuo, it was separated by 60% trifluoroacetic acid in dichloromethane (5 ml, 2 hours) The supernatant obtained was evaporated in vacuo and the crude product was purified by HPLC or TLC.
5- (S)-(N-acetamidomethyl) -3- [4'-acetamido-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol), according to the general method for preparing 5- (S)-(N-acylaminomethyl) -3- [4'-acylamino-3'-fluorophenyl] oxazolidin-2-one. The intermediate aniline was acylated with an acetic anhydride-pyridine-dichloromethane mixture (1: 1.5: 3, 2 ml) The isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane) yield 0.014 g (46%) MS:.. 310 [M + H] + 1 H NMR.
5- (S)-(N-acetamidomethyl) -3- [4 '-(2 ", 4" -thiazol-5 "-yl) carbonylamino-3'-fluorophenyl] oxazolidine 2-on
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol), according to the general method for preparing 5- (S)-(N-acylaminomethyl) -3- [4'-acylamino-3'-fluorophenyl] oxazolidin-2-one. Acylation was previously activated with diisopropylcarbodiimide (0.086 ml, 0.55 mmol) and pyridine (0.081 ml, 1 mmol) in a N, N-dimethylformamide-dichloromethane 4: 1 mixture (2 ml). The reaction was carried out overnight at room temperature using, 4-dimethylthiazole-5-carboxylic acid (0.157 g, 1 mmol) The separated crude product was purified by TLC (eluent: 10% methanol in dichloromethane) yield 0.028 g (68%) MS:. . 407 [M + H] + 1 H NMR.
5- (S)-(N-acetamidomethyl) -3- [4 '-(pyridin-3 "-yl) carbonylamino-3'-fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.02 mmol), according to the general method for preparing 5- (S)-(N-acylaminomethyl) -3- [4'-acylamino-3'-fluorophenyl] oxazolidin-2-one. Acylation was carried out by O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate in N, N-dimethylformamide (1 ml). 0.160 g, 0.20 mmol) and nicotinic acid (0.049 g, 0.40 mmol) preactivated with N, N-diisopropyl-N-ethylamine (0.21 ml, 1.20 mmol) was run overnight at room temperature. TLC of the product.: was purified by (eluent dichloromethane 10% methanol in dichloromethane) yield g 0.023 (62%) MS:.. 373 [M + H] ^{+ 1} H NMR.
Sulfonamido oxazolidinone derivatives
General method for preparing 5- (S)-(N-acylaminomethyl) -3- [4'-sulfonamido-3'-fluorophenyl] oxazolidin-2-one
Suitable BAL resin immobilized 5- (S) -acylaminomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol) was deprotected by stirring with 20% piperidine (4 ml) in DMF for 45 minutes The resulting aniline resin was washed thoroughly with N, N-dimethylformamide, dichloromethane, methanol and dried in vacuo. This resin was suspended in 20% pyridine (2 ml) in dichloromethane and a solution of selected sulfonyl chloride reagent (1-2 mmol, preferably 1.25 mmol) in dichloromethane was added. Stir for 12 to 36 hours (usually overnight at room temperature) The resin was filtered, washed with methanol and suspended in 0.1 M lithium hydroxide monohydrate (4 ml) in methanol The mixture was allowed to mix at room temperature for 30 to 90 minutes. Was stirred (usually 90 minutes). , Sufficiently washed with N, N-dimethylformamide, dichloromethane, methanol, dried in vacuo and separated by 60% trifluoroacetic acid (5 ml, 2 hours) in dichloromethane The supernatant obtained was evaporated in vacuo. The crude product was purified by HPLC or TLC.
5- (S)-(N-acylaminomethyl) -3- [4'-methylsulfonamido-3'-fluorophenyl] oxazolidin-2-one
5- (S) -acylaminomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol) and methanesulphate 5- (S)-(N-acylaminomethyl) -3- [4'-sulfonamido-3'-fluorophenyl] oxazolidin-2-one was obtained from polyvinyl chloride (0.2 ml, 1.25 mmol). Prepared according to the general method of preparation The isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane) yield 0.022 g (65%) MS (m / z): 346 [M + H] ^{+ 1} H NMR.
5- (S)-(N-acylaminomethyl) -3- [4 '-(benzo-2 ", 1", 3 "-thiadiazol-4" -yl) sulfonamido-3'-fluoro Phenyl] oxazolidin-2-one
5- (S) -acylaminomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol) and benzo- From 2,1,3-thiadiazole-4-sulfonyl chloride (0.295 g, 1.25 mmol), 5- (S)-(N-acylaminomethyl) -3- [4'-sulfonamido-3 ' Prepared according to the general method for preparing -fluorophenyl] oxazolidin-2-one The isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane) yield 0.024 g (52%). MS (m / z): 466 [M + H] ⁺ .
5- (S)-(N-acetamidomethyl) -3- [4 '-(4 ", 5" -dibromothiophen-2 "-yl) sulfonamido-3'-fluorophenyl] oxa Zolidin-2-one
BAL resin immobilized 5- (S) -acylaminomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol ) And 2,3-dibromothiophen-5-sulfonyl chloride (0.43 g, 1.25 mmol) from 5- (S)-(N-acylaminomethyl) -3- [4'-sulfonamido-3 Prepared according to the general method for preparing '-fluorophenyl] oxazolidin-2-one The isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane) yield 0.044 g (77%) MS (m / z): 572 [M + H] ⁺ .
5- (S)-(N-acetamidomethyl) -3- [4 '-(6 "-chloroimidazo [2,1-b] thiazol-5" -yl) sulfonamido-3'- Fluorophenyl] oxazolidin-2-one
BAL resin immobilized 5- (S) -acylaminomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol ) And 5- (S)-(N-acylaminomethyl) -3- [4 ′ from 6-chloro-imidazo [2,1-b] thiazole-5-sulfonyl chloride (0.32 g, 1.25 mmol) Prepared according to the general procedure for preparing sulfonamido-3'-fluorophenyl] oxazolidin-2-one The isolated crude product was purified by TLC (eluent: 10% methanol in dichloromethane). 0.019 g (39%). ¹ H NMR.MS (m / z): 572 [M + H] ⁺ .
5- (S)-(N-acetamidomethyl) -3- [4 '-(2 "-acetamido-4" -methylthiazol-5 "-yl) sulfonamido-3'-fluoro Phenyl] oxazolidin-2-one
5- (S) -acylaminomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol) and 2- 5- (S)-(N-acylaminomethyl) -3- [4'-sulfonamido-3'-fluoro from acetamido-4-methyl-5-thiazolesulfonyl chloride (0.32 g, 1.25 mmol) phenyl] were prepared according to the general procedure for preparing the oxazolidin-2-one the separated crude product TLC...: was purified by (product 10% methanol in dichloromethane) to yield 0.025 g (52%) ¹ H NMR MS (m / z): 486 [M + H] ⁺ .
5- (S)-(N-acetamidomethyl) -3- [4 '-(N-methyl) methylsulfonamido-3'-fluorophenyl] oxazolidin-2-one
As described in the above synthesis of 5- (S)-(N-acetamidomethyl) -3- [4'-methylsulfonamido-3'-fluorophenyl] oxazolidin-2-one, BAL Resin immobilized 5- (S) -acylaminomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one (0.1 mmol) And from methanesulfonyl chloride (0.2 ml, 1.25 mmol) BAL resin fixed 5- (S)-(N-acetamidomethyl) -3- [4'-methylsulfonamido-3'-fluorophenyl ] Oxazolidin-2-one was prepared N-methylpyrrolidin-2-one (2 ml) was added, methyl iodide (0.16 ml, 2.5 mmol) and 1,8-diazabicyclo [5.4 .0] undec-7-ene (0.37 ml, 2.5 mmol) was added The mixture was stirred at rt overnight The resin was filtered off, washed thoroughly with dichloromethane and methanol and dried in vacuo. The product was separated by 60% trifluoroacetic acid (5 ml, 2 hours) in dichloromethane and the solvent Removal in vacuo and the crude product was purified by TLC (eluent: 10% methanol in dichloromethane) yield 0.017 g (48%) ¹ H NMR MS (m / z): 360 [M + H] ⁺ .
Method for preparing 3- (heteroaryl) oxazolidin-2-one derivative
5- (S) -azidomethyloxazolidin-2-one
5- (R) -chloromethyloxazolidin-2-one (Danielmeier et al., Efficient Pathways to (R)-and (S) -hydroxymethyl-2-oxazolidinone and some derivatives. Tetrahedron: Asymmetry. 1995. vol. 6, pp. 1181-1190) (5 mmol) with sodium azide (7-10 mmol) in acetone (approx. 40-50 ml) at room temperature for approximately 24 hours (the reaction will be complete). Until the reaction). The solids were filtered off and the supernatant was evaporated in vacuo to yield the product which was used directly in the next step. In some cases, this synthesis was carried out by reaction with sodium azide (5 to 10 ml) or tetrabutylammonium azide (5 to 10 mmol) in anhydrous N, N-dimethylformamide under a nitrogen atmosphere. The resulting solution of 5- (S) -azidomethyloxazolidin-2-one was used in the next step without removing the solvent.
Its use for the preparation of 5- (S) -azidomethyl-3- (heteroaryl) oxazolidin-2-one and 3- (heteroaryl) oxazolidin-2-one
Suitable heteroarylchloride or heteroarylbromide (e.g. pyridyl, pyrimidyl, thienyl, thiazolyl or thiadiazolyl halide, 5 mmol) is dissolved in anhydrous N, N-dimethylformamide (approximately 30-50 ml). To a solution of (S) -azidomethyloxazolidin-2-one (approximately 5 mmol) was added at 0-20 ° C. (usually 10-15 ° C.) and a strong base (usually sodium hydride, 5-15 mmol) was added. Add. The mixture is stirred at 20-120 ° C. for 2 to 24 hours (usually 6 hours at room temperature). Excess base was carefully quenched with acetic acid (pH approximately 5-7) and most solvent was removed in vacuo. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water, 3% citric acid aqueous solution, water and the crude product is purified by crystallization in a suitable solvent or by silica gel chromatography. As described in the above synthesis of BAL resin immobilized 5- (S) -aminomethyl-3- [4'-tert-butoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one, 5- (S) -azidomethyl-3- (heteroaryl) oxazolidin-2-one was immobilized on the BAL resin and each of the above 3- (fluorophenyl) using the polymeric reagent thus obtained Similar to the synthesis of oxazolidinone, 3- (heteroaryl) oxazolidin-2-ones are synthesized.
5- (S) -azidomethyl-3- [5'-methoxycarbonyl-6'-trifluoromethylpyrimidin-2'-yl] oxazolidin-2-one
This compound is 2-chloro-5-methoxycarbonyl-6-trifluoromethylpyrimidine (1 mmol) and 5- (S) -azidomethyloxazoli in N, N-dimethylformamide (5 ml). From din-2-one (1.2 mmol), it was prepared according to the synthesis method for 5- (S) -azidomethyl-3-heteroaryloxazolidin-2-one. This reaction was carried out with 60% sodium hydride (3 mmol) in oil at 15-20 ° C. for approximately 2 hours. The crude product was purified by silica gel chromatography.
5- (S) -azidomethyl-3- [5'-carboxy-6'-trifluoromethylpyrimidin-2'-yl] oxazolidin-2-one
0.2 M lithium hydroxide or sodium hydroxide (approximately 10 ml, 2 mmol) in a tetrahydrofuran-water mixture was added 5- (S) -azidomethyl-3- [5'-methoxycarbonyl-6'-trifluoro Methylpyrimidin-2'-yl] oxazolidin-2-one (1 mmol) was added and the mixture was stirred at room temperature until the reaction was complete (check by TLC analysis). Tetrahydrofuran was removed in vacuo, 3% citric acid aqueous solution was added to pH approximately 2-4, and this acid product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over MgSO ₄ . The solvent was removed in vacuo and the crude product was purified by silica gel chromatography.
BAL resin immobilized 5- (S) -aminomethyl-3- [5'-carboxy-6'-trifluoromethylpyrimidin-2'-yl] oxazolidin-2-one and 3- (pyrimidyl) Its use for the preparation of oxazolidin-2-ones
Triphenylphosphine (3 mmol) was added BAL aldehyde resin (0.3 mmol) and 5- (S) -azidomethyl in tetrahydrofuran (10 ml) containing bis (trimethylsilyl) acetamide (approximately 6 mmol). To a mixture of -3- [5'-hydroxy-6'-trifluoromethylpyrimidin-2'-yl] oxazolidin-2-one (3 mmol) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and at 75 ° C. for 16 hours. The mixture was cooled to room temperature and 1 M sodium cyanoborohydride (6 ml, 6 mmol) in THF was added in one portion. The reaction mixture was stirred for 6-8 hours and the resulting amine resin was filtered off, washed sufficiently with methanol and dichloromethane and dried in vacuo. Thus obtained using BAL resin immobilized 5- (S) -aminomethyl-3- [5'-carboxy-6'-trifluoromethylpyrimidin-2'-yl] oxazolidin-2-one Synthesis of each 3- (fluorophenyl) oxazolidinone from BAL resin fixed 5- (S) -aminomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one in Synthesis of 3- (pyrimidyl) oxazolidin-2-ones as described below.
3- (pyridin-2-yl) oxazolidinone derivative
t-butyl 6-chloronicotinate
Thionyl chloride (25 ml) was added to 6-chloronicotinic acid (5.00 g, 0.0317 mol) containing 1 drop of N, N-dimethylformamide and the mixture was refluxed for 2 hours. The solution was evaporated in vacuo and the residue was completely dried in vacuo. The acid chloride thus obtained was dissolved in tetrahydrofuran (50 ml) and 1 M lithium t-butoxide (66.6 ml, 0.0666 mol) in tetrahydrofuran was added dropwise at room temperature. The mixture was stirred overnight, diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with saturated aqueous NaHCO ₃ , brine and dried over MgSO ₄ . The solvent was removed in vacuo to give pure ester as off white solid. Yield 6.23 g (92%). ¹ H NMR. MS (m / z): 214 [M + H] ⁺ .
3- (t-butoxycarbonyl) -6-[(R) -propane-1,2-diol-3-yl] aminopyridine
A mixture of t-butyl 6-chloronicotinate (4.69 g, 0.0220 mol) and (R) -3-amino-1,2-propanediol (5.00 g, 0.0549 mol) in isopropanol (20 ml) at 100 ° C Heated overnight. The solvent was removed in vacuo and the residue was treated with ethyl acetate and then washed with water, brine, dried over MgSO ₄ and evaporated to afford almost pure product as a yellow oil. Yield 5.90 g (99%). ¹ H NMR. MS: 269 [M + H] ⁺ .
