Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof

A method of treating a bacterial infection in a mammalian patient in need thereof, comprising administering to said patient an effective amount of a compound of formula I wherein the compound of formula I is

• its enantiomer, diastereomer, pharmaceutically acceptable salt, hydrate or prodrug thereof wherein:
• R1 represents
• i) hydrogen,
• ii) (CH2)nNR5R6,
• iii) CR7R8R9, C(R)2OR14 or CH2NHR14,
• iv) C(═O)R13, C(═NOH)H, C(═NOR13)H, C(═NOR13)R13, C(═NOH)R13, C(═O)N(R13)2, C(═NOH)N(R13)2, NHC(═X1 )N(R13)2, NRCO2R, (C═NH)R7, N(R13)C(═X1)N(R13)2, COOR13, SO2R14, N(R13)SO2R14 or N(R13)COR14,
• v) (C1-6alkyl)CN, CN, CH═C(R)2, (CH2)pOH, C(═O)CHR13, C(═NR13)R13 or NR10C(═X1)R13, or
• vi) C5-10 heterocycle optionally substituted with 1-3 groups of R7, which may be attached through either a carbon or a heteroatom;
• X represents
• Y represents NR*, O, CN or S(O)p;
• represents aryl or heteroaryl, heterocycle, heterocyclyl or heterocyclic;
• R3 represents NR(C═X2)R12, NR*R12, C6-10 aryl or —(O)nC5-10 heterocyclyl which may be attached through either a carbon or a heteroatom;
• said aryl and heterocyclyl optionally substituted with 1-3 groups of R7;
• R4, R4a, R4b, and R4c independently represent
• i) hydrogen,
• ii) halogen,
• iii) C1-6 alkoxy, or
• iv) C1-6 alkyl;
• r and s independently are 1-3, with the provision that when (R4a)s and (R4)r or (R4b) and (R4c)s are attached to an Ar or HAr ring the sum of r and s is less than or equal to 4;
• R5 and R6 independently represent
• i) hydrogen,
• ii) C1-6 alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C1-6 alkoxy, amino, imino, hydroxyamino, alkoxyamino, C1-6 acyloxy, C1-6 alkylsulfenyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, C1-6 alkylaminosulfonyl, C1-6 dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethylenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF3, C1-6 alkyl or C1-6 alkoxy,
• iii) C1-6 acyl optionally substituted with 1-3 groups of halogen, OH, SH, C1-6 alkoxy, naphthalenoxy, phenoxy, amino, C1-6 acylamino, hydroxylamino, alkoxylamino, C1-6 acyloxy, aralkyloxy, phenyl, pyridine, C1-6 alkylcarbonyl, C1-6 alkylamino, C1-6 dialkylamino, C1-6 hydroxyacyloxy, C1-6 alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3 groups of halo, OH, CN, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl,
• iv) C1-6 alkylsulfonyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, amino, hydroxylamino, alkoxylamino, C1-6 acyloxy, or phenyl;
• said phenyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl,
• v) arylsulfonyl optionally substituted with 1-3 of halogen, C1-6 alkoxy, OH or C1-6 alkyl,
• vi) C1-6 alkoxycarbonyl optionally substituted with 1-3 of halogen, OH, C1-6 alkoxy, C1-6 acyloxy or phenyl, said phenyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl,
• vii) aminocarbonyl, C1-6 alkylaminocarbonyl or C1-6 dialkylaminocarbonyl, said alkyl groups optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy or phenyl,
• viii) 5- to 6-membered heterocycles optionally substituted with 1-3 groups of halogen, OH, CN, amino, C1-6 acylamino, C1-6 alkylsulfonylamino, C1-6 alkoxycarbonylamino, C1-6 alkoxy, C1-6 acyloxy or C1-6 alkyl, said alkyl optionally substituted with 1-3 groups of halogen or C1-6 alkoxy,
• ix) C3-6 cycloalkylcarbonyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy or CN,
• x) benzoyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, C1-6 alkyl, CF3, C1-6 alkanoyl, amino or C1-6 acylamino,
