PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`IN I ERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 6 :
`WO 99/37630
`CO7D 263/20, 413/12, 417/12, COIF
`9/653, CO7D 417/04, 413/04
`(21) International Application Number: (cid:9)
`
`Al
`
`(11) International Publication Number: (cid:9)
`
`(43) International Publication Date: (cid:9)
`
`29 July 1999 (29.07.99)
`
`PCT/US99/01318
`
`(22) International Filing Date: (cid:9)
`
`22 January 1999 (22.01.99)
`
`(30) Priority Data:
`09/012,535
`09/086,702
`
`23 January 1998 (23.01.98) (cid:9)
`28 May 1998 (28.05.98) (cid:9)
`
`US
`US
`
`(63) Related by Continuation (CON) or Continuation-in-Part
`(CIP) to Earlier Applications
`US
`Filed on
`US
`Filed on
`
`09/012,535 (CIP)
`23 January 1998 (23.01.98)
`09/086,702 (CIP)
`28 May 1998 (28.05.98)
`
`(71) Applicant (for all designated States except US): VERSICOR,
`INC. [US/US]; 34790 Ardentech Court, Fremont, CA 94555
`(US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): GORDEEV, Mikhail F.
`[RU/US]; 15267 Hesperian Boulevard, San Leandro, CA
`94578 (US). LUEHR, Gary, W. [US/US]; 33252 Palomino
`Common, Fremont, CA 94555-1522 (US). PATEL, Dinesh,
`V. [US/US]; 45109 Cougar Circle, Fremont, CA 94539
`
`(US). NI, Zhi—Jie [CN/US]; 34497 Winslow Terrace, Fre-
`mont, CA 94555 (US). GORDON, Eric [US/US]; 955 Chan-
`ning Avenue, Palo Alto, CA 94301 (US).
`
`(74) Agents: JOHNSTON, Madeline, I. et al.; Morrison & Foerster
`LLP, 755 Page Mill Road, Palo Alto, CA 94304-1018 (US).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD,
`GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP,
`KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
`MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU,
`ZW, ARIPO patent (GH, GM, KE, LS, MW, SD, SZ, UG,
`ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European patent (AT, BE, CH, CY, DE, DK, ES, FI,
`FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent
`(BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE,
`SN, TD, TG).
`
`Published
`With international search report.
`
`(54) Title: OXAZOLIDINONE COMBINATORIAL LIBRARIES, COMPOSITIONS AND METHODS OF PREPARATION
`
`(57) Abstract
`
`Oxazolidinones and methods for their synthesis are provided. Also provided are combinatorial libraries comprising oxazolidinones,
`and methods to prepare the libraries. Further provided are methods of making biologically active oxazolidinones as well as pharmaceutically
`acceptable compositions comprising the oxazolidinones. The methods of library preparation include the attachment of oxazolidinones to
`a solid support. The methods of compound preparation in one embodiment involve the reaction of an iminophosphorane with a carbonyl
`containing polymeric support.
`
`MYLAN - EXHIBIT 1012
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

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`WO 99/37630 (cid:9)
`
`PCT/US99/01318
`
`OXAZOLIDINONE COMBINATORIAL LIBRARIES,
`COMPOSITIONS AND METHODS OF PREPARATION
`
`5 (cid:9)
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`This application is a continuation in part of U.S. Patent Application Serial
`
`No. 09/012,535, filed January 23, 1998, and a continuation in part of U.S. Patent
`
`Application Serial No. 09/086,702, filed May 28, 1998, the disclosures of which are
`
`10 (cid:9)
`
`incorporated herein by reference in their entirety.
`
`FIELD OF THE INVENTION
`
`The present invention is directed to oxazolidinones; oxazolidinone compositions;
`
`oxazolidinone combinational libraries; and methods for their preparation and use.
`
`15
`
`BACKGROUND ART
`
`Oxazolidinones are compounds where an amine group and a hydroxyl group on
`
`adjacent carbon atoms have been cyclized to form a 5-membered ring containing a
`
`carbonyl group. Certain oxazolidinones have been shown to exhibit a variety of biological
`
`20 (cid:9)
`
`activities. For example, some oxazolidinones are inhibitors of monoamine oxidase-B, an
`
`enzyme implicated in Parkinson's disease. See, for example, Ding et al., J Med. Chem.