5- (R) -hydroxymethyl-3- [3 "-(t-butoxycarbonyl) pyridin-6" -yl] oxazolidin-2-one
Triethylamine (0.0518 ml, 0.558 mmol) was added 3- (t-butoxycarbonyl) -6-[(R) -propane-1,2-diol-3-yl] aminopyridine in dichloromethane (3 ml). (0.100 g, 0.372 mmol) was added to the solution. The mixture was cooled in an ice bath and 20% phosgene (0.236 ml, 0.446 mmol) in toluene was added dropwise with stirring. The reaction was allowed to warm to room temperature and then stirred at room temperature for 2 hours. Water (3 ml) was added and the organic layer was separated, washed with brine and dried over MgSO ₄ . Evaporation in vacuo gave a white solid residue which was purified by flash column chromatography (eluent: ethyl acetate-hexane 1: 1). Yield 0.093 g (85%). ¹ H NMR. MS (m / z): 295 [M + H] ⁺ .
5- (S) -azidomethyl-3- [3 "-(t-butoxycarbonyl) pyridin-6" -yl] oxazolidin-2-one
Methanesulfonyl chloride (1.38 ml, 0.0179 mol) was added 5- (R) -hydroxymethyl-3- [3 '-(t-butoxycarbonyl) pyridin-6 "-yl] in dichloromethane (50 ml). To a solution of oxazolidin-2-one (5.00 g, 0.0170 mol) and triethylamine (3.55 ml, 0.0255 mol) was added dropwise with stirring at 0 ° C. The reaction mixture was allowed to warm to room temperature and then poured into water. The organic layer was separated, washed with water, saturated aqueous NaHCO ₃ , brine and dried over MgSO _{4. The} solvent was removed in vacuo to give the mesylate intermediate The intermediate thus obtained was treated with N, N-dimethylformamide (approximately). Heated with sodium azide (5.53 g, 0.085 mol) in 40 ml) for 12 h at 65 ° C. The reaction mixture was diluted with water (approximately 100 ml) and extracted with ethyl acetate The organic layer was water and brine. washed, dried over MgSO _4. the solvent was removed in vacuo to and the residue Column chromatography. (Eluent: ethyl acetate-hexane) to give the pure product was obtained by Rt 5.0 bun ^{1 H NMR MS (m / z} ): 320 [M + H] +.
5- (S)-(N-acylaminomethyl) -3- [3 "-[(non) substituted amino] carbonylpyridin-6" -yl] oxazolidin-2-one
As described above in the preparation of BAL resin immobilized 5- (S) -aminomethyl-3- [4'-tert-butoxycarbonyl-3'-fluorophenyl] oxazolidin-2-one, 5- (S) -azidomethyl-3- [3 '-(t-butoxycarbonyl) pyridin-6 "-yl] oxazolidine-2- using phenylphosphine and sodium cyanoborohydride One was fixed to the BAL resin, and the obtained polymeric resin was subjected to BAL resin fixed 5- (S) -aminomethyl-3- [4'-carboxy-3'-fluorophenyl] oxazolidin-2-one. Deprotected as described in the preparation of 5- (S)-(N-acylaminomethyl) -3- [4 '-[(non) substituted amino] carbonyl-3'-fluorophenyl] oxa Similar to the general method A for preparing zolidin-2-one, the obtained BAL resin immobilized 5- (S)-(N-acylaminomethyl) -3- (3 "-carboxypyridin-6" -yl) oxa 5- (S)-(N-acylaminomethyl) -3- [3 "-[(non) substituted amino] carbonylpyridin-6" -yl] oxazole using zolidin-2-one An-2-one was synthesized.
BAL resin immobilized 5- (S)-(N-acylaminomethyl) -3- [3 "-(9" '-fluorenylmethoxycarbonyl) amino] pyridin-6 "-yl] oxazolidine-2 Its use for the preparation of -one and 3- (pyridyl) oxazolidinones
This compound is derived from BAL resin fixed 5- (S)-(N-acylaminomethyl) -3- (3 "-carboxypyridin-6" -yl) oxazolidin-2-one, the BAL resin fixed 5 As described in the preparation of-(S) -acetamidomethyl-3- [4 '-(9 "-fluorenylmethoxycarbonyl) amino-3'-fluorophenyl] oxazolidin-2-one Using the thus obtained polymeric reagent, the obtained product was mixed with 5- (S) except that the resulting product was mixed with 3- (pyridyl) oxazolidinone group instead of 3- (fluorophenyl) oxazolidinone group. -(N-acylaminomethyl) -3- [4'-acylamino-3'-fluorophenyl] oxazolidin-2-one, 5- (S)-(N-acylaminomethyl) -3- [ As described above in the general method for preparing 4'-sulfonamido-3'-fluorophenyl] oxazolidin-2-one, each 3 "-acylated and also 3" -sulfonylated 3- (Pyridyl) oxazolidinones were synthesized.
Preparation of Fixed Epoxides (Formula 12a)
To PNP resin (23a) (0.5 g, 0.77 mmol / g load) at room temperature was added allylamine (125 μl, 1.67 mmol) in 2 ml of DMF. The resin was stirred overnight and then filtered. Washed in the order of DMF and DCM. After drying in vacuo, the olefin resin (Formula 24a, 100 mg) was treated with mCPBA (80%, 72 mg, 0.355 mmol) in DCM for 16 hours. The reaction mixture was filtered and the resin was washed with DCM. The epoxide resin (Formula 12a) was obtained by drying in vacuo (see FIG. 25).
General Method for Reacting Immobilized Epoxides
To the epoxide resin (Formula 12a) was added lithium triflate (LiOTf, 5 equiv) and amine (1 M in ACN, 10 equiv) at room temperature. The mixture was stirred at room temperature for 15 hours to give amino alcohol bound to the resin. This resin was filtered off and washed in the order of ACN and DMF. This resin was treated with TFA in DCM to separate amino alcohols. The reaction mixture was filtered and the resin washed with DCM. The filtrate was concentrated in vacuo to give free amino alcohol.
Amino alcohol library
Lithium triflate and amine units (0.5 mmol) were added to each reaction chamber arrangement, each containing particles or beads of epoxide resin (Formula 12a) (25 mg) in ACN. The amine units of Table 2 were used. This arrangement was stirred at room temperature for 15 hours, filtered and washed in the order of ACN and DMF. The amino alcohol resin was isolated by treatment with TFA. This resin was filtered off and washed with DCM. The filtrate array was concentrated in vacuo to afford various amino alcohols.
General method for preparing oxazolidinone
To the resin bound amino alcohol (Formula 8a) in DMF at room temperature was added -methylformoline (NMM, 10 equiv) and carbonyldiimidazole (CDI, 5 equiv). The resin was stirred for 10 hours, filtered and washed in the order of DMF and DCM. This resin was treated with TFA in DCM for 0.5 hours to separate the oxazolidinones. This resin was filtered off and washed with DCM. The filtrate was concentrated in vacuo to give an oxazolidinone amine residue (Formula 16a). Semi-purified HPLC gave pure oxazolidinone amine.
Acetylation of Oxazolidinone Amine
Pyridine (30 equiv) and acetic anhydride (20 equiv) were added to the crude-oxazolidinone amine residue (Formula 16a) in DCM at room temperature. The solution was stirred for 2 hours and concentrated in vacuo. Oxazolidinone acetamide residue was purified by HPLC to give pure oxazolidinone acetamide.
Oxazolidinone Library
Lithium triflate and amine units (0.5 mmol) were added to each reaction chamber array, each containing particles or beads of epoxide resin (C 12a) (25 mg) in CAN. The amine units of Table 2 were used. This arrangement was stirred at room temperature for 15 hours, filtered and washed in the order of CAN and DMF. To the amino alcohol resin array was added NMM (10 equiv) and CDI (5 equiv). This arrangement was stirred at room temperature for 10 hours, filtered and washed in the order of DMF and DCM. Oxazolidinone resin was isolated by treatment with TFA. This resin was filtered off and washed with DCM. The filtrate array was concentrated in vacuo, dissolved in DCM and treated with pyridine (20 equiv) and acetic anhydride (10 equiv) for 30 minutes. This solution arrangement was concentrated in vacuo to give various oxazolidinones.
Preparation of N-[(3-phenyl-2-oxo-5-oxazolidinyl) methyl] acetamide (Formula 22a)
To the epoxide resin (AC 12a) (100 mg) in ACN at room temperature was added LiOTf (50 mg, 0.32 mmol) and aniline (61 μl, 0.66 mmol). After 16 h the mixture was filtered and the resin washed in the order of ACN and DMF. This resin (50 mg) in DMF (0.5 ml) was treated with CDI (27 mg, 0.17 mmol) and NMM (50 μl) to give oxazolidinone (Formula 20a) bound to the resin. After leaving this mixture for 2 hours, the resin was filtered and then washed with DMF and DCM. This resin was treated with TFA (90% in DCM, 1 ml) for 1 hour, filtered and washed with DCM. The filtrate was concentrated in vacuo to give a residue (Formula 21a). This residue was treated with triethylamine (18 μl, 0.13 mmol) and acetyl chloride (10 μl, 0.13 mmol) at 0 ° C. for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product which was purified by semi-purified HPLC to give oxazolidinone (Formula 22a) (3.6 mg).
Direct Preparation of Oxazolidinones (Formula 20a)
To a solution of N-phenyl O-benzyl carbamate (152 mg, 0.67 mmol) in THF (2 ml) at −78 ° C. was added n-butyl lithium (1.5 M, 0.6 ml, 0.9 mmol). After stirring for 10 minutes, an epoxide resin (Formula 12a) (100 mg) was added to this reaction mixture. The mixture was allowed to warm to room temperature and stirred overnight. Saturated ammonium chloride solution was added to the reaction mixture. This resin was filtered off and washed in the order of water, DMF and DCM. A portion of this resin was treated with TFA (90% in DCM, 1 ml) to separate oxazolidinones, which were isolated by concentration in vacuo.
Preparation of N-[(3- (4-bromophenyl) -2-oxo-5-oxazolidinyl) methyl] acetamide
To the epoxide resin (12a) (300 mg) in ACN (2 ml) at room temperature was added LiOTf (219 mg, 1.41 mmol) and 4-bromoaniline (0.5 g, 2.9 mmol) was added. The reaction mixture was left overnight. The resin was then filtered, washed in the order of ACN, DMF and DCM and dried in vacuo. Resin (230 mg) was suspended in DMF (2 ml) at room temperature and treated with CDI (125 mg, 0.77 mmol) and NMM (84 μl, 0.77 mmol). After stirring overnight, the resin was filtered off and washed in the order of DMF and DCM. To a portion of this resin (20 mg) was added TFA (50% in DCM, 1 ml) at room temperature and the resulting mixture was stirred for 30 minutes. The resin was filtered off and washed with DCM. The filtrate was concentrated in vacuo to give a residue. Acetic anhydride (0.1 ml) and pyridine (0.1 ml) were added to the resin in DCM (2 ml). The mixture was concentrated and purified by semi-purified HPLC to give N-[(3- (4-bromophenyl) -2-oxo-5-oxazolidinyl) methyl] acetamide (2 mg, 41 of theory. % Yield). ¹ H NMR.
Preparation of N-[[3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (Formula 28a)
To the epoxide resin (Formula 5a) (100 mg) in ACN (1.0 ml) at room temperature was added LiOTf (78 mg, 0.5 mmol) and 3-fluoro-4-morpholinylaniline (197 mg, 1.0 mmol) was added. Was added. The reaction mixture was stirred overnight. The resin was then filtered off, washed in the order of ACN, DMF and DCM and dried in vacuo. A portion of the resin (Formula 25a) was suspended in DMF (0.8 ml) and treated with CDI (60 mg, 0.38 mmol) and NMM (100 μl, 0.91 mmol). After stirring overnight, the resin was filtered off and washed in the order of DMF and DCM. To a portion of the resin (Formula 26a, 48 mg) was added TFA (90% in DCM, 1 ml) and the resulting mixture was left for 1 hour. The resin was filtered off and washed with DCM. The filtrate was concentrated in vacuo to give a residue. Acetyl chloride (12 μl, 0.17 mmol) and triethylamine (37 μl, 0.268 mmol) were added to the residue in DCM (2 ml) at 0 ° C. The mixture was concentrated and purified by semi-preparative HPLC to give N-[[(3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide (28a ) was obtained (1.8 mg, 15% yield of theory). ¹ H NMR.
Preparation of N-[[3- (4-fluoro-2-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide
To epoxide resin (12a) (50 mg) in methanol (0.5 ml) was added 4-fluoro-2-morpholinylaniline (50 mg, 0.255 mmol). The reaction mixture was heated at 60 ° C. overnight and then cooled to room temperature. The resin was filtered off, washed in order of methanol and DCM and dried in vacuo. To the resin in DMF (0.5 ml) was added CDI (25 mg, 0.15 mmol) and NMM (50 μl, 0.45 mmol). The reaction mixture was stirred for 4 hours. This mixture was filtered and the resin washed in the order of DMF and DCM. A portion of the resin (19 mg) was treated with TFA (90% in DCM, 1 ml) for 1 hour. The reaction mixture was filtered and the resin washed with DCM. The filtrate was concentrated to give a residue. This residue was dissolved in DCM (2 ml) and treated with pyridine (100 μl) and acetic anhydride (100 μl) at room temperature for 1 hour. The mixture was concentrated in vacuo and purified by semi-crystalline HPLC to afford N-[[3- (4-fluoro-2-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl] acetamide ( 1.8 mg, 36% yield of theory.) ¹ H NMR.
Coupling an Amine (Formula 32a) to a Solid Support
