13-Methyl erythromycin derivatives

A compound of formula 1

• 76
• or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
• A is H or halogen;
• X is selected from —C(O)—, —CH(NR8R9)—, —CHR8NR9—, —NR9CHR8—, —C(═NR8)— and —C(═N—OR8)—, wherein the first dash of each of the foregoing X groups is attached to the C-10 carbon of the compound of formula 1 and the last dash of each group is attached to the C-8 carbon of the compound of formula 1;
• Y is selected from CH2, C(O), CHF, CF2, C═C(RaRb), CHSR7, CHR7, C═S, —C(═NR8)—, —C(═N—OR8), CH(OR8), CH(OC(O)R8), CH(OC(O)Ar), CH(OC(O)NR8R9), CH(O(CRaRb)nAr), CH(OC(O)(CRaRb)nAr), CH(OC(O)(CRaRb)nNR8(CRaRb)nAr), CH(OC(O)NR8NR8R9), CH(OC(O)NR8(CRaRb)nNR8(CRaRb)nAr), CH(OC(O)NR8N R8(CRaRb)nNR8(CRaRb)nAr), —CH(NR8R9)—, CH(NR8C(O)R8), CH(NR8C(O)NR8R9), CH(NR8C(O)OR8), CH(S(CRaRb)nAr), —CH(NH(CRaRb)nNR8(CRaRb)nAr) and CH(NH(CRaRb)nAr), wherein n is an integer ranging from 0 to 10;
• or Y has the following structure:
• 77
• R1 and R2 can be taken separately or together;
• when taken separately, R1 is independently selected from OR8, OC(O)R8, OC(O)NR8R9, NR8R9, NR8C(O)R8, NR8C(O)NR8R9, O(CRaRb)nAr, S(CRaRb)nAr and N(CRaRb)nAr, wherein n is an integer ranging from 0 to 10;
• when taken separately, R2 is independently selected from OR8, O-mesyl, O-tosyl, OC(O)R8, OC(O)NR8R9, NR8R9, NR8C(O)R, NR8C(O)NR8R9, O(CRaRb)nAr, S(CRaRb)nAr and NH(CRaRb)nAr, wherein n is an integer ranging from 0 to 10;
• each of Ra and Rb is independently selected from H, halo and a C1-C6 alkyl;
• Ra and Rb together with the carbon to which they are attached can form a 3- to 10-membered cyclic or heterocyclic diradical, wherein one or two carbons of said diradical are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• (CRaRb)n is alkylene, wherein n is an integer ranging from 0 to 10, uninterrupted or interrupted by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• when taken together, R1 and R2 taken with the intervening atoms form an additional ring having one of the following structures:
• 78
• B1 issielected from O, (CRaaRbb)m, SO2, O and NR7, wherein m is 0 or 1;
• Z is seblected from (CRaaRbb)m, C(O), C(NRaa), P-ORaa, P(O)ORaa, P(O)NRaaRbb, Si(RcRd), SO, SO2, (CRaaRbb)mCO and CO(CRaaRbb)m, wherein m is 1 or 2;
• Rc and Rd are independently selected from a C1-C8 alkyl, a C6-C10 aryl and a C4-C10 heterocyclic;
• Raa and Rbb are independently selected from H and a C1-C6 alkyl;
• Raa and Rbb together with the carbon to which they are attached can form a 3- to 10-membered cyclic or heterocyclic diradical, wherein one or two carbons of said diradical are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• when B1 is NR7, B1 and R6 together with the nitrogen to which they are attached can form a 3- to 10-membered ring wherein one or two carbons of said ring are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• when B1 is NR7, B1 and R6 together with the nitrogen to which they are attached can form —N═C(R7)(RaRb)nAr, wherein n is an integer ranging from 0 to 10;
• R1, R2 and X can be taken together;
• when taken together, R1, R2 and X taken with the intervening atoms form an additional two rings having one of the following structures:
• 79 80
• each of D, E, F and G is independeflts seletdfrom H halo, a C1-C12 alkyl, a C3-C10 alkenyl, a C3-C10 alkynyl and CH2(RaRb)nAr, wherein n is an integer ranging from 0 to 10, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• D and E or F and G together with the carbon to which they are attached can form a 3- to 10-membered cyclic or heterocyclic diradical, wherein one or two carbons of said diradical are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• each of J, J1 and K is independently selected from C(O)R8, C(O)NR8R9, C(O)OR8, (CRaRb)nAr, S(CRaRb)nAr and NH(CRaRb)nAr;
• wherein n is an integer ranging from 0 to 10;
• each of L, M, Q and V is independently selected from the group S substituents;
• one or two carbons of the phenyl ring in which L, M, Q and V are attached can be replaced with nitrogen;
• R1 and X can be taken together;
• when taken together, R1 and X taken with the intervening atoms form an additional ring having one of the following structures:
• 81
• R2 and X can be taken together;
• when taken together, R2 and X taken with the intervening atoms form an additional ring having one of the following structures:
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• R3 and X can be taken together;
• when taken together, R3 and X taken with the intervening atoms form an additional ring having one of the following structures:
• 83
• R 3and Y can be taken together;
• when taken together, R3 and Y taken with the intervening atoms form an additional ring having one of the following structures:
• 84