`
`36:3606-3610 (1993).
`
`A a ten step synthesis of oxazolidinone antibiotics has been described. U.S. Patent
`
`No. 5,547,950. A four step synthesis of the antibacterial compound U-100592 also has
`
`25 (cid:9)
`
`been reported. Schauss et al., Tetrahedron Letters, 37:7937-7940 (1996). A five step
`
`preparation of enantiomerically pure cis- and trans-N-
`
`(propionyl)hexahydrobenzoxazolidin-2-ones further was reported. De Parrodi et al.,
`
`Tetrahedron: Asymmetry, 8:1075-1082 (1997).
`
`Scientists have reported that certain oxazolidinone derivatives exhibit beneficial
`
`30 (cid:9)
`
`antibacterial effects. For instance, N-[3-[3-fluoro-4-(morpholin-4-yl)pheny1]2-
`
`oxooxazolidin-5(s)-ylmethyl] acetamide (below) has been reported to be useful for the
`
`

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`(cid:9) (cid:9)
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`5
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`10
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`15
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`WO 99/37630 (cid:9)
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`PCT/US99/01318
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`treatment of bacterial infections. Lizondo et al., Drugs of the Future, 21:1116-1123
`
`(1996).
`
`0
`
`N)LO
`
`CFi3
`
`O
`The synthesis of the oxazolidinone antibacterial agent shown below has been
`
`reported. Wang et al., Tetrahedron, 45:1323-1326 (1989). This oxazolidinone was made
`
`using a process that included the reaction of an aniline with glycidol to provide an amino
`
`alcohol, and the diethylcarbonate mediated cyclization of the amino alcohol to afford an
`
`oxazolidinone.
`
`H3C
`
`0
`
`
`
`N)0 H . (cid:9)
`
`O
`
`The synthesis of oxazolidinone antibacterial agents, including the compound shown
`
`below has been reported. U.S. Pat. No. 4,705,799. The process used to make the
`
`compound shown below included a metal mediated reduction of a sulfonyl chloride to
`
`provide a sulfide.
`
`CH3S
`
`0
`N)LO H
`N CH3
`
`0
`
`The synthesis of oxazolidinone antibacterial agents, including the pyridyl
`
`compound shown below has been reported. U.S. Patent No. 4,948,801. The process used
`
`included an organometallic mediated coupling of an organotin compound and an aryl
`
`20 (cid:9)
`
`iodide.
`
`0
`N) 0
`
`2
`
`N,CH3
`0
`
`

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`WO 99/37630 (cid:9)
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`PCT/US99/01318
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`Synthetic routes to oxazolidinones often allow a chemist to produce only one
`
`compound at a time. These laborious methods can provide a limited number of
`
`compounds for evaluation in a biological screen. These methods cannot, however, provide
`
`5
`
`the number of compounds required to supply a high-throughput biological screen, an assay
`
`technique whereby the activity of thousands of drug candidates, for example, per week,
`
`may be analyzed. This limitation on compound production is of practical importance since
`
`high-throughput screens are desirable and efficient for the discovery of new drugs.
`
`10 (cid:9)
`
`SUMMARY OF INVENTION
`
`Provided are oxazolidinones and combinatorial libraries, compositions comprising
`
`oxazolidinones, as well as methods of their synthesis and use. Using the methods provided
`
`herein, one of skill in the art can rapidly produce the large number of compounds required
`
`for high-throughput screening.
`
`15 (cid:9)
`
`In one embodiment, provided are methods for the solid phase synthesis of
`
`oxazolidinones.
`
`In one embodiment, the method comprises attaching an olefin to a solid support,
`
`oxidizing the olefin to provide an epoxide functionality, opening the epoxide with an
`
`amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
`
`20 (cid:9)
`
`In another embodiment, the method comprises attaching an allylic amine to a solid
`
`support, oxidizing the olefin of the allylic amine to provide an epoxide, opening the
`
`epoxide with an amine, and cyclizing the resulting amino alcohol using a phosgene
`
`equivalent.