DIEA (30% in DCM, 150 ml) was added to dry Peg HS HCl resin (30 g, manufactured by Perseptive Inc.). The mixture was stirred at rt for 30 min. The resin was filtered off, washed in order of DCM, methanol and DCM and dried in vacuo. Resin (30 g, 18 mmol) in DMF (80 ml) to BAL linker (Formula 30a) (8.04 g, 1.7 equiv., Perceptive Inc.), HATU (11.3 g, 1.6 eq.) And DIEA (18 ml, 3.5 equiv. ) Was added. The reaction mixture was left at rt overnight. The mixture was filtered and washed in the order of DMF, MeOH, DCM and TMOF. To this resin was added 100 ml of amine (TM 32a) (18.2 g, 3 equiv) in TMOF. After the mixture was stirred for 1 hour, 50 ml of NaBH ₃ (CN) -THF solution (1 M) was added. The reaction mixture was stirred for 30 minutes, filtered and washed sequentially with methanol and DCM. The filtrate was concentrated in vacuo to give an amine resin (Formula 33a). A portion of the resin was treated with TFA and separated to give amine (Formula 32a) in a yield of 70% of theory (0.6 mmol / g). ¹ H NMR.
Preparation of Amides Derived from Amines (Formula 33a)
To a amine resin (33 mg) (25 mg) in DMF (1 ml) at room temperature was added a solution of carboxylic acid (0.5 mmol) and diisopropylcarbodiimide (0.25 mmol). After 16 h, the reaction mixture was filtered and the resin (Formula 36a) was washed in the order of DMF and DCM. The resin was treated with TFA (90% in DCM), filtered and concentrated in vacuo to give the free amide (Formula 37a). HPLC and MS analysis of the amide residue showed its purity above 80%.
Preparation of Sulfonamides Derived from Amines (Formula 33a)
To the amine resin (33a) (25 mg) at room temperature was added a solution of sulfonyl chloride (0.5 mmol) in DCM. After 16 hours, the reaction mixture was filtered and the resin was washed sequentially with DMF and DCM. The resin was treated with TFA (90% in DCM), filtered and concentrated in vacuo to give free sulfonamide (Formula 35a). HPLC and MS analysis of this amide residue showed its purity above 80%.
Preparation of Urea Derived from Amine (Formula 33a)
To the amine resin (33 mg) (25 mg) at room temperature was added a solution of isocyanate (0.5 mmol) in DCM. After 16 hours, the reaction mixture was filtered and the resin was washed sequentially with DMF and DCM. The resin was treated with TFA (90% in DCM), filtered and concentrated in vacuo to give free urea (Formula 39a). HPLC and MS analysis of this amide residue showed its purity above 80%.
Preparation of Phenylsulfide Derived from Amine (Formula 33a)
To the amine resin (33a) at room temperature was added a solution of bromoacetic acid (3 equiv) and DIC (1.5 equiv) in DMF. After 16 hours, the reaction mixture was filtered to give a bromoacetyl derivative (Formula 40a). The resin was washed sequentially with DMF and DCM and dried in vacuo. To a resin (50 mg) in DMF was added potassium carbonate (50 mg) and thiophenol (0.5 mmol). The mixture was stirred overnight, filtered and washed sequentially with DMF, water, DMF and DCM. The resin was treated with TFA (90% in DCM) to give sulfides (5.0 mg, 40% yield).
Wittig Reaction of Acetyl Bromide (Formula 40a)
Triphenylphosphine (10 equiv) was added to bromoacetyl resin (40, 50 mg) in DMF (1 ml). After 16 hours at room temperature, the resin was washed with DMF and treated with potassium carbonate (20 equiv) and benzaldehyde (10 equiv) for 16 hours at room temperature. The resin was washed with DMF, water, DMF and DCM and separated by TFA (50% in DCM) to give (S) -N-[[3- (3-fluoro-4-morpholinylphenyl) -2- Oxo-5-oxazolidinyl] methyl] cinnamamide (Formula 44) was obtained. ¹ H NMR (300 MHz) 7.62 (d, J = 15.6 Hz, 1H), 7.54-7.33 (m, 6H), 7.09 (d, J = 8.8 Hz, 1H), 6.94 (t, J = 9.2 Hz, 1H ), 6.53 (d, J = 15.6 Hz, 1H), 4.87-4.82 (m, 1H), 4.08 (t, J = 9.0 Hz, 1H), 3.86 (t, J = 4.2 Hz, 4H), 3.84-3.63 (m, 3 H), 3.05 (t, J = 4.2 Hz, 4H); MS (m / z) 426 (M ⁺ +1).
Arylsulfide library
Potassium carbonate and thiol units were added at room temperature to separate reaction chamber arrays each containing particles or beads of bromoacetyl resin (Formula 40a) in DMF. The thiol units shown in Table 1 were used. This arrangement was stirred for 10 hours and washed in the order of filtered water DMF, water, DMF and DCM. The thio alcohol resin was separated by treatment with TFA. The resin was filtered off and washed with DCM. The filtrate was concentrated in vacuo to afford various sulfides.
Preparation of Amide Library Derived from Amine (Formula 33a)
A solution of carboxylic acid unit and diisopropylcarbodiimide was added to a separate reaction chamber arrangement, each containing particles or beads of an amine resin (Formula 33a) in DMF. The carboxylic acid unit shown in Table 4 was used. This arrangement was stirred at rt for 16 h, filtered and washed in the order of DMF and DCM. The amide resin was separated by treatment with TFA. This resin was filtered off and washed with DCM. The filtrate was concentrated in vacuo to afford various amides.
Preparation of Sulfonamide Libraries Derived from Amine (Formula 33a)
A solution of sulfonyl chloride units was added to a separate reaction chamber arrangement, each containing particles or beads of an amine resin (Formula 33a) in DCM. The sulfonyl chloride units shown in Table 3 were used. This array was left for 16 hours. Then it was filtered and washed in the order of DMF and DCM. Sulfonamide resin was isolated by treatment with TFA. This resin was filtered off and washed with DCM. The filtrate was concentrated in vacuo to give various sulfonamides.
Preparation of Urea Library Derived from Amine (Formula 33a)
A solution of isocyanate units was added to an individual reaction chamber arrangement, each containing particles or beads of an amine resin (Formula 33a) in DCM. The isocyanates shown in Table 3 were used. This array was left for 16 hours. It was then filtered and washed in the order of DMF and DCM. Urea resin was isolated by treatment with TFA. This resin was filtered off and washed with DCM. The filtrate was concentrated in vacuo to afford various ureas.
Preparation of Amide Library Using the Amine Monomer of FIG. 30
The amine subunits in TMOF were added to individual reaction chamber arrangements each containing particles or beads of an aldehyde functionalized resin (Formula 31a). The subunits listed in FIG. 30 were used. The mixture was stirred for 1 hour and then NaBH ₃ (CN) -THF solution was added. The reaction was stirred for 30 minutes, filtered and washed in the order of methanol and DCM. The filtrate was concentrated in vacuo to give each amine resin. Each amine resin was placed in a separate reaction chamber arrangement. To a separate reaction chamber was added a solution of carboxylic acid units and diisopropylcarbodiimide. The carboxylic acid unit shown in Table 4 was used. This arrangement was stirred at rt for 16 h, filtered and washed in the order of DMF and DCM. The amide resin was isolated by treatment with TFA. This resin was filtered off and washed with DCM. The filtrate was concentrated in vacuo to afford various amides.
Preparation of Amide Libraries Using Amine Units of FIGS. 29, 30 and 31
To the epoxide resin (Formula 7a) (X = NH) in DMF was added a solution of carboxylic acid unit and diisopropylcarbodiimide. The carboxylic acid unit shown in Table 4 was used. After 3 hours, this resin was filtered off, washed sequentially with DMF and DCM and dried in vacuo. Each resin was placed in a separate reaction chamber arrangement. LiOTf was added to the resin in CAN contained in the individual reaction chamber and amine units were added. The amine units shown in FIGS. 29, 30 and 31 were used. This arrangement was stirred at room temperature for 15 hours, filtered and washed with CAN and DMF. To the amino alcohol resin array was added NMM (10 equiv) and CDI (5 equiv). This arrangement was stirred at rt for 10 h, filtered and washed sequentially with DMF and DCM. Oxazolidinone resin was isolated by treatment with TFA. This resin was filtered off and washed with DCM. The solution arrangement was concentrated in vacuo to give various oxazolidinones. (The amines of FIGS. 29, 30 and 31 are described in US Pat. Nos. 4,948,801, 4,705,799, 5,164,510, 4,975,538, 5,225,565, 5,182,403, 5,247,090, 5,231,188 4,461,773, EP 0 785 201 A1, WO 97/19089, DE 196 01 265 A1, WO 97/27188, EP 0 789 026 A1, DE 196 01 264 A1, WO 97/30995, WO 97/09328 , Van Delft et al. (1997) Synthesis 450-454, Wang et al. (1989) Tetrahedron 45: 1323-1326, and Denis et al. (1994) Bioorg. & Med. Chem. Lett. 4: 1925-1930 Can be prepared according to the method described in the
Analytical Methods of Inhibiting β-lactamase
Lactamase (20-120 ng / ml) was incubated for 30 minutes at room temperature with potential inhibitor, 1% DMSO, 0.005% Brij-35 in 50 mM potassium phosphate buffer (pH 7.0). Hydrolysis of nitrosepin was then observed by adding 100 μM of nitrosepine to this reaction mixture and measuring the increase in absorbance at 490 nm. Inhibition of potential compounds was calculated by comparing the rate of absorption increase with a control sample containing the same mixture except the inhibitor. IC ₅₀ was obtained by applying the suppression data to the standard two-parameter IC ₅₀ equation using a non-linear least-square fitting program (DeltaGraph).
Analysis method of antimicrobial activity
Minimum inhibitory concentrations (MIC) were measured using the microdilution method in 96-well format plates. Compounds were suspended at 5 or 10 mg / ml in DMSO and stored at 4 ° C. until use. These were diluted in Mueller-Hinton Broth (MHB) or Trypticase Soy Broth (TSB) and used for MIC measurements. The final concentration range of 64 to 0.0625 μg / ml was tested using a 2-fold dilution scheme.
Inoculum was prepared from cells grown on Trypticase Soy Agar (TSA), incubated overnight at 35 ° C. and inoculated with MHB or TSB using 5-10 colonies, which were overnight at 35 ° C. Incubated. Overnight cultures were diluted to 1:10, aliquoted at 35 ° C. for 1 hour, diluted to the appropriate inoculum concentration and placed in wells containing broth and test compounds. Inoculum concentrations were between 1 × 10 ⁵ and 5 × 10 ⁵ CFU / ml. The strains used were P. aeruginosa VPAE1001, P. aureus V VEFA1001, P. aeruginosa V. E. faecium VanA VEFA1002, S. aureus VSAU1003, S. aureus ) MRSA VSAU1004, E. coli VEC05, and E. coli (arc-) VEC05.
Plates were incubated at 35 ° C. for 48 hours and MICs were recorded 18 hours after incubation for bacteria and 48 hours after yeast. MIC is defined as the minimum concentration of compound that does not show visible growth after incubation.
Antimicrobial Activity of Representative Compounds on Animals
To demonstrate the practical utility of oxazolidinone for the treatment of bacterial infections in animals, in vivo data for representative compounds (formulas i, ii and iii) were obtained.
18-22 grams of CD1 female mice (Charles River Laboratories) were injected intraperitoneally with a 0.2 ml suspension containing Staphylococcus aureus (Smith strain) 3 × 10 ⁷ cfu in 7% swine gastric mucosa (mucin). These mice were treated intravenously (iv) or orally (po) 1 and 5 hours after infection. Five groups of 6 mice were administered different doses (25 mg / kg to 1.56 mg / kg) representing a 2-fold dilution of each compound. All of these compounds were formulated in 40% hydroxypropyl-β-cyclodextrin in PBS, and the untreated control group received vehicle only.
Mortality in each group was observed daily for 6 days and 50% protective dose (PD ₅₀ ) was measured from the cumulative mortality rate, which was determined by Reed and Muench's method [(a) Lorian, V. Antibiotics in laboratory medicine. Baltimore: Williams & Wilkins. 1996, p. 635-636; (b) Reed, LJ; Muench H. A simple method of estimating fifty percent endpoints. Am. J. Hyg. 1938, 27, pp. 493-497] (Table 1). For animals that received vehicle only, the mortality rate was 79% (19/24) in the oral group and the mortality rate was 88% (17/15) in the intravenous group.
PD ₅₀ of the compound was 2.3 to 7.2 mg / kg for intravenous administration, 7.5 to 14.9 mg / kg for oral administration, the compound of formula (iii) is most preferred.
TABLE 1
Thiols
2-mercaptobenzothiazole
2-mercapto-4-methylpyrimidine HCl
2-mercaptothiazoline
2-mercaptopyridine
2-mercapto- (3H) -quinazoline
2-mercapto-1-methyl imidazole
5- (methylthio) -1,3,4-thiodiazol-2-thiol
2-mercapto-6-thien-2-yl-4- (trifluoromethyl) pyridine-3-carbonitrile
Thiazolo [4,5-b] pyridine-2-thiol
4- (4-methoxyphenyl) pyrimidine-2-thiol
2-mercapto-3- (trifluoromethyl) pyridine
4,6-dimethyl-2-mercaptopyridine-3-carbonitrile
4-trifluoromethylpyrimidine-2-thiol
Ethyl 3-cyano-2-mercapto-6-methylpyridine-4-carboxylate
2-mercapto-5- (trifluoromethyl) pyridine
5-chloro-2-mercaptobenzothiazole
4-methyl-4H-1,2,4-triazole-3-thiol
2,4,6-trimethylbenzylmercaptan
2-quinolinethiol
8-quinolinethiol HCl
3-chloro-5- (trifluoromethyl) pyridine-2-thiol
7-trifluoromethyl-4-quindine-thiol
2,4,6-trichlorobenzenethiol
5- [3- (trifluoromethyl) benzylthio] -1,3,4-thiadiazole-2-thiol
4- (4-chlorophenyl) pyrimidine
Thiomalic acid
2,6-dichlorobenzenethiol
4-hydroxythiophenol
5- (4,5-dichloroimidazole)
3-mercaptopropionic acid
3,4-dichlorobenzenethiol
2,6-dichlorobenzenethiol
2-methoxybenzenethiol
2-bromothiophenol
4-fluorothiophenol
4-bromo-2- (trifluoromethoxy) benzenethiol
