Macrolide antibiotics

A compound of the formula

• or the pharmaceutically acceptable salt thereof;
• wherein the dashed line between positions 10 and 11 represents an optional double bond;
• a is 0 or 1;
• R1 is hydrogen or (C1–C10)alkyl optionally substituted by fluoro, cyano, R7, R7O2C, R7C(O)NH or R7S(O)n wherein n is 0, 1 or 2 and R7 is (C1–C6)alkyl, (C2–C12)alkenyl, (C2–C12)alkynyl, (C3–C10)cycloalkyl(C1–C6)alkyl, (C2–C9)heterocycloalkyl(C1–C6)alkyl, (C6–C10)aryl(C1–C6)alkyl or (C2–C9)heteroaryl(C1–C6)alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three of halo, (C1–C3)alkoxy, hydroxy, nitro, cyano, (C6–C10)aryl, (C2–C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) or R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1–C6)alkyl optionally substituted by (C6–C10)aryl or (C2–C9)heteroaryl;
• R2 is hydrogen or a hydroxy protecting group;
• R3 is amino, cyano, N3, R10NH, R10C(O)NH, R10NHC(O)NH, R10NHC(S)NH, R10NHNHC(O)NH, R10ONHC(O)NH, R10O, R10OC(O)NH, R10S(O)n, R10phosphoramido, R10sulfonamido, SH, or R10S wherein n is defined above and R10 is (C1–C6)alkyl, (C2–C12)alkenyl, (C2–C12)alkynyl, (C3–C10)cycloalkyl(C1–C6)alkyl, (C2–C9)heterocycloalkyl(C1–C6)alkyl, (C6–C10)aryl, (C6–C10)aryl(C1–C6)alkyl or (C2–C9)heteroaryl(C1–C6)alkyl;
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1–C3)alkoxy, hydroxy, nitro, cyano, (C6–C10)aryl, (C2–C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) or R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1–C6)alkyl optionally substituted by (C6–C10)aryl or (C2–C9)heteroaryl;
• or R3 is R12R13N wherein R12 and R13 are each independently hydrogen, (C1–C6)alkyl, (C6–C10)aryl(C1–C6)alkyl or (C2–C9)heteroaryl (C1–C6)alkyl;
• R4 is hydrogen, or is methyl optionally substituted by one to of two nitro, cyano, R14C(O) or R14OC(O);
• or R4 is N3, R14O, R14NH, R14S wherein R14 is (C1–C6)alkyl, (C2–C12)alkenyl, (C2–C12)alkynyl, (C3–C10)cycloalkyl(C1–C6)alkyl, (C2–C9)heterocycloalkyl(C1–C6)alkyl, (C6–C10)aryl, (C6–C10)aryl(C1–C6)alkyl or (C2–C9)heteroaryl(C1–C6)alkyl;
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1–C3)alkoxy, hydroxy, nitro, cyano, (C6–C10)aryl, (C2–C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) or R8OC(O)2, wherein R8 and R9 are each independently hydrogen, (C1–C6)alkyl optionally substituted by (C6–C10)aryl or (C2–C9)heteroaryl;
• or R4 is R15N(C1–C6)alkyl wherein R15 is hydrogen, (C1–C6)alkyl, (C6–C10)aryl(C1–C6)alkyl or (C2–C9)heteroaryl(C1–C6)alkyl;
• X is oxygen or NOR16 wherein R16 is (C1–C6)alkyl, (C2–C12)alkenyl, (C2–C12)alkynyl, (C3–C10)cycloalkyl(C1–C6)alkyl, (C2–C9)heterocycloalkyl(C1–C6)alkyl, (C6–C10)aryl(C1–C6)alkyl or (C2–C9)heteroaryl(C1–C6)alkyl;
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1–C3)alkoxy, hydroxy, nitro, cyano, (C6–C10)aryl, (C2–C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) or R8OC(O)2, wherein R8 and R9 are each independently hydrogen or (C1–C6)alkyl optionally substituted by (C6–C10)aryl or (C2–C9)heteroaryl;
• R5 is hydrogen or methyl;
• or R3 and R4 may be taken together with the carbons to which they are attached to form a ring such that the compound is represented by the formula II
• wherein the dashed line, between the nitrogen and the variable W of formula II, represents an optional double bond;
• W is C═O, C═S, SO2 or C═NR10 wherein R10 is as defined above;
• Y is oxygen, sulfur or NR17 wherein R17 is hydrogen, R19, R19O or R19NH wherein R19 is hydrogen, (C1–C6)alkyl, (C2–C12)alkenyl, (C2–C12)alkynyl, (C3–C10)cycloalkyl(C1–C6)alkyl, (C2–C9)heterocycloalkyl(C1–C6)alkyl, (C6–C10)aryl, (C6–C10)aryl(C1–C6)alkyl or (C2–C9)heteroaryl(C1–C6)alkyl;
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1–C3)alkoxy, hydroxy, nitro, cyano, (C6–C10)aryl, (C2–C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) or R8OC(O)2 wherein R8 and R9 are each independently hydrogen, or (C1–C6)alkyl optionally substituted by (C5–C10)aryl or (C2–C9)heteroaryl;
• R18 is hydrogen, (C1–C6)alkyl, (C6–C10)aryl, (C6–C10)aryl(C1–C6)alkyl or (C2–C9)heteroaryl(C1–C6)alkyl;
• wherein the aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1–C3)alkoxy, hydroxy, nitro, cyano, (C6–C10)aryl, (C2–C9)heteroaryl, R20R21N, R20C(O), R20C(O)O, R20OC(O), R20C(O)NH, R20NHC(O), R20R21NC(O), and R20OCO2 wherein R20 and R21 are each independently hydrogen, or (C1–C6)alkyl optionally substituted by (C6–C10)acyl or (C5–C10)aryl or (C2–C9)heteroaryl;
• R6 is hydrogen, (C1–C6)alkyl, (C2–C6)alkenyl, (C2–C6)alkynyl, (C1–C6)alkoxy(C1–C6)alkyl or (C1–C6)alkylthio(C1–C6)alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo;
• or R6 is (C3–C10)cycloalkyl or (C5–C10)cycloalkenyl optionally substituted by (C1–C6)alkyl or halo;
• or R6 is (C2–C8)heterocycloalkyl or (C2–C9)heteroaryl optionally substituted by (C1–C6)alkyl, (C2–C8)alkenyl, (C2–C8)alkynyl, (C3–C10)cycloalkyl, (C5–C10)cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C1–C6)alkoxy or halo;
• with the proviso that at least one of R17 or R18 is hydrogen;
• with the proviso that when the dashed line between positions 10 and 11 represents a double bond, R4 is hydrogen;
• and
• with the proviso that when a is zero, R1 is hydrogen.