`
`In another embodiment, the method comprises attaching allylamine to a solid
`
`25 (cid:9)
`
`support, oxidizing the olefin of allylamine to provide an epoxide, opening the epoxide with
`
`an amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
`
`In another embodiment, the method comprises attaching an olefin to a solid
`
`support, oxidizing the olefin to provide an epoxide, opening the epoxide with an amino
`
`acid and cyclizing the resulting amino alcohol using a phosgene equivalent.
`
`3
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`(cid:9)
`(cid:9)
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`WO 99/37630 (cid:9)
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`PCT/US99/01318
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`In another embodiment, the method comprises attaching an olefin to a solid
`
`support, oxidizing the olefin to provide an epoxide, opening the epoxide with an aromatic
`
`amine and cyclizing the resulting amino alcohol using a phosgene equivalent.
`
`Methods also are provided for the synthesis of oxazolidinone combinatorial
`
`5 (cid:9)
`
`libraries.
`
`In one embodiment, the method comprises attaching an olefin group to an array of
`
`solid supports, oxidizing the individual olefin groups to provide an array of solid support
`
`bound epoxides, opening the epoxides with amine units, and cyclizing the resulting array
`
`of amino alcohols using a phosgene equivalent.
`
`10 (cid:9)
`
`In another embodiment, the method comprises attaching an allylic amine to an
`
`array of solid supports, oxidizing the individual olefin groups to provide an array of solid
`
`support bound epoxides, opening the epoxides with amine units and cyclizing the resulting
`
`array of amino alcohols using a phosgene equivalent.
`
`In another embodiment, the method comprises attaching allyl amine to an array of
`
`15 (cid:9)
`
`solid supports, oxidizing the individual olefin groups to provide an array of solid support
`
`bound epoxides, opening the epoxides with amine units and cyclizing the resulting array of
`
`amino alcohols using a phosgene equivalent.
`
`In another embodiment, the method comprises attaching an olefin to an array of
`
`solid supports, oxidizing the individual olefin groups to provide an array of solid support
`
`20 (cid:9)
`
`bound epoxides, opening the epoxides with amino acid units and cyclizing the resulting
`
`array of amino alcohols using a phosgene equivalent.
`
`In another embodiment, the method comprises attaching an olefin to an array of
`
`solid supports, oxidizing the individual olefin groups to provide an array of solid support
`
`bound epoxides, opening the epoxides with aromatic amine units and cyclizing the
`
`25 (cid:9)
`
`resulting array of amino alcohols using a phosgene equivalent.
`
`Provided are a variety of oxazolidinones and combinatorial libraries thereof In one
`
`embodiment, the oxazolidinones have the structure:
`
`4
`
`(cid:9)
`(cid:9)
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`WO 99/37630 (cid:9)
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`PCT/US99/01318
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`R3- N
`
`0
`
`R12 )
`R2 R1
`
`R11
`
`la
`
`where R1 is selected from the group consisting of alkyl, heteroalkyl aryl and heteroaryl; R2
`
`5 (cid:9)
`
`is selected from the group consisting of hydrogen, alkyl, heteroalkyl; aryl and heteroaryl;
`
`R3 is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl and
`
`heteroaryl; RH is selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl
`
`and heteroaryl; and R12 is selected from the group consisting of hydrogen, alkyl,
`
`heteroalkyl, aryl and heteroaryl.