3- (trifluoromethyl) benzenethiol
Thiolactate
3,4-dimethoxybenzenethiol
4-methoxybenzenethiol
2- (trifluoromethyl) benzenethiol
4- (trifluoromethoxy) benzylthiol
TABLE 2
Amines
4-iodoaniline
2-iodoaniline
4-phenoxyaniline
3-trifluoromethylamine
m-anisidine
o-anisidine
2-trifluoromethylaniline
3-chloroaniline
1,4-benzodioxane-6-amine
5-aminoindane
3,4- (methylenedioxy) aniline
3-phenoxyaniline
4-morpholinoaniline
4-amino-1-benzylpiperidine
2-bromoanaline
3-fluoroanaline
4-trifluoromethoxyaniline
4-methyllimercaptoaniline
3-bromoaniline
2-fluoroaniline
4-fluoroaniline
2,4-difluoroaniline
3,4-difluoroaniline
2,5-difluoroaniline
1-amino-5,6,7,8-tetrahydronaphthalene
3,5-difluoroaniline
3-fluorobenzylamine
4-fluorobenzylamine
4-aminoacetophenone
4-aminobenzophenone
3-benzyloxyaniline
1- (3-aminopropyl) imidazole
4- (2-aminoethyl) morpholine
m-phenetidine
3-chloro-4-fluoroaniline
2-bromo-5- (trifluoromethyl) aniline
2-amino-3-benzyloxypyridine
2'-aminoacetophenone
4-aminobenzoic acid
4-aminobiphenyl
3'-aminocetophenone
4- (3'-aminopropyl) morpholine
Aminopyrazine
2-aminopyridine
3-aminopyridine
4-aminopyridine
6-aminoquinoline
8-aminoquinoline
4-aminoveratrol
4-bromo-2,6-difluoroaniline
4-bromo-2-fluoroaniline
4-bromo-3- (trifluoromethyl) aniline
4-bromo-3-methylaniline
2-bromo-4-fluoroaniline
2-bromo-4-methylaniline
3-bromo-4-methylaniline
4-butoxyaniline
3-fluoro-4-methylaniline
4-aminoquinaldine
2-chloro-4,6-dimethylaniline
2-chloro-4-aminotoluene
2-chloro-4-fluoroaniline
4-chloroaniline
2,4-dibromo-6-fluoroaniline
2,4-dibromoaniline
2,5-dibromoaniline
2,4-dichloroaniline
2,5-dichloroaniline
3,4-dichloroaniline
3,5-dichloroaniline
2,3-difluoroaniline
N, N-dimethyl-1,4-phenylenediamine
5-fluoro-2-methylaniline
2-fluoro-4-iodoaniline
5-amino-2-methoxypyridine
2-methylmercapto) -aniline
Sulfanamide
Sulfisomidine
p-bromoaniline
2- (4-aminophenyl) -6-methylbenzothiazole
4-amino-4'-nitrodiphenyl sulfide
3-aminophenol
4-aminophenol
4'-aminoacetanilide
3-aminobenzyl alcohol
4-aminophenethyl alcohol
2-aminoanthraquinone
6-aminonicotinamide
2-amino-6-fluorobenzothiazole
2-amino-5- (4-nitrophenylsulfon) thiazole
2-amino-4-methoxybenzothiazole
2-amino-4-chlorobenzothiazole
2-amino-5-bromothiazole HBr
2-aminothiazole
2-aminobenzothiazole
2-amino-6-methoxybenzothiazole
2-amino-6-nitrobenzothiazole
2-amino-4-methylbenzothiazole
2-amino-4- (4-chlorophenyl) thiazole
2-amino-5,6-dimethylbenzothiazole
2-amino-6-methylbenzothiazole
2-amino-6-chlorobenzothiazole
2-amino-6-ethoxybenzothiazole
2-amino-5-nitrothiazole
2-amino-5- (ethylthio) -1,3,4-thiadiazole
Methyl 3-amino-2-thiophene carboxylate
N- [4- (4-aminobenzyl) phenyl] -5-norbornene-2,3-dicarboximide
2-amino-4-phenylthiazole HBr
2-amino-3,5-dichloropyridine
2-amino-5-bropyridine
2-amino-4-picolin
5-amino-2-chloropyridine
2-amino-4,6-dimethylpyridine
2-amino-5-chloropyridine
2-amino-2-chloropyridine
2-amino-5-picolin
2-amino-6-picolin
9-aminoacridine
4-aminoisoquinoline
3-aminoquinoline
2-amino-4,6-dimethylpyrimidine
1-aminoisoquinoline
5-aminoquinoline
2-amino-4,6-dichloropyrimidine
3-amino-5,6-dimethyl-1,2,4-triazine
2-amino-4-chloro-6-methylpyrimidine
2-amino-4-methylpyrimidine
5-amino-3-methylisothiazole
2-amino-5-bromopyrimidine
2-amino-4,6-dimethoxypyrimidine
2-amino-4-methoxy-6-pyrimidine
4-amino-6-chloro-2- (methylthio) pyrimidine
2-amino-5-chlorobenzoxazole
2-amino-5-trifluoromethyl-1,3,4-thiadiazole
3-amino-5-methylisoxazole
4-amino-2,1,3-benzothiadiazole
2-amino-1,3,4-thiadiazole
3-amino-1-phenyl-2-pyrazolin-5-one
6-amino-1,3-dimethyluracil
4-amino-1,2-naphthoquinone hemihydrate
3-amino-1- (2,4,6-trichlorophenyl) -2-pyrazolin-5-one
1- (2-aminophenyl) pyrrole
N- (4-amino-2-methylphenyl) -4-chlorophthalimide
2-amino-3-chloro-5- (trifluoromethyl) pyridine
2-amino-3-picolin
2-amino-4-methyl-4-nitropyridine
2-amino-4-methylthiazole
2-amino-5-ethyl-1,3,4-thiadiazole
2-aminopyrimidine
3-aminocrotononitrile
3-amino-1,2,4-triazole
3-aminopyrazole
4-amino-2,3,5,6-tetrafluoropyridine
4-aminopyrimidine
5-amino-1-ethylpyrazole
5-amino-1-phenyl-4-pyrazolecarboxamide
5-amino-3-methylisoxazole
5-aminouracil
TABLE 3
Sulfonyl chlorides and isocyanates
p-toluenesulfonyl chloride
2,4-dichlorobenzenesulfonyl chloride
2-thiophenesulfonyl chloride
Styrenesulfonyl chloride
2-methoxycarbonylphenyl isocyanate
4-acetylphenyl isocyanate
Cyclohexyl isocyanate
p-tolyl isocyanate
TABLE 4
Carboxylic acids
Pyruvic acid
p-toluic acid
o-tolyl acetic acid
Phenylacetic acid
Trans-2-pentenoic acid
Methylthio acetic acid
4-methoxycinnamic acid
Nonan
3-methoxypropionic acid
4-methoxycyclohexanecarboxylic acid
Phenylpropioic acid
1-naphthyl acetic acid
Pentafluoropropionic acid
Piperonylic acid
N- (2-furoyl) glycine
Propionic acid
2,3,4,5,6-pentafluorophenylacetic acid
4-pentenoic acid
Octanoic acid fluorocinnamic acid phenyl acetic acid
4-methylcinnamic acid
Metal acrylic acid
p- (dimethylamino) cinnamic acid
Phenylpyruvic acid
Nicotinic acid
2-methylcinnamic acid
Methoxyacetic acid
Phenoxybenzoic acid
Cyclopropanecarboxylic acid
Glycolic acid
Trans-3-hexenoic acid
4- (trifluoromethyl) mandelic acid
2- (2-methoxyethoxy) acetic acid
Diphenylacetic acid
2-Bromo-4,5-dimethoxycinnamic acid
3,4-dihydroxyhydrocinnamic acid
3-methoxycinnamic acid
4-chlorophenoxy acetic acid
4- (4-nitrophenyl) butyric acid
3- (4-chlorobenzoyl) propionic acid
2- (4-hydroxyphenoxy) propionic acid
2-chlorocinnamic acid
2-biphenylcarboxylic acid
2- (4-Chlorophenoxy) -2-methylpropionic acid
Benzoylpropionic acid
3- (phenylthio) acrylic acid
3,5-di-tert-butyl-4-hydroxycinnamic acid
4-bromobutyric acid
4-bromomandelic acid
Decanoic acid
4-hydroxycinnamic acid
2-nitrocinnamic acid
2,3,4-trifluorocinnamic acid
Homovanic acid
3-methoxycyclohexanecarboxylic acid
2-ethoxycinnamic acid
2,5-difluorophenylacetic acid
4-fluorocinnamic acid
2,6-difluorophenylacetic acid
3,3, -diphenylpropionic acid
Cis-pinonic acid
2-fluorobenzoic acid
Cyanoacetic acid
1,2,3,4-tetrahydro-2-naphric acid
Trans-2-phenyl-1-cyclopropanecarboxylic acid
4- (4-methoxyphenyl) butyric acid
2-formylphenoxyacetic acid
3- (4-fluorobenzoyl) propionic acid
Difluoroacetic acid
3-Chlorobenzo [b] thiophene-2-carboxylic acid
4-methoxybenzylidenecyanoacetic acid
1-adamantane acetic acid
1-adamantanecarboxylic acid
1-fluorenecarboxylic acid
(2-naphthoxy) acetic acid
1H-benzimidazole-5-carboxylic acid
2- (2,4,5-trichlorophenoxypropionic acid)
3-hydroxycinnamic acid
Aviete
Isoxazole-5-carboxylic acid
(4-Chloro-o-tolyloxy) -butyric acid
3-pyridylacetic acid
α-methyl-2,4,5-trimethoxycinnamic acid
2-chlorophenylacetic acid
3-fluorophenylacetic acid
(S)-(+)-mandelic acid
2,4-difluorophenylacetic acid
Butyric acid
4-methoxyphenylacetic acid
4-ethoxyphenylacetic acid
Trans-2-hexenoic acid
3,4-dihydroxycinnamic acid
2,3-dichlorophenoxy acetic acid
S-benzylthioglycolic acid
3,4- (methylenedioxy) phenylacetic acid
(α, α, α-trifluoro-m-tolyl) acetic acid
3,4-difluorophenylacetic acid
2-furiosan
4-acetylphenoxyacetic acid
4- (3,4-dimethoxyphenyl) butyric acid
Cyclohexanepropionic acid
7-methoxy-2-benzofuran carboxylic acid
2- (trifluoromethyl) cinnamic acid
2,4-dinitrophenylacetic acid
2,4-dichlorophenylacetic acid
2-nitrophenylpyruvic acid
Iodoacetic acid
Acetic acid
4- (2,4-dichlorophenoxy) butyric acid
3- (3,4,5-trimethoxyphenyl) propionic acid
6-chloro-2H-1-benzopyran-3-carboxylic acid
4-acetamido shinnamsan
3-hydroxyphenylacetic acid
2-Chloro-6-fluorocinnamic acid
3-fluoro-4-hydroxyphenylacetic acid
4-fluorophenylacetic acid
Trans-3-fluorocinnamic acid
3-bromosinnamsan
2-pyridylacetic acid
α-fluorocinnamic acid
4- (2-cyclohexenyloxy) benzoic acid
1-naphthoic acid
2-bromophenylacetic acid
4-nitrocinnamic acid
2-propylpentanoic acid
3,4-dihydro-2,2-dimethyl-4-oxo-2h-pyran-6-carboxylic acid
3- (2-methoxyphenyl) propionic acid
2-fluorocinnamic acid
Tiglic acid
(4-pyridylthio) acetic acid
4-hydroxyphenylacetic acid
4-bromophenylacetic acid
Chloroacetic acid
Chromone-2-carboxylic acid
4-bromosinnamsan
α-phenylcinnamic acid
Benzoyl formic acid
Dichloroacetic acid
3,5-dimethoxy-4-hydroxycinnamic acid
Trans-4- (trifluoromethyl) cinnamic acid
Cyclohexyl acetic acid
Cyclopentylpropionic acid
(-)-Methoxyacetic Acid
α-fluorophenylacetic acid
3- (3,4-dimethoxyphenyl) propionic acid
3,4-dichlorocinnamic acid
4-fluorophenoxyacetic acid
Thiophenoxyacetic acid
3,5-bis (trifluoromethyl) phenylacetic acid
(4-methylphenoxy) acetic acid
6-methylchromone-2-carboxylic acid
(3,4-dimethoxyphenyl) acetic acid
3-chlorophenylacetic acid
2,3,4,5,6-pentafluorocinnamic acid
3-indolepropionic acid
2-thiophene acetic acid
6-bromocomarin-3-carboxylic acid
4-pyridylacetic acid
α-methylhydrocinnamic acid
α-phenylcinnamic acid
Cis-2-methoxycinnamic acid
4-phenylcinnamic acid
4-Chloro-o-anisic acid
4-ethoxycinnamic acid
2-phenylpropionic acid
3,4- (methylenedioxy) cinnamic acid
1-phenyl-1-cyclopropanecarboxylic acid
3-cyanobenzoic acid
3,4,5-trimethoxyphenylacetic acid
(2-amino-thiazol-4-yl) acetic acid
2,3-dimethoxybenzoic acid
4-chlorophenylacetic acid
Bis (4-chlorophenoxy) acetic acid
Tetrahydro-2-furoic acid
Trans-styrylacetic acid
4-chlorocinnamic acid
α-methylcinnamic acid
α-cyanocinnamic acid
4-methyl valeric acid
4-pyrazolecarboxylic acid
2-fluorophenylacetic acid
3- (1-naphthyl) acrylic acid
3-bromophenylacetic acid
α-cyano-3-hydroxycinnamic acid
2- (3-chlorophenoxy) propionic acid
2,5-dimethylcinnamic acid
2,6-dichlorophenylacetic acid
3-phenoxypropionic acid
2,6-dichlorocinnamic acid
(2,5-dimethoxyphenyl) acetic acid
2,3,4-trimethoxycinnamic acid
2,3,4-triphenoxybenzoic acid
2-chlorobenzoic acid
3,4,5-trimethoxycinnamic acid
Cyclobutanecarboxylic acid
Cyclohexene-1-carboxylic acid
4-nitrophenylacetic acid
Benzoylbutyric acid
3,5-dimethoxybenzoic acid
α-cyano-4-hydroxycinnamic acid
Cyclopentanecarboxylic acid
5- (Pyrid-2-yl) thiophene-2-carboxylic acid
Bromoacetic acid
Trans-4-hydroxy-3-methoxycinnamic acid
4-chloro-2-fluorocinnamic acid
2-octynic acid
3- (p-tolyl) propionic acid
4-chlorobenzoic acid
2-methoxyphenylacetic acid
4-biphenylcarboxylic acid
2-chloro-4-fluorocinnamic acid
2-norbornamemeacetic acid
2-naphthyl acetic acid
2-Methyl-1-cyclohexanecarboxylic acid
(1-naphthoxy) acetic acid
2,5-dimethoxybenzoic acid
Cyclopentyl acetic acid
Ethoxyacetic acid
Cyclohexanebutyric acid
2-Methylcyclopropane-carboxylic acid
4-methylcyclohexaneacetic acid
4-hydroxymandelic acid monohydrate
4-bromo-2-fluorocinnamic acid
Lauric acid
2-bromovaleric acid
2,6-dimethoxybenzoic acid
Trans-2,3-dimethoxycinnamic acid
3- (4-hydroxyphenyl) propionic acid
3- (4-methoxybenzoyl) propionic acid acetamicincinnamanthol) acetic acid
Hydrocinnamic acid
3,4-difluorocinnamic acid
3,5-bis (trifluoromethyl) benzoic acid
(3,5-dimethoxyphenyl) acetic acid
9-anthracenecarboxylic acid
3- (trifluoromethyl) cinnamic acid
m-tolyl acetic acid
4-formylcinnamic acid
3-furic acid
Crotonic acid
α-acetamidocinnamic acid
α-phenylcyclopentaneacetic acid
Diphenylacetic acid
4,5-dimethoxy-2-nitrocinnamic acid
4- (methylthio) phenylacetic acid
3,5-dimethoxycinnamic acid
3-nitrocinnamic acid
5-chlorobenzo [b] thiophene-3-acetic acid
3-methyl-2-phenylvaleric acid
3- (trifluoromethoxy) cinnamic acid
4-biphenylacetic acid
3-bromo-4-fluorocinnamic acid
3- (2-hydroxyphenyl) propionic acid
2,4-difluorocinnamic acid
5-methoxy-1-indanon-3-acetic acid
α-methoxyphenylacetic acid
2-thiophenecarboxylic acid
3- (4-methoxyphenyl) propionic acid
4-acetoxy-3-methoxycinnamic acid
2-methoxycinnamic acid
3-benzoylbenzoic acid
Levulinic acid
3,4-dichlorophenylacetic acid
3-methylindene-2-carboxylic acid
4-phenoxybutyric acid
2-hydroxycinnamic acid
2-ethoxy-1-naphthoic acid
2-Chloro-5-nitrocinnamic acid
3,3-dimethylacrylic acid
4-petinic acid
4-acetoxycinnamic acid
2- (p-toluoyl) benzoic acid
3,5-difluorocinnamic acid
2-ethoxybenzoic acid
Trans-2-methyl-2-pentenoic acid
Cycloheptanecarboxylic acid
Tetrahydro-3-furoic acid
3,5-difluorophenylacetic acid
Trans-2,6-difluorocinnamic acid
Tioctic acid
5-Bromo-2-fluorocinnamic acid
11-phenoxy undecanoic acid
2,4-dichlorophenoxy acetic acid
2- (2,4-dichlorophenoxy) propionic acid
2,2-dimethylbutyric acid
o-tolulic acid
2-Bromo-4,5- (methylenedioxy) cinnamic acid
α-bromophenylacetic acid
Trans-N- (2-furfurylideneacetyl) glycine-3-chlorobenzoic acid
D-3-phenyllactic acid
2-phenoxybutyric acid
2- (4-chlorophenoxy) propionic acid
2-acetoxycinnamic acid
(R)-(-)-mandelic acid
(+/-)-6-methoxy-α-methyl-2-naphthaleneacetic acid
(+/-)-2- (2-chlorophenoxy) propionic acid
(+/-)-2-phenyloxypropionic acid
1-methyl-1-cyclohexanecarboxylic acid
2,5-dimethoxycinnamic acid
2- (2-aminothiazol-4-yl-2-methoxyiminoacetic acid
2-acetamidoacrylic acid
Although the invention has been described in detail by way of example for purposes of clarity and understanding, it will be apparent to those skilled in the art that slight changes and modifications may be made. Accordingly, the description and examples herein do not limit the scope of the invention.

