Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereo

The present invention relates to compounds of formula I:

• its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof wherein:
• R1 and R2 independently represent
• i) hydrogen,
• ii) (CH2)nNR5R6,
• iii) CR7R8R9, C(R)2OR14, 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, (C═NH)R7, N(R13)C(═X1)N(R3)2, COOR13, SO2R14, N(R13)SO2R14, N(R13)COR14,
• v) (C1-6alkyl)CN, CN, CH═C(R)2, (CH2)pOH, C(═O)CHR13, C(═NR13)R13, 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;
• R1a represents (CH2)nNR5R6, CR7R8R9, C(R)2OR14, CH2NHR14, 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, (C═NH)R7, N(R13)C(═X1)N(R13)2, COOR13,SO2R14, N(R13)SO2R14, N(R13)COR14, (C1-6alkyl)CN, CN, CH═C(R)2, (CH2)pOH, C(═O) CHR13, C(═NR13)R13, NR10C(═X1)R13;
• or C5-10 heterocycle optionally substituted with 1-3 groups of R7, which may be attached through either a carbon or a heteroatom;
• X is selected from the group consisting of,
• Z represents (O)n, H, OH, or halogen;
• A represents C (when --- is present provided Z=(O)n and n=0), C (when --- is not present provided Z is H, OH or halogen), or N (when --- is not present and Z=(O)n and n=1);
• --- represents a bond;
• represents aryl or heteroaryl, provided that in the case of a heteroaryl, a cyclopropyl is not attached to a nitrogen atom on the ring;
• Rx represents hydrogen or C1-6 alkyl;
• R3 represent
• i) NR13(C═X2)R12,
• ii) NR13(C═X1)R12,
• iii) NR13SO2R14,
• iv) N(R13)heteroaryl,
• v) NR13(CHR13)0-4aryl,
• vi) NR13(CHR13)0-4heteroaryl,
• vii) S(CHR13)0-4aryl,
• viii) S(CHR13)0-4heteroaryl,
• ix) O(CHR13)0-4aryl,
• x) O(CHR13)0-4heteroaryl,
• xi) NOH(C═X1)R12,
• xii) —OC═N(OCOaryl)C1-6 alkyl
• xiii) —OC═N(OH)C1-6 alkyl
• xiv) C5-10 heteroaryl which may be attached through either a carbon or a heteroatom;
• said aryl and heteroaryl 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 halo, 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) five to six 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, 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 represent
• i) hydrogen, halogen, 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
• ii) (CH2)namino, (CH2)nC1-6 alkylamino, 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 represents
• i) H, CN,
• ii) C1-6 alkyl optionally substituted with 1-3 halogen, CN, OH, C1-6 alkoxy, C1-6 acyloxy, or amino,
• iii) phenyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy;
• or
• R7 and R8 taken together can form a 3-7 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, CR2Cl, (CH2)nSR, (CH2)nCN, (CH2)nSO2R, (CH2)nS(O)R, C1-6 alkylamino, C5-10 heteroaryl or C1-6 dialkylamino, where said alkyl may be substituted with 1-3 groups of halo, CN, OH or C1-6 alkoxy, said heteroaryl 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)2R8, CN, OH, C1-6 alkylS(O)R, C1-6 alkoxycarbonyl, hydroxycarbonyl, —OCOaryl, C1-6 acyl, 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 3-7 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;
• R14 represents amino, C1-6 alkyl, C1-6 haloalkyl, five to six membered heterocycles or phenyl, said phenyl and heterocycles optionally substituted with 1-3 group of halo, C1-6 alkoxy, C1-6 acylamino, or C1-6 alkyl, hydroxy and/or amino, said amino and hydroxy optionally protected with an amino or hydroxy protecting group;
• R15 is 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 is hydrogen, C5-10heteroaryl, C6-10aryl, said heteroaryl and aryl optionally substituted with 1-3 groups of R7;
• p represents 0-2 and
• n represents 0-1.