`
`10 (cid:9)
`
`In another embodiment, oxazolidinones and combinatorial libraries are provided
`
`wherein the oxazolidinones are of the structure lb, wherein R2, R3, R4 and R5 are,
`
`independently, hydrogen, alkyl,
`
`15
`
`H
`N ,
`
`Rs
`
`heteroalkyl, heteroaryl or an electron withdrawing group; R0 is acyl or sulfonyl; and, R1 is
`
`one of the following functional groups: C(0)NR,R8, wherein R7 and R8 are,
`
`independently, hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; C(0)0R9, wherein R9 is
`
`20 (cid:9)
`
`hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; C(0)R10, wherein R10 is hydrogen, alkyl,
`
`heteroalkyl, aryl or heteroaryl; SR11, wherein R11 is hydrogen, alkyl, heteroalkyl, aryl or
`
`heteroaryl; S(0)2R11, wherein R11 is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl;
`
`S(0)R11, wherein R11 is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; NR12R13, wherein
`
`R12 and R13 are, independently, hydrogen, acyl, sulfonyl, alkyl, heteroalkyl, aryl or
`
`25 (cid:9)
`
`heteroaryl; 2-oxazolyl, wherein R14 is at the 4-position and R15 is at the 5-position of the
`
`oxazolyl, and wherein R14 and R15 are, independently, hydrogen, alkyl, heteroalkyl, aryl,
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`heteroaryl or an electron withdrawing group; 2-aminothiazolyl, wherein R16 is at the 4-
`
`position and R17 is at the 5-position of the thiazole, and wherein R16 and R17, are,
`
`independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing
`
`group; and, CH2NR18R,9, wherein R18 and R19 are, independently, hydrogen, alkyl,
`
`5 (cid:9)
`
`heteroalkyl, aryl, heteroaryl, acyl or sulfonyl.
`
`All compounds disclosed herein can exist as different isomer forms including
`
`stereoisomers and enantiomerically pure forms, and all such isomers and forms are within
`
`the scope of the invention. For example, while structure lb is shown with the preferred
`
`embodiment of a S isomer at the 5 position of the oxazolidinone, the R isomer is within the
`
`10 (cid:9)
`
`scope of the invention. Similarly, in all of the other oxazolidinone compounds. in the case
`
`where a preferred stereoisomer is shown at the 5 position of the oxazolidinone. both
`
`stereoisomers are within the scope of the invention.
`
`In one embodiment of structure lb, R, is C(0)R7R8.
`
`In another embodiment of structure lb, R, is C(0)0R9.
`
`15 (cid:9)
`
`In another embodiment of structure ib, R, is C(0)R10.
`
`In another embodiment of structure lb, R, is SR11.
`
`In another embodiment of structure lb, R, is S(0)2R11.
`
`In another embodiment of structure ib, R, is S(0)R11 .
`
`In another embodiment of structure lb, R, is NR12R13. In another embodiment, R,
`
`20 (cid:9)
`
`is NR„(C=0)R,„ wherein Rx and R3, are independently hydrogen, alkyl, heteroalkyl, aryl, or
`
`heteroaryl;
`
`or R, is NR„(S02)Ry, wherein Rx and R), are independently hydrogen, alkyl,
`
`heteroalkyl, aryl, or heteroaryl with the proviso that Ry is not H;
`
`In another embodiment of structure lb, R, is 2-oxazolyl, wherein R14 is at the 4-
`
`25 (cid:9)
`
`position and R15 is at the 5-position of the oxazole group.
`
`In another embodiment of structure lb, R, is 2-aminothiazolyl, wherein R16 is at the
`
`4-position and R17 is at the 5-position of the aminothiazolyl group.
`
`In another embodiment of structure ib, R, is CH2NR18R19.
`
`In another embodiment of structure lb, R, is C(0)NR7R8; and, R3, R4 and R5 are
`
`30 (cid:9)
`
`hydrogen.
`
`In another embodiment of structure lb, R1 is C(0)NR7R8; R3, R4 and R5 are
`6
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`hydrogen; and, R2 is fluorine.
`In another embodiment of structure lb, R, is C(0)NR,R8; R3, R4 and R5 are
`
`hydrogen; R2 is fluorine; and, R6 is C(0)CH3.
`In another embodiment of structure lb, R, is C(0)NR,R8; R3, R4 and R5 are
`
`5 (cid:9)
`
`hydrogen; R2 is fluorine; R6 is C(0)CH3; and, R, is hydrogen.
`In another embodiment of structure lb, R, is C(0)NR,R8; R3, R4 and R5 are
`hydrogen; R2 is fluorine; R6 is C(0)CH3; R, is hydrogen; and, R8 is heteroaryl.
`
`A variety of methods of preparing combinatorial libraries comprising
`
`oxazolidinones are provided.
`
`10 (cid:9)
`
`In one embodiment, the method is for the preparation of oxazolidinones, such as
`
`those of structure lb. The method comprises the steps of: attaching a plurality of aryl
`
`oxazolidinones to a plurality of solid supports; functionalizing the 4-position of the aryl
`
`groups of the attached oxazolidinones; and, optionally, removing the oxazolidinones from
`
`the solid supports.