权利要求:
Claims (100)
[1" claim-type="Currently amended] a) binding the olefin to a solid support,
b) oxidizing the olefin to provide an epoxide functional group,
c) ring opening the epoxide with an amine to form an amino alcohol, and
d) cyclizing the amino alcohol using a phosgene equivalent
Solid phase synthesis method of oxazolidinone comprising a.
[2" claim-type="Currently amended] The method of claim 1 wherein the olefin is allyl amine or allylamine.
[3" claim-type="Currently amended] The method of claim 1 wherein the amine is an amino acid or an aromatic amine.
[4" claim-type="Currently amended] a) binding an olefin group to a solid support array,
b) oxidizing each olefin group to provide an epoxide bound to a solid phase support, and
c) ring opening the epoxide with an amine to form an amino alcohol, and
d) cyclizing the amino alcohol using a phosgene equivalent
Synthesis method of oxazolidinone combinatorial library comprising a.
[5" claim-type="Currently amended] The method of claim 4 wherein the olefin is allyl amine or allylamine.
[6" claim-type="Currently amended] The method of claim 4 wherein the amine unit is an amino acid or an aromatic amine.
[7" claim-type="Currently amended] An oxazolidinone combinatorial library in which an oxazolidinone constituting the library is a compound of Formula 1a
<Formula 1a>