• xi) pyrrolylcarbonyl optionally substituted with 1-3 of C1-6 alkyl,
• xii) C1-2 acyloxyacetyl where the acyl is optionally substituted with amino, C1-6 alkylamino, C1-6 dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl or 4-(glycylamino)phenyl, or
• R5 and R6 taken together with any intervening atoms can form a 3- to 7-membered heterocyclic ring containing carbon atoms and 1-2 heteroatoms independently chosen from O, S, SO, SO2, N or NR8;
• R7 represents
• i) hydrogen, halogen, (CH2)pC5-10 heterocyclyl, CN, CO2R, CON(R)2, CHO, (CH2)0-3NHAc, C(═NOR), OH, C1-6 alkoxy, C1-6 alkyl, alkenyl, hydroxy C1-6 alkyl, (CH2)1-3NHC(O)C1-6 alkyl, (CH2)0-3N(C1-6 alkyl)2, NHCO2R or —OCOC1-6 alkyl, or
• ii) (CH2)namino, (CH2)nC1-6 alkylamino, C1-6 acylamino, C1-6 dialkylamino, hydroxylamino or C1-2 alkoxyamino, all of which can be optionally substituted on the nitrogen with C1-6 acyl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl, said acyl and alkylsulfonyl optionally substituted with 1-2 of halogen or OH;
• R8 and R9 independently represent
• i) H or CN,
• ii) C1-6 alkyl optionally substituted with 1-3 halogen, CN, OH, C1-6 alkoxy, C1-6 acyloxy or amino, or
• iii) phenyl optionally substituted with 1-3 groups of halogen, OH or C1-6 alkoxy, or R7 and R8 taken together can form a 3- to 7-membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, NH and NR8;
• X1 represents O, S or NR13, NCN, NCO2R16 or NSO2R14;
• X2 represents O, S, NH or NSO2R14;
• R10 represents hydrogen, C1-6 alkyl or CO2R15;
• R12 represents hydrogen, C1-6 alkyl, NH2, OR, CHF2, CHCl2, C(R)2Cl, (CH2)nSR, (CH2)nCN, (CH2)nSO2R, (CH2)nS(O)R, C1-6 alkylamino, C3-6 cycloalkyl, C5-10 heterocyclyl or C1-6 dialkylamino, where said alkyl, and cycloalkyl may be substituted with 1-3 groups of halo, CN, OH or C1-6 alkoxy, said heterocyclyl optionally substituted with 1-3 groups of R7;
• each R13 represents independently hydrogen, C1-6 alkyl, C6-10 aryl, NR5R6, SR8, S(O)R8, S(O)2 R8, CN, OH, C1-6 alkylS(O)R, C1-6 alkoxycarbonyl, hydroxycarbonyl, —OCOaryl, C1-6 acyl or C3-7-membered carbon ring optionally interrupted with 1-4 heteroatoms chosen from O, S, SO, SO2, NH and NR8, where said C1-6 alkyl, aryl or C1-6 acyl groups may be independently substituted with 0-3 halogens, hydroxy, N(R)2, CO2R, C6-10 aryl, C5-10 heteroaryl or C1-6 alkoxy groups;
• when two R13 groups are attached to the same atom or two adjacent atoms they may be taken together to form a 3- to 7-membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, NH and NR8;
• R represents hydrogen or C1-6 alkyl;
• R* represents hydrogen, CN, C(═O)R14, (CH2)pCO2C1-6 alkyl, (CH2)pC5-10heterocyclyl or C1-6 alkyl, said alkyl and heterocyclyl optionally substituted with 1 to 3 groups of R7;
• R14 represents amino, C1-6 alkyl, C3-6 cycloalkyl, (CH2)pC5-10heterocyclyl, C1-6 haloalkyl or phenyl, said alkyl, cycloalkyl, phenyl, heterocyclyl optionally substituted with 1-3 group of R7, when R7 is an amino or hydroxyl group or a nitrogen that forms part of the heterocycle, said amino and hydroxy optionally protected with an amino or hydroxy protecting group;
• R15 represents C1-6 alkyl or benzyl, said benzyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino or C1-6 alkyl;
• R16 represents hydrogen, C5-10heteroaryl or C6-10aryl, said heteroaryl and aryl optionally substituted with 1-3 groups of R7;
• p represents 0-2;
• and
• n represents 0-1,
• wherein the bacterial infection is selected from the group consisting of Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecium and Morcaxella catarrhalis.