`
`15 (cid:9)
`
`In another embodiment, the aryl oxazolidinone is attached to a solid support
`
`through the reaction of an iminophosphorane with a carbonyl containing resin to form an
`
`imine. In another embodiment, the aryl oxazolidinone is attached to a solid support
`
`through the reaction of an amine with a carbonyl containing resin to form an imine.
`
`In another embodiment, the aryl oxazolidinone is attached to a solid support
`
`20 (cid:9)
`
`through the reaction of an iminophosphorane with a carbonyl containing resin to form an
`
`imine, and the imine is reduced to form an amine. In another embodiment, the aryl
`
`oxazolidinone is attached to a solid support through the reaction of an amine with a
`
`carbonyl containing resin to form an imine, and the imine is reduced to form an amine.
`
`Also provided are biologically active oxazolidinones and compositions comprising
`
`25 (cid:9)
`
`biologically active oxazolidinones. For example, the oxazolidinones may have antibiotic
`
`activity.
`In one embodiment, the biologically active oxazolidinones are of the structure lb.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`
`lb, wherein R, of the oxazolidinone is C(0)NR,R8.
`
`30 (cid:9)
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`
`lb, wherein R, of the oxazolidinone is 2 oxazolyl containing R14 at the 4-position and R15
`7
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`at the 5-position of the oxazole.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein RI of the oxazolidinone is 2-aminothiazolyl containing R16 at the 4-position
`
`and RI, at the 5-position of the aminothiazole.
`
`5 (cid:9)
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein RI of the oxazolidinone is C(0)NR,R8, and wherein R3, R4 and R5 are
`
`hydrogen.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein R, of the oxazolidinone is 2 oxazolyl containing R14 at the 4-position and R15
`
`10 (cid:9)
`
`at the 5-position of the oxazole, and wherein R3, R4 and R5 are hydrogen.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein R, of the oxazolidinone is 2-aminothiazolyl containing R16 at the 4-position
`and R17 at the 5-position of the aminothiazole, and wherein R3, R4 and R5 are hydrogen.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein RI of the oxazolidinone is C(0)NR,R8, and wherein R3, R4 and R5 are
`
`15 (cid:9)
`
`hydrogen, and further wherein R2 is fluorine.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein RI of the oxazolidinone is 2 oxazolyl containing R14 at the 4-position and R15
`
`at the 5-position of the oxazole, and wherein R3, R4 and R5 are hydrogen, and further
`
`20 (cid:9)
`
`wherein R2 is fluorine.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein RI of the oxazolidinone is 2-aminothiazolyl containing R16 at the 4-position
`and RI, at the 5-position of the aminothiazole, and wherein R3, R4 and R5 are hydrogen, and
`
`further wherein R2 is fluorine.
`
`25 (cid:9)
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`30 (cid:9)
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein RI of the oxazolidinone is C(0)NR,R8, wherein R, is hydrogen and R8 is 5-
`
`chloropyridine-3-yl, thiazole-2-yl, 5'-(5-aminopyridine-2-yl)thiopyridine-3'-yl, or
`
`pyridine-3-y'; and wherein R3, R4 and R5 are hydrogen; and further wherein R2 is fluorine;
`
`and further wherein R6 is C(0)CH3.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb, wherein R1 of the oxazolidinone is C(0)NR,R8, wherein R, is hydrogen and R8 is 5-
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`chloropyridine-3-yl; and wherein R3, R4 and R5 are hydrogen; and further wherein R2 is
`
`fluorine; and further wherein R6 is C(0)CH2SMe.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`
`lb wherein R, of the oxazolidinone is C(0)NR,R8. wherein R, is hydrogen and R8 is 5-
`
`5 (cid:9)
`
`chloropyridine-3-yl; and wherein R3, R4 and R5 are hydrogen; and further wherein R2 is
`
`fluorine; and further wherein R6 is C(0)CHCH(pyridine-3-yl).
