Macrocyclic broad spectrum antibiotics

A compound of Formula (I):

• wherein:
• E1 is (C1-C6)alkyl, (C2-C7)alkenyl, (C2-C7)alkynyl, (C3-C7)cycloalkyl, heterocyclyl, heteroaryl, or aryl;
• E2 is (C2-C7)alkenyl, (C2-C7)alkynyl, (C3-C7)cycloalkyl, heterocyclyl, heteroaryl, or aryl;
• L1 is a bond, —O—, —S—, —NR4—, —C(O)—, —CH2O—, —OCH2—, —CH2S—, —SCH2—, —CH2NR4—, —NR4CH2—, —NR4C(O)—, —C(O)NR4—, —NR4S(O)2—, —S(O)2NR4—, —NR4C(O)NR4—, —NR4C(O)O—, —OC(O)NR4—, or (C1-C4)alkylene optionally substituted with OH, CN, NO2, halogen, or (C1-C6)alkyl;
• L2 is a bond;
• X is a group of formula
• wherein n4, n5, and n6 are each independently 1, 2 or 3;
• n7 is 0, 1 or 2;
• R21b and R22b are independently at each occurrence hydrogen, hydroxy, (C1-C6)alkyl, (C3-C7)cycloalkyl, 5- to 7-membered heteroaryl, 5- to 7- membered heterocyclyl, or (C6-C10) aryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 3 J;
• R25 is H, OH,
• ORC,
• or NR25aR25b where R25a and R25b are each independently H, SO2(C1-C6)alkyl, or alkyl;
• RB1 and RB2 are each independently H, (C1-C6) alkyl, (C3-C6) cycloalkyl, ORC, C(═O)N(RC)2, OC(═O)N(RC)2, C(═O)ORC, OC(═O)ORC, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkoxy, (C1-C6)thioalkoxy, N(RC)2, 5-7 membered heterocyclyl or 5-7 membered heteroaryl, or (C6-C10) aryl;
• RC is independently at each occurrence H or (C1-C6) alkyl, and a wavy line indicates a point of attachment of X to a carbon of formula (I) bearing X;
• or
• X is CO2H, CH2CO2H, C(═O)NHCH2C(═O)H, CH2C(═O)H,
• C(═O)N(H)CH(R7)B(ORB3)(ORB4), or
• wherein R7 is H, methyl, ethyl, or —CH2OH;
• or R7 and RB3 together with the boron atom form a 5- or 6-membered boron containing ring;
• RB3 and RB4 are each independently H, (C1-C6)alkyl, —CH2CO2H, or —CH2CH2CO2H;
• or RB3 and RB4 together with the boron atom form an optionally substituted 5- or 6-membered boron containing ring;
• R5 is aryl, heteroaryl, or a linear or branched alkyl chain of about 1-22 carbon atoms, wherein R5 is bonded to the carbonyl carbon to which it is attached directly or by an NR4, to provide an amide or urea linkage, respectively;
• optionally comprising within the chain or at a
• chain terminus
• wherein Z is a bond, O, S, NH, CH2 or C≡C;
• R2 and R3 are each independently nitro, halo, cyano, hydroxy, glycosyloxy, amino, (C1-C4)alkoxy, (C1-C4)acyloxy, (C1-C4)alkyl, or a group cleavable under physiological conditions to provide a compound of formula (I) wherein R2 or R3 respectively is hydroxy, wherein any carbon atom is optionally substituted with J;
• n1 is 1;
• n2 is 0;
• n3 and n8 are independently 0, 1 , or 2;
• each m is independently 0 or 1;
• R1 is hydrogen or (C1-C6)alkyl optionally substituted with 1 to 3 J;
• or R1 together with E1 form a ring;
• R4, R4′, and R4″are each independently at each occurrence hydrogen, or (C1-C6)alkyl optionally substituted with 1 to 3 J;
• R6 is hydrogen, or (C1-C6)alkyl optionally substituted with 1 to 3 J;
• or R6 together with RA4 form a ring;
• RA1, RA1′,RA2, RA3, RA3′, RA4, RA4′, RA7, RA7′, RA8, RA8′, RA9, RA9′, RA10, and RA10′ are independently at each occurrence hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, 5- to 7- membered heteroaryl, 5- to 7- membered heterocyclyl, or (C6-C10) aryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 3 J;
• RA6 is amino, (C1-C6)alkyl, (C3-C7)cycloalkyl, 5- to 7- membered heteroaryl, 5- to 7- membered heterocyclyl, or (C6-C10) aryl, wherein any alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 3 J;
• J is halogen, R′, OR′, CN, CF3, OCF3, (CH2)0-pN(R′)2, (CH2)0-pSR′, (CH2)0-pS(O)2R′, (CH2)0-pS(O)2N(R′)2, (CH2)0-pSO3R′, (CH2)0-pC(O)R′(CH2)0-pC(O)OR′(CH2)0-pC(O)N(R′)2, (CH2)0-pOC(O)N(R′)2, (CH2)0-pNH—C (O)R′(CH2)0-pN(R′)SO2R′(CH2)0-pN(R′)C(O)OR′(CH2)0-pN(R′)C(O)R′, (CH2)0-pN(R′)C(O)N(R′)2, or (CH2)0-pC(═NH)N(R′)2, wherein p is 4;
• each R′ is independently at each occurrence hydrogen, (C1-C6)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, aryl, or heteroaryl wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl is optionally substituted with a substituent selected from F, Cl, Br, I, —CN, —NO2, —OH, —CF3, —OCF3, —OCH3, —NH2,—N((C1-C4)alkyl)2, —NH(C1-C4)alkyl, C1-C6alkyl, C3-C8cycloalkyl, or C1-C6heteroalkyl;
• or a pharmaceutically acceptable salt, solvate, or prodrug thereof.