Where
R ₁ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl,
R ₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₃ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₁ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₁₂ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
[8" claim-type="Currently amended] 8. The combination library of claim 7, wherein R ₃ is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl groups are aryl and heteroaryl groups bonded to the amines of Table 2 and FIGS. 29, 30 and 31.
[9" claim-type="Currently amended] The combination library according to claim 7, wherein R ₃ is a heteroaryl group selected from the group consisting of pyridyl group, thienylphenyl group, oxazolyl group, pyrrolyl group, and morpholinofluorophenyl group.
[10" claim-type="Currently amended] An antimicrobial compound which is a compound having a structure of the following formula.

Where
m is 0, 1, 2 or 3,
R ₂₂ , R ₂₃ and R ₂₄ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.
[11" claim-type="Currently amended] The antimicrobial compound of claim 10 wherein m is 0, R ₂₂ and R ₂₃ are hydrogen, and R ₂₄ is an aryl group.
[12" claim-type="Currently amended] The antimicrobial compound of claim 11, wherein the compound has a structure of:

Where
R ₃₅ , R ₃₆ and R ₃₇ are each independently selected from the group consisting of hydrogen, an electron withdrawing group, alkyl, heteroalkyl, aryl and heteroaryl.
[13" claim-type="Currently amended] An antimicrobial compound which is a compound having a structure of the following formula.