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`
`lb wherein R, of the oxazolidione is 5-amino-4-cyanooxazole-2-yl; and wherein R2 is
`
`fluorine; and further wherein R3, R4 and R5 are hydrogen; and still further wherein R6 is
`
`10 (cid:9)
`
`C(0)CH3.
`
`In another embodiment, the biologically active oxazolidinones are of the structure
`lb wherein R, of the oxazolidione is 4-phenylthiazole-2-yl-amino; and wherein R, is
`
`fluorine; and further wherein R3, R4 and R5 are hydrogen; and still further wherein R6 is
`
`C(0)CH3.
`
`15 (cid:9)
`
`A variety of methods of synthesizing biologically active oxazolidinones are
`
`provided.
`
`In one embodiment, methods are provided for the preparation of oxazolidinones,
`
`such as those of the structure lb, and comprise the steps of: providing an
`
`iminophosphorane; mixing the iminophosphorane with a resin that comprises carbonyl
`
`20 (cid:9)
`
`groups to form an imine intermediate; and, reducing the imine intermediate to afford a
`
`compound attached to the resin through an amine linkage. In another embodiment, the
`
`iminophosphorane is provided from an azide that is reacted with a phosphine. In another
`
`embodiment, the iminophosphorane is provided from an amine that is reacted with a
`
`(trisubstituted)phosphine dihalide.
`
`25 (cid:9)
`
`In another embodiment, the resin comprising carbonyl groups is of the structure
`
`R2
`
`, R25
`0
`
`
`
`is
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`wherein R23 is hydrogen, alkyl, aryl, 0-alkyl or 0-aryl; R24 is hydrogen, CH3O or NO2; R25
`is (CH2).CONH, wherein n is an integer ranging between 1 and about 5; and, the filled
`
`circle is a polymeric support.
`
`In another embodiment of structure lc, R23 is hydrogen, R24 is CH3O, R25 is
`
`5 (cid:9)
`
`(CH2)3CONH and the filled circle is Tentagel, (cross-linked)polystyrene, (cross-
`
`linked)polyethylene glycol or polyethyleneglycol-polystyrene compositions.
`
`Methods also are provided of synthesizing biologically active oxazolidinone
`
`compositions from a corresponding amine. In one embodiment, the method is for the
`
`preparation of oxazolidinones, for example, of the structure lb, and comprises the steps of:
`
`10 (cid:9)
`
`reacting an amine with a resin that comprises carbonyl groups to form an imine
`
`intermediate; and, reducing the imine intermediate to afford a compound attached to the
`
`resin through an amine linkage.
`
`15 (cid:9)
`
`Figure 1 is shows the structure of an oxazolidinone lb.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 2 is a scheme showing the synthesis of a combinatorial library comprising
`
`oxazolidinones of structure lb, wherein R, is C(0)R7R8.
`
`Figure 3 is a scheme showing the synthesis of a set of azido oxazolidinones.
`
`Figure 4 is a scheme showing the synthesis of a combinatorial library comprising
`
`20 (cid:9)
`
`oxazolidinones of structure lb, wherein R, is C(0)R7R8, and wherein R1, R4 and R5 are
`
`hydrogen; and wherein in Figure 4, the N-Ac group of 17, 18 and 19 also may be NCOR1 ,
`
`wherein R1 is a substituent, such as H, alkyl, heteroalkyl, aryl, or heteroaryl.
`
`Figure 5 is a scheme showing the synthesis of combinatorial libraries comprising
`
`oxazolidinones of structure lb, wherein R, is C(0)0R, or C(0)R10.
`
`25 (cid:9)
`
`Figure 6 is a scheme showing the synthesis of combinatorial libraries comprising
`
`oxazolidinones of structure ib, wherein R, is SR11.
`
`Figure 7 is a scheme showing the synthesis of combinatorial libraries comprising
`
`oxazolidinones of structure lb, wherein R, is S(0)R11 or S(0)2R11.
`
`Figure 8 is a scheme showing the synthesis of a set of thio substituted azido
`
`30 (cid:9)
`
`oxazolidinones.
`
`Figure 9 is a scheme showing the synthesis of a combinatorial library comprising
`10
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`oxazolidinones of structure lb, wherein R, is NRI2R13.
