Ether linked macrolides useful for the treatment of microbial infections

A compound of formula (I)

• wherein
• A is a bivalent radical selected from the group consisting of —C(O)—, —C(O)NH—, —NHC(O)—, —N(R7)—CH2—, —CH2—N(R7)—, —CH(NR8R9)— and —C(═NR10)—;
• R1 is —O(CH2)dXR11;
• R2 is hydrogen or a hydroxyl protecting group;
• R3 is hydrogen, C1-4alkyl, or C3-6alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl;
• R4 is hydroxyl, C2-6alkenyloxy optionally substituted by 9 to 10 membered fused bicyclic heteroaryl, or C1-6alkoxy optionally substituted by C1-6alkoxy or —O(CH2)eNR7R12,
• R5 is hydroxyl, or
• R4 and R5 taken together with the intervening atoms form a cyclic group having the following structure:
• wherein Y is a bivalent radical selected from —CH2—, —CH(CN)—, —O—, —N(R13)— and —CH(SR13)—;
• R6 is hydrogen or fluorine;
• R7 is hydrogen or C1-6alkyl;
• R8 and R9 are each independently hydrogen, C1-6alkyl, —C(═NR10)NR14R15 or —C(O)R14, or R8 and R9 together form ═CH(CR14R15)faryl, ═CH(CR14R15)fheterocyclyl, ═CR14R15 or ═C(R14)C(O)OR14, wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R16;
• R10 is —OR17, C1-6alkyl, —(CH2)garyl, —(CH2)gheterocyclyl or —(CH2)hO(CH2)iOR7, wherein each R10 group is optionally substituted by up to three groups independently selected from the group consisting of R16;
• R11 is a heterocyclic group having the following structure:
• R12 is hydrogen or C1-6alkyl;
• R13 is hydrogen or C1-4alkyl substituted by a group selected from the group consisting of optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl and optionally substituted 9 to 10 membered fused bicyclic heteroaryl;
• R14 and R15 are each independently hydrogen or C1-6alkyl;
• R16 is halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R21, —C(O)OR21, —OC(O)R21, —OC(O)OR21, —NR22C(O)R23, —C(O)NR22R23, —NR22R23, hydroxyl, C1-6alkyl, —S(O)kC1-6alkyl, C1-6alkoxy, —(CH2)maryl or —(CH2)mheteroaryl, wherein the alkoxy group is optionally substituted by up to three groups independently selected from the group consisting of —NR14R15, halogen and —OR14, and the aryl and heteroaryl groups are optionally substituted by up to five groups independently selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, azido, —C(O)R24, —C(O)OR24, —OC(O)OR24, —NR25 C(O)R26, —C(O)NR25R26, —NR25R26, hydroxyl, C1-6alkyl and C1-6alkoxy;
• R17 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl or a 5 or 6 membered heterocyclic group, wherein the alkyl, cycloalkyl, alkenyl and heterocyclic groups are optionally substituted by up to three substituents independently selected from the group consisting of optionally substituted 5 or 6 membered heterocyclic group, optionally substituted 5 or 6 membered heteroaryl, —OR27, —S(O)nR27, —NR27R28, —CONR27R28, halogen and cyano;
• R18 is hydrogen, —C(O)OR29, —C(O)NHR29, —C(O)CH2NO2, or —C(O)CH2SO2R7;
• R19 is hydrogen;
• C1-4alkyl optionally substituted by hydroxyl, cyano, C1-4alkoxy, NH2, —NH(C1-4alkyl) or —N(C1-4alkyl)2;
• C2-4alkenyl optionally substituted by hydroxyl, cyano, C1-4alkoxy, NH2, —NH(C1-4alkyl) or —N(C1-4alkyl)2;
• C1-4alkoxy;
• C3-7cycloalkyl;
• —NH2;
• —NH(C1-4alkyl);
• —N(C1-4alkyl)2;
• (C1-4alkyl)OC(O)N(C1-4alkyl);
• or optionally substituted phenyl or benzyl;
• R20 is halogen, C1-4alkyl, C1-4thioalkyl, C1-4alkoxy, —NH2, —NH(C1-4alkyl) or —N(C1-4alkyl)2;
• R21 is hydrogen, C1-10alkyl, —(CH2)paryl or —(CH2)pheteroaryl;
• R22 and R23 are each independently hydrogen, —OR14, C1-6alkyl, —(CH2)qaryl or —(CH2)qheterocyclyl;
• R24 is hydrogen, C1-10alkyl, —(CH2)raryl or —(CH2)rheteroaryl;
• R25 and R26 are each independently hydrogen, —OR14, C1-6alkyl, —(CH2)saryl or —(CH2)sheterocyclyl;
• R27 and R28 are each independently hydrogen, C1-4alkyl or C1-4alkoxyC1-4alkyl;
• R29 is hydrogen or C1-6alkyl optionally substituted by up to three groups independently selected from the group consisting of halogen, C1-4alkoxy, —OC(O)C1-6alkyl and —OC(O)OC1-6alkyl, or —(CH2)qheterocyclyl, —(CH2)qheteroaryl, —(CH2)qaryl, —(CH2)qC3-7cycloalkyl;
• R30 is hydrogen, C1-4alkyl, C3-7cycloalkyl, optionally substituted phenyl or benzyl, acetyl or benzoyl;
• R31 is hydrogen or R20, or R31 and R19 are linked to form the bivalent radical selected from the group consisting of —O(CH2)2—,
• —(CH2)t—, —NR7(CH2)a—, —OCH2NR7—, —SCH2NR7—, —CH2NR7CH2—, —CH2OCH2—, —CH2SCH2, and —(CH2)aNR7—;
• R32 is hydrogen, or R32 and R19 are linked to form the bivalent radical selected from the group consisting of —S(CH2)b—, —N(R7)(CH2)b—, and —O(CH2)b—;
• R33 is C1-8alkyl, C2-6alkenyl or C2-6alkynyl;
• X is —U(CH2)vB(CH2)vD-, —U(CH2)vB—R33—, —U(CH2)vB(CH2)vD(CH2)vE-, or —U(CH2)vB(CH2)vD-R33—
• or X is a group selected from the group consisting of:
• U, B, D and E are independently divalent radicals selected from —N(R30)—, —O—, —S(O)z—, —N(R30)C(O)—, —C(O)N(R30)— and —N[C(O)R30]—;
• W is —C(R31)— or —N—;
• a is 1 or 2
• b is an integer from 1 to 3;
• d is an integer from 2 to 6;
• e is an integer from 2 to 4;
• f, g, h, m, p, q, r and s are each independently integers from 0 to 4;
• i is an integer from 1 to 6;
• j, k, n and z are each independently integers from 0 to 2;
• t is 2 or 3;
• v is an integer independently selected for each occurrence from 1 to 8;
• or a pharmaceutically acceptable salt thereof.