Where
R ₃ is selected from the group consisting of aryl and heteroaryl,
R ₂₀ is selected from the group consisting of groups of the formulas A, B, C, I, J and K.

(Wherein
m is 0, 1, 2 or 3,
n is 0, 1, 2 or 3,
R ₂₁ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl,
R ₂₂ , R ₂₃ and R ₂₄ are each independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₂₅ is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl,
R ₃₀ is selected from the group consisting of alkyl, heteroalkyl, aryl and heteroaryl)
[14" claim-type="Currently amended] A compound of formula
<Formula 2c>

Where
R ₆ is acyl or sulfonyl,
R ₇ is aryl or heteroaryl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, NRC (= 0), C (= 0), C (= 0) O, OC (= 0), S ( = O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR 'or (CH ₂ ) _n O, where n is 0 to 6 and R and R' are independently of each other H, alkyl, heteroalkyl , Aryl or heteroaryl,
R ₉ is hydrogen, OH, alkyl, aryl, heteroalkyl or heteroaryl.
[15" claim-type="Currently amended] The method of claim 14,
R ₆ is C (═O) R, wherein R is H, alkyl or aryl,
R ₇ is aryl,
R ₈ is NH (C═O) or NR ′ (C═O), wherein R ′ is H, alkyl, or aryl,
R ₉ is hydrogen, pyridinyl, thiazolyl, benzothiazolyl, isothiazolyl, quinolinyl, 1,3,4-triazolyl or 1,3,4-thiadiazolyl.
[16" claim-type="Currently amended] A compound of formula 1b
<Formula 1b>

Where
R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl or sulfonyl,
R ₁ is C (O) NR ₇ R ₈ (wherein R ₇ and R ₈ are independently of each other hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), C (O) OR ₉ (here, R ₉ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), C (O) R ₁₀ (wherein R ₁₀ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), SR ₁₁ (where R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, S (O) ₂ R ₁₁ , wherein R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, S (O) R ₁₁ (Wherein R ₁₁ is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl), NR ₁₂ R ₁₃ (wherein R ₁₂ and R ₁₃ are independently of each other hydrogen, acyl, sulfonyl, alkyl, heteroalkyl , Aryl or heteroaryl, 2-oxazolyl having R ₁₄ at position 4 of oxazolyl and R ₁₅ at position 5 of oxazolyl, wherein R ₁₄ and R ₁₅ are independently of each other hydrogen , Alkyl, heteroal , Aryl, heteroaryl or giim attract electrons), and in position 4 of the thiazole is R _16, 2- amino-thiazolyl group, a 5-position of thiazole is R ₁₇ (where, R ₁₆ and R ₁₇ is Independently of one another, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group, and CH ₂ NR ₁₈ R ₁₉ , wherein R ₁₈ and R ₁₉ are independently of each other hydrogen, alkyl, heteroalkyl, Aryl, heteroaryl, acyl or sulfonyl).
[17" claim-type="Currently amended] Combination library of compounds according to claim 16.
[18" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is C (O) NR ₇ R ₈ , C (O) OR ₉ , C (O) R ₁₀ , SR ₁₁ , S (O) ₂ R ₁₁ , S (O) R ₁₁ or NR ₁₂ R ₁₃ .
[19" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is C (O) NR ₇ R ₈ .
[20" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is C (O) OR ₉ .
[21" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is C (O) R ₁₀ .
[22" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is SR ₁₁ .
[23" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is NR _x (C═O) R _y , wherein R _x and R _y are independently of each other hydrogen, alkyl, heteroalkyl, aryl or heteroaryl.
[24" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is NR _x (SO ₂ ) R _y , wherein R _x and R _y are independently of each other hydrogen, alkyl, heteroalkyl, aryl or heteroaryl, provided that R _y is H Non-compound.
[25" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is NR ₁₂ R ₁₃ .
[26" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is 2-oxazolyl, wherein R ₁₄ is at position 4 of the oxazole group and R ₁₅ is located at position 5 of the oxazole group.
[27" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is 2-aminothiazolyl, wherein R ₁₆ is at position 4 of the aminothiazolyl group and R ₁₇ is at position 5 of the aminothiazolyl group.
[28" claim-type="Currently amended] The compound of claim 16, wherein R ₁ is CH ₂ NR ₁₈ R ₁₉ .
[29" claim-type="Currently amended] 19. The compound of claim 18, wherein R ₃ , R ₄ and R ₅ are hydrogen.
[30" claim-type="Currently amended] The compound of claim 29, wherein R ₂ is fluorine.
[31" claim-type="Currently amended] The compound of claim 30, wherein R ₆ is C (O) CH ₃ .
[32" claim-type="Currently amended] 32. The compound of claim 31, wherein R ₁ is C (O) NR ₇ R ₈ and R ₇ is hydrogen.
[33" claim-type="Currently amended] 33. The compound of claim 32, wherein R ₈ is heteroaryl.
[34" claim-type="Currently amended] A biologically active oxazolidinone derived from the combinatorial library according to claim 17.
[35" claim-type="Currently amended] The compound of claim 19, wherein R ₃ , R ₄ and R ₅ are hydrogen.
[36" claim-type="Currently amended] The compound of claim 26, wherein R ₃ , R ₄ and R ₅ are hydrogen.
[37" claim-type="Currently amended] The compound of claim 27, wherein R ₃ , R ₄ and R ₅ are hydrogen.
[38" claim-type="Currently amended] The compound of claim 35, wherein R ₂ is fluorine.
[39" claim-type="Currently amended] The compound of claim 36, wherein R ₂ is fluorine.
[40" claim-type="Currently amended] 38. The compound of claim 37, wherein R ₂ is fluorine.
[41" claim-type="Currently amended] The compound of claim 38, wherein R ₆ is C (O) CH ₃ and NR ₇ R ₈ is NH (5 ′-(5-aminopyridin-2-yl) thiopyridin-3′-yl) or NH (pyridine- 3-yl).
[42" claim-type="Currently amended] The compound of claim 38, wherein R ₆ is C (O) CH ₂ SMe and NR ₇ R ₈ is NH (5-chloropyridin-3-yl).
[43" claim-type="Currently amended] The compound of claim 38, wherein R ₆ is C (O) CHCH (pyridin-3-yl) and R ₇ R ₈ is NH (5-chloropyridin-3-yl).
[44" claim-type="Currently amended] a) coupling various aryl oxazolidinones to various solid phase supports,
b) functionalizing the position 4 of the aryl group of the bound oxazolidinone, and optionally
c) separating oxazolidinones from the solid phase support
Method of producing a combination library according to claim 17 comprising a.
[45" claim-type="Currently amended] 45. The method of claim 44, wherein the aryl oxazolidinone is bound to the solid support by reacting iminophosphoran with a resin containing carbonyl to form an imine.
[46" claim-type="Currently amended] 45. The method of claim 44, wherein the aryl oxazolidinone is bound to the solid support by reacting the amine with a resin containing carbonyl to form an imine.
[47" claim-type="Currently amended] 46. The method of claim 45, wherein the binding process further comprises reducing the imine.
[48" claim-type="Currently amended] 47. The method of claim 46, wherein the binding process further comprises reducing the imine.
[49" claim-type="Currently amended] a) providing iminophosphoran,
b) mixing iminophosphoran with a resin containing carbonyl to form imine intermediates, and
c) reducing the imine intermediate to obtain a compound bound to the resin via an amine linker
Method of synthesizing a compound according to claim 16 comprising a.
[50" claim-type="Currently amended] The method of claim 49, wherein the azide is reacted with phosphine to provide iminophosphoran.
[51" claim-type="Currently amended] The method of claim 49, wherein the amine is reacted with (trisubstituted) phosphine dihalide to provide iminophosphoran.
[52" claim-type="Currently amended] The method of claim 49, wherein the resin containing a carbonyl group is a structure of Formula 1c.
<Formula 1c>

Where
R ₂₃ is hydrogen, alkyl, aryl, O-alkyl or O-aryl,
R ₂₄ is hydrogen, CH ₃ O or NO ₂ ,
R ₂₅ is (CH ₂ ) _n CONH, where n is an integer from 1 to about 5, and
Blacked circles are polymeric supports.
[53" claim-type="Currently amended] 53. The method of claim 52, wherein R ₂₃ is hydrogen, R ₂₄ is CH ₃ O, R ₂₅ is (CH ₂ ) ₃ CONH, and the blackened circles are tentagel, (crosslinked) polystyrene, (crosslinked) polyethylene glycol Or a polyethyleneglycol-polystyrene composition.
[54" claim-type="Currently amended] a) reacting an amine with a resin containing a carbonyl group to form an imine intermediate, and
b) reducing the imine intermediate to obtain a compound bound to the resin via an amine linker
Method of synthesizing a compound according to claim 16 comprising a.
[55" claim-type="Currently amended] The compound of claim 14, wherein the compound is selected from the group consisting of compounds of the formula:

[56" claim-type="Currently amended] The compound of claim 14, wherein the compound is selected from the group consisting of compounds of the formula:

[57" claim-type="Currently amended] The compound of claim 14, wherein the compound is selected from the group consisting of compounds of the formula:


[58" claim-type="Currently amended] The compound of claim 14, wherein the compound is selected from the group consisting of compounds of the formula:


[59" claim-type="Currently amended] The compound of claim 14, wherein the compound is selected from the group consisting of compounds of the formula:


[60" claim-type="Currently amended] The compound of claim 14, wherein R ₆ is C (═O) R, wherein R is H, alkyl, heteroalkyl, aryl or heteroaryl, R ₇ is aryl, and R ₈ is NH (C═O) ) And R ₉ is hydrogen or OH.
[61" claim-type="Currently amended] The compound of claim 14, wherein the compound is selected from the group consisting of compounds of the formula:

[62" claim-type="Currently amended] A compound of formula
<Formula 3c>

Where
R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, NRC (= 0), C (= 0), C (= 0) O, OC (= 0), S ( = O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ', or (CH ₂ ) _n O, where n is 0 to 6 and R and R' are independently of each other H, alkyl, heteroalkyl , Aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl.
[63" claim-type="Currently amended] 63. The compound of claim 62, wherein R ₆ is C (= 0) CH ₃ , R ₇ is aryl, R ₈ is S, and R ₉ is heteroalkyl.
[64" claim-type="Currently amended] 63. The compound of claim 62, wherein the compound is selected from the group consisting of compounds of the formula

[65" claim-type="Currently amended] 63. The compound of claim 62, wherein the compound is selected from the group consisting of compounds of the formula

[66" claim-type="Currently amended] 63. The compound of claim 62, wherein the compound is selected from the group consisting of compounds of the formula

[67" claim-type="Currently amended] 63. The compound of claim 62, wherein R ₆ is C (= 0) CH ₃ , R ₇ is aryl, R ₈ is OC (= 0) and R ₉ is alkyl.
[68" claim-type="Currently amended] 63. The compound of claim 62, wherein the compound is selected from the group consisting of compounds of the formula

[69" claim-type="Currently amended] A compound of formula 4c.
<Formula 4c>

Where
R ₆ is acyl or sulfonyl,
Het ₁ is heteroaryl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n O, where n is 0 to 6 and R and R ′ are independently of each other, H, alkyl, heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl.
[70" claim-type="Currently amended] A compound of formula 5c.
<Formula 5c>

Where
R ₂ , R ₃ , R ₄ and R ₅ are, independently of one another, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group,
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, NRC (= 0), C (= 0) NOR, C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n 0, where n is 0 to 6 and R and R ′ are independently of each other, H, alkyl, heteroalkyl, aryl or heteroaryl,
Het ₂ is a heterocyclic group.
[71" claim-type="Currently amended] The compound of claim 70, wherein R ₆ is C (═O) CH ₃ , R ₇ is aryl, R ₈ is S, and Het ₂ is a thienylphenyl or thiazolyl group.
[72" claim-type="Currently amended] The compound of claim 70, wherein the compound is selected from the group consisting of compounds of the formula:

[73" claim-type="Currently amended] The compound of claim 70, wherein R ₆ is C (═O) CH ₃ , R ₇ is aryl, R ₈ is NH, and Het ₂ is 1,3,5-triazinyl.
[74" claim-type="Currently amended] The compound of claim 70, wherein the compound is selected from the group consisting of compounds of the formula:

[75" claim-type="Currently amended] A compound of formula 6c
<Formula 6c>

Where
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, NRC (= 0), C (= 0) NOR, C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n 0, where n is 0 to 6 and R and R ′ are independently of each other, H, alkyl, heteroalkyl, aryl or heteroaryl,
Het ₁ is heteroaryl,
Het ₂ is a heterocyclic group.
[76" claim-type="Currently amended] 76. The method of claim 75,
Het ₁ is selected from the group consisting of thienylphenyl, thiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, phenyl and fluorophenyl,
Het _divalent oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, thienylphenyl, thiazolyl, isothiazolyl , 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4- Triazinyl, 1,3,5-triazinyl and 1,2,4,5-tetrazinyl.
[77" claim-type="Currently amended] To a compound of formula 7c or 8c.
<Formula 7c>

<Formula 8c>

Where
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n 0, where n is 0 to 6 and R and R ′ are independently of each other, H, alkyl, heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl,
R ₁₀ , R ₁₁ and R ₁₂ independently of one another are hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing groups, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S ( = O) R ", SO ₂ R", C (= O) R ", C (= O) OR", OC (= O) R ", C (= O) NR" R "', N (R" ) C (= 0) R "'or an N-oxide group in the pyridine nucleus, wherein R" and R "', independently of each other, are H, alkyl, heteroalkyl, aryl or heteroaryl.
[78" claim-type="Currently amended] A compound of formula 9c or 10c.

Where
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n 0, where n is 0 to 6 and R and R ′ are independently of each other, H, alkyl, heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl,
R ₁₀ and R ₁₁ are independently of each other hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S (= 0) R ", SO ₂ R", C (= O) R ", C (= O) OR", OC (= O) R ", C (= O) NR" R "', N (R") C ( ═O) R ″ ′ or an N-oxide group in the pyrimidine nucleus, wherein R ″ and R ″ ′, independently of one another, are H, alkyl, heteroalkyl, aryl or heteroaryl.
[79" claim-type="Currently amended] A compound of Formula 11c, 12c or 13c.

Where
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n 0, where n is 0 to 6 and R and R ′ are independently of each other, H, alkyl, heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl,
R ₁₀ and R ₁₁ are independently of each other hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S (= 0) R ", SO ₂ R", C (= 0) R ", C (= 0) OR", OC (= 0) R ", C (= 0) NR" R "'or N (R") C ( = O) R "'wherein R" and R "', independently of each other, are H, alkyl, heteroalkyl, aryl or heteroaryl.
[80" claim-type="Currently amended] To compounds of formulas 14c, 15c or 16c.

Where
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n 0, where n is 0 to 6 and R and R ′ are independently of each other, H, alkyl, heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl,
R ₁₀ is hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN, NO ₂ , NR "R"', OR ", SR", S (= O) R ", SO ₂ R" , C (= 0) R ", C (= 0) OR", OC (= 0) R ", C (= 0) NR" R "'or N (R") C (= 0) R "' , Wherein R ″ and R ″ ′, independently of one another, are H, alkyl, heteroalkyl, aryl or heteroaryl.
[81" claim-type="Currently amended] A compound of formula 17c.
<Formula 17c>

Where
R ₆ is acyl or sulfonyl,
R ₈ is C ₁ -C ₇ alkyl, NR, O, S, C (= 0) NR, C (= 0) NOR, NRC (= 0), C (= 0), C (= 0) O, OC (═O), S (═O), SO ₂ , SO ₂ NR, NRSO ₂ , NRCONR ′ or (CH ₂ ) _n 0, where n is 0 to 6 and R and R ′ are independently of each other, H, alkyl, heteroalkyl, aryl or heteroaryl,
R ₉ is alkyl, aryl, heteroalkyl or heteroaryl.
[82" claim-type="Currently amended] A composition for the treatment or prevention of an infectious disease, comprising an effective amount of the compound of claim 14 and a pharmaceutically acceptable carrier.
[83" claim-type="Currently amended] 83. The composition of claim 82, wherein the compound is represented by the formula:

[84" claim-type="Currently amended] 83. The composition of claim 82, wherein the compound is represented by the formula:

[85" claim-type="Currently amended] 83. The composition of claim 82, wherein the compound is represented by the formula:

[86" claim-type="Currently amended] 83. The composition of claim 82, wherein the compound is represented by the formula:

[87" claim-type="Currently amended] 83. The composition of claim 82, wherein the compound is represented by the formula:

[88" claim-type="Currently amended] 83. The composition of claim 82, wherein the compound is represented by the formula:

[89" claim-type="Currently amended] A composition for the treatment or prevention of an infectious disease, comprising an effective amount of the compound of claim 55 and a pharmaceutically acceptable carrier.
[90" claim-type="Currently amended] A composition for the treatment or prevention of an infectious disease, comprising an effective amount of the compound of claim 57 and a pharmaceutically acceptable carrier.
[91" claim-type="Currently amended] 83. The composition of claim 82, wherein the compound is represented by the formula:

[92" claim-type="Currently amended] A composition for the treatment or prevention of an infectious disease, comprising an effective amount of the compound of claim 61 and a pharmaceutically acceptable carrier.
[93" claim-type="Currently amended] A composition for the treatment or prevention of an infectious disease comprising an effective amount of the compound of claim 64 and a pharmaceutically acceptable carrier.
[94" claim-type="Currently amended] A composition for the treatment or prevention of an infectious disease comprising an effective amount of the compound of claim 72 and a pharmaceutically acceptable carrier.
[95" claim-type="Currently amended] A method of treating or preventing an infectious disease in a human or other animal subject, comprising administering an effective amount of the compound of claim 14 to the subject.
[96" claim-type="Currently amended] A method of treating or preventing an infectious disease in a human or other animal subject, comprising administering an effective amount of the compound of claim 55 to the subject.
[97" claim-type="Currently amended] A method of treating or preventing an infectious disease in a human or other animal subject, comprising administering an effective amount of the compound of claim 57 to the subject.
[98" claim-type="Currently amended] A method of treating or preventing an infectious disease in a human or other animal subject, comprising administering to the subject an effective amount of the compound of claim 61.
[99" claim-type="Currently amended] A method of treating or preventing an infectious disease in a human or other animal subject, comprising administering to the subject an effective amount of the compound of claim 64.
[100" claim-type="Currently amended] A method of treating or preventing an infectious disease in a human or other animal subject, comprising administering to the subject an effective amount of the compound of claim 72.

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同族专利:

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公开号 | 公开日

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CA2318969A1|1999-07-29|

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CN1288462A|2001-03-21|

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JP2002501059A|2002-01-15|

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US6239152B1|2001-05-29|

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US6531470B1|2003-03-11|

---

EP1049682A1|2000-11-08|

---

BR9907183A|2003-06-10|

---

WO1999037630A1|1999-07-29|

---

AU764184B2|2003-08-14|

---

AU2464499A|1999-08-09|

---

NZ505902A|2003-08-29|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-01-23|Priority to US1253598A

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1998-01-23|Priority to US09/012,535

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1998-05-28|Priority to US8670298A

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1998-05-28|Priority to US09/086,702

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1999-01-22|Application filed by 로렌스 티. 마이젠헬더, 파마시아 앤드 업존 캄파니

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1999-01-22|Priority to PCT/US1999/001318

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2001-02-26|Publication of KR20010015910A

优先权:

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申请号 | 申请日 | 专利标题

---

US1253598A| true| 1998-01-23|1998-01-23|

---

US09/012,535|1998-01-23|

---

US8670298A| true| 1998-05-28|1998-05-28|

---

US09/086,702|1998-05-28|

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PCT/US1999/001318|WO1999037630A1|1998-01-23|1999-01-22|Oxazolidinone combinatorial libraries, compositions and methods of preparation|