`
`Figure 10 is a scheme showing the synthesis of a combinatorial library comprising
`
`oxazolidinones of structure lb, wherein R, is an oxazole.
`
`Figure 11 is a scheme showing the synthesis of combinatorial libraries comprising
`
`5 (cid:9)
`
`oxazolidinones of structure lb, wherein R, is an oxazole.
`
`Figure 12 is a scheme showing the synthesis of combinatorial libraries comprising
`
`oxazolidinones of structure lb, wherein R, is an aminothiazole.
`
`Figure 13 is a scheme showing the synthesis of combinatorial libraries comprising
`
`oxazolidinones of structure lb, wherein R, is CH2NRI8R19.
`
`10 (cid:9)
`
`Figure 14 is a scheme showing the synthesis of a set of acetal containing azido
`
`oxazolidinones.
`
`Figure 15 is a scheme showing a general synthetic method for the preparation of
`
`oxazolidinones.
`
`Figure 16 is a scheme showing a general synthetic method for the preparation of
`
`15 (cid:9)
`
`azido oxazolidinones.
`
`20 (cid:9)
`
`25 (cid:9)
`
`Figure 17 is a graphical depiction of a linking portion connecting an oxazolidinone
`
`to a solid support.
`Figure 18 is a scheme showing the synthesis of an oxazolidinone of structure lb,
`
`wherein RI is NR12R13.
`Figure 19 is a scheme showing the synthesis of an oxazolidinone of structure lb
`
`wherein R, is an aminothiazole.
`Figure 20 is a scheme showing the synthesis of an oxazolidinone of structure lb,
`
`wherein RI is an oxazole.
`Figure 21 is a scheme showing the synthesis of oxazolidinones of structure lb
`
`wherein R1 is C(0)RI0.
`Figure 22 is a scheme showing the synthesis of oxazolidinones of structure lb,
`
`wherein RI is NR12R13.
`
`Figure 23 is a scheme showing a general synthetic method for the preparation of
`
`oxazolidinones.
`
`30 (cid:9)
`
`Figure 24 is a scheme showing a method of preparation of N-[(3-pheny1-2-oxo-5-
`
`oxazolidinypmethyl]acetamide.
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`Figure 25 is a scheme showing a method of preparation of N4[3-(3-fluoro-4-
`
`morpholinylpheny1)-2-oxo-5-oxazolidinyl]methyliacetamide.
`
`Figure 26 is a scheme showing a method of preparation for solid support bound
`
`(S)-N-R3-(3-fluoro-4-morpholinylpheny1)-2-oxo-5-oxazolidinyll-methyl]acetamide.
`
`5 (cid:9)
`
`Figure 27 is a scheme showing a method of preparation for sulfonyl, amidyl and
`
`ureayl derivatives of (S)-N-R3-(3-fluoro-4-morpholinylpheny1)-2-oxo-5-oxazolidinyli-
`
`methyl]acetamide.
`
`Figure 28 is a scheme showing the preparation of a-thio acetamide, a, 13-
`
`unsaturated acetamide and a-amino acetamide derivatives of (S)-N-[[3-(3-fluoro-4-
`
`10 (cid:9)
`
`morpholinyl-phenyl)-2-oxo-5-oxazolidiny1]-methyllacetamide.
`
`Figure 29 shows a nonlimiting group of amines that are used in the preparation of
`
`sulfonyl, amidyl and ureayl oxazolidinone combinatorial libraries.
`
`Figure 30 shows another nonlimiting group of amines that are used in the
`
`preparation of sulfonyl, amidyl and ureayl oxazolidinone combinatorial libraries.
`
`15 (cid:9)
`
`Figure 31 shows another nonlimiting group of amines that are used in the
`
`preparation of sulfonyl, amidyl and ureayl oxazolidinone combinatorial libraries.
`
`Figure 32 shows a nonlimiting group of amines that are attached to a solid support
`
`in a manner analogous to amine 32a in Figure 26 and then used to construct sulfonamide,
`
`amide and urea oxazolidinone libraries in an manner analogous to solid support bound
`
`20 (cid:9)
`
`amine 33a in Figure 27.