• R4 is selected from H, a C(O)(C1-C18)alkyl, C(O)Ar, a OC(O)(C1-C18)alkyl and OC(O)Ar, wherein the alkyl moieties of the foregoing R4 groups are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• R5 is selected from H, halo, a C1-C10 alkyl, a C3-C10alkenyl, a C3-C10 alkynyl, —C(RaRb)— C(Ra)═C(Rb)—Ar, (CRaRb)nAr, OR8, O(CO)R8, OC(O)NR8R9, NR8R9, NR8C(O)R8, NR8C(O)NR8R9, O(CRaRb)nAr, S(CRaRb)nAr and NR8(CRaRb)nAr, wherein n is an integer ranging from 0 to 10, wherein one or two carbons of said alkyl, alkenyl and alkynyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• R5 and Y can be taken together;
• when taken together, R5 and Y taken with the intervening atoms form the following structure:
• 85
• R6 is selected from H, a C1-C12 alkyl, a C3-C10 alkenyl, a C3-C10 alkynyl and CH2(RaRb)nAr, wherein n is an integer ranging from 0 to 10, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• each of R7, R8 and R9 is independently selected from H and a Cl-CI2 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• R8 and R9 together with the nitrogen to which they are attached can form a 3- to 10-membered ring, in which one or two carbons are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• R10 is selected from a C1-C10 alkyl, a C3-C10 alkenyl, a C3-C10 alkynyl, —C(RaRb)— C(Ra)═C(Rb)—Ar and (CRaRb)nAr, wherein n is an integer ranging from 1 to 10, wherein one or two carbons of said alkyl, alkenyl and alkynyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents, provided that R10 is not unsubstituted methyl;
• R11 is H or OCH3;
• R12 and R13 together with the carbon to which they are attached can form —C(O)—, —C(═NR8)— or —C(═N—OR8);
• R12 and R13 together with the carbon to which they are attached can form a 3- to 10-membered ring, wherein one or two carbons of said ring are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• R12 is selected from H, a C1-C10 alkyl, a C3-C10 alkenyl, a C3-C10 alkynyl, —C(RaRb)— C(Ra)═C(Rb)—Ar and (CRaRb)nAr, wherein n is an integer ranging from 0 to 10, wherein one or two carbons of said alkyl, alkenyl and alkynyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• R13 is selected from H, a C1-C10 alkyl, a C3-C10 alkenyl, a C3-C10 alkynyl, OR8, OC(O)R8, OC(O)(CRaRb)nAr, OC(O)(CRaRb)nNR8(CRaRb)nAr, OC(O)NR8R9, OC(O)NR8NR8R9, OC(O)NR8(CRaRb)nNR8(CRaRb)nAr, OC(O)NR8NR8(CRaRb)nNR8(CRaRb)nAr, NR8R9, NR8(CO)R8, NR8C(O)NR8R9, NR8C(O)OR8, O(CRaRb)nAr, O(CRaRb)nNR8(CRaRb)nAr, S(CRaRb)nAr, NH(CRaRb)nNR8(CRaRb)nAr and NH(CRaRb)nAr, wherein n is an integer ranging from 0 to 10;
• each of R14 and R15 is independently selected from H, a C1-C12 alkyl, an aryl-substituted C1-C12 alkyl and a heteroaryl-substituted C1-C12 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6) alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• R14 and R15 together with the carbon to which they are attached can form a 3- to 10-membered ring, in which one or two carbons are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents;
• R17 is a C1-C20 alkyl, wherein one or two carbons of said alkyl are optionally replaced by a diradical independently selected from —O—, —S—, —S(O)—, —S(O)2—, a —N(C1-C6)alkyl- and —C(O)— and are optionally substituted by 1 to 3 substituents independently selected from the group S substituents, provided that R17 is not unsubstituted ethyl;
• R18 is selected from the group consisting of an aryl, a substituted aryl, a heteroaryl, a substituted heteroaryl and a heterocycloalkyl;
• each of R19 and R20 is independently selected from the group consisting of a C1-C12 alkenyl, a C1-C12 alkynyl, an aryl, a C3-C8 cycloalkyl, a heterocycloalkyl and a heteroaryl, wherein said alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl are substituted or unsubstituted;
• R19 and R20 together with the carbon to which they are attached can form a 3- to 10-membered heterocycloalkyl ring that may be substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, a C1-C3 alkoxy, a C1-C3 alkoxy-C1-C3 alkoxy, oxo, a C1-C3 alkyl, a halo-C1-C3 alkyl and a C1-C3 alkoxy-C1-C3 alkyl;
• each Ar is independently a 4- to 10-membered heterocyclic or a C6-C10 aryl, wherein said heterocyclic and aryl groups are optionally substituted by one or more substituents independently selected from the group S substituents;
• and
• the group S substituents are selected from the group consisting of:
• nitro, halogens, hydroxy, N3, CN, CHO, C1-C10 alkoxy, C1-C3 alkoxy-C1-C3 alkoxy, oxo, C1-C10 alkanoyl, C1-C10 alkyl, C1-C12 alkyl substituted with an aromatic heterocyclic, C1-C6 alkyl substituted with O—SO2, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, substituted C3-C10 cycloalkyl, 4 to 10 membered heterocyclic, substituted heterocyclic, aryl, substituted aryl, trialkylsilyl, —C(O)R8, —C(O)R18, —C(O)OR8, —C(O)NR8R9, —NR8R9, —NR19R20, —NHC(O)R8, —NHC(O)NR8R9, ═N—O—R8, ═N—NR8R9, ═N—NR19R20, ═N—R8, ═N—R18, ═N—NHC(O)R8, ═N—NHC(O)NR8R9, —C≡N, —S(O)n, wherein n is 0, 1 or 2, S(O)nR8, wherein n is 0, 1 or 2, —O—S(O)nR8, wherein n is 0, 1 or 2, and —SO2NR8R9.