`
`Figure 33 is a group of amines for use in the preparation of oxazolidonones that
`
`was for example used to prepare combinatorial libraries comprising oxazolidinones of
`
`structure lb, wherein R1 is derived from the shown amine, R2 is fluorine, R3 is hydrogen,
`
`R4 is hydrogen, R5 is hydrogen and R6 is C(0)CH3.
`
`25 (cid:9)
`
`Figure 34 is a group of amines for use in the preparation of oxazolidinones that was
`
`for example used to prepare combinatorial libraries comprising oxazolidinones of structure
`lb, wherein R1 is derived from the shown amine, R2 is fluorine, R3 is hydrogen, R4 is
`
`hydrogen, R5 is hydrogen and R6 is C(0)CH3.
`
`Figure 35 is a group of amines for use in the preparation of oxazolidinones that was
`
`30 (cid:9)
`
`for example used to prepare combinatorial libraries comprising oxazolidinones of structure
`
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`lb, wherein R, is derived from the shown amine, R2 is fluorine, R3 is hydrogen, R4 is
`
`hydrogen, R5 is hydrogen and R6 is C(0)CH3.
`
`Figure 36 is a group of amines for use in the preparation of oxazolidinones that was
`
`5
`
`used for example to prepare combinatorial libraries comprising oxazolidinones of structure
`ib, wherein R, is derived from the shown amine, R2 is fluorine, R3 is hydrogen, R4 is
`hydrogen, R5 is hydrogen and R6 is C(0)CHCHC6H4CH(p-NOCH3) or C(0)CHCHC6H4(p-
`
`OCH3).
`
`Figure 37 is a group of amines for use in the preparation of oxazolidinones that was
`
`used for example to prepare combinatorial libraries comprising oxazolidinones of structure
`
`10 (cid:9)
`
`lb, wherein R, is derived from the shown amine, R2 is fluorine, R3 is hydrogen, R4 is
`
`hydrogen, R5 is hydrogen and R6 is C(0)CH2SCH3 or C(0)CHCH(3-C5H4N).
`
`Figure 38 shows a group of biologically active oxazolidinone compounds, with an
`
`MIC range of about 1.25-20 µg/ml against E. faecium.
`
`Figure 39 is a scheme showing the synthesis of acylamino oxazolidinone
`
`15 (cid:9)
`
`compounds and libraries, wherein R, and R2 are substituents, for example, H, alkyl,
`
`heteroalkyl, aryl, heteroaryl, or alkoxy.
`
`Figure 40 is a scheme showing the synthesis of sulfonamide oxazolidinone
`
`compounds and libraries, wherein R, is a substituent, for example, H, alkyl, heteroalkyl,
`
`aryl, heteroaryl, or alkoxy.
`
`20 (cid:9)
`
`Figure 41 is a scheme showing the synthesis of sulfide oxazolidinone compounds
`
`and libraries, wherein R, is a substituent, for example, H, alkyl, heteroalkyl, aryl,
`
`heteroaryl, or alkoxy.
`
`Figures 42 and 43 illustrate building blocks R2COOH that may be used for
`
`synthesis of acylamino oxazolidinone libraries and compounds as shown in Figure 39, and
`
`25 (cid:9)
`
`also may be used in other syntheses such as those shown in Figure 9.
`
`Figures 44 and 45 illustrate building blocks R2X, where X is halo, which may be
`
`used in the synthesis of sulfide oxazolidinone libraries and compounds as shown in Figure
`
`41 and also can be used as RI,X in the synthesis shown in Figure 6.
`
`Figure 46 illustrates sulfonyl chloride building blocks R2S02C1 that may be used in
`
`30 (cid:9)
`
`the synthesis of sulfonamide oxazolidinone libraries and compounds as shown in Figure
`
`40, and also may be used in the syntheses shown in Figure 18.
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`Figure 47 illustrates amine building blocks R7R8NH that may be used in the
`
`synthesis of oxazolidinone libraries and compounds as shown in Figure 4.
`
`Figure 48 shows building blocks R2R3NH and R,COOH that may be used to make
`
`compounds of formula lk and libraries thereof
`
`5
`
`Figure 49 is a general scheme showing routes of synthesis of 3-
`
`(heteroaryl)oxazolidinones.
`
`Figure 50 is another general scheme showing routes of synthesis