4''-Substituted-9-deoxo-9a-aza-9a homoerythromycin a derivative

A method of preparing a compound of the formula

• 31
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is H, hydroxy or methoxy;
• R2 is hydroxy;
• R3 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, —CH2S(O)nR8 wherein n is an integer ranging from 0 to 2, —CH2OR8, —CH2N(OR9)R8, —CH2NR8R15, —(CH2),(C1-C10 aryl), or —(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R3 groups are optionally substituted by 1 to 3 R10 groups;
• or R2 and R3 are taken together to form an oxazolyl ring as shown below
• 32
• R4 is H, —C(O)R9, —C(O)OR9, —C(O)NR9R10 or a hydroxy protecting group;
• R5 is —SR8, —(CH2)nC(O)R8 wherein n is 0 or 1, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)m(C6-C10 aryl), or —(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R5 groups are optionally substituted by 1 to 3 R16 groups;
• each R6 and R7 is independently H, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(CH2)m(C6-C10 aryl), or —(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4;
• each R8 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)qCR11R12(CH2)rNR3R14 wherein q and r are each independently an integer ranging from 0 to 3 except q and r are not both 0, (CH2)m(C6-C10 aryl), or —(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R8 groups, except H, are optionally substituted by 1 to 3 R16 groups;
• or where R8 is as —CH2NR8R15, R15 and R8 may be taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R8)—, in addition to the nitrogen to which R15 and R8 are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R16 groups;
• each R9 and R10 is independently H or C1-C6 alkyl;
• each R11, R12, R13 and R14 is independently selected from H, C1-C10 alkyl, —(CH2)m(C6-C10 aryl), and —(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R11, R12, R13 and R14 groups, except H, are optionally substituted by 1 to 3 R16 groups;
• or R11 and R13 are taken together to form —(CH2)p— wherein p is an integer ranging from 0 to 3 such that a 4-7 membered saturated ring is formed that optionally includes 1 or 2 carbon-carbon double or triple bonds;
• or R13 and R14 are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and —N(R8)—, in addition to the nitrogen to which R13 and R14 are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R16 groups;
• R15 is H, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl, wherein the foregoing R15 groups are optionally substituted by 1 to 3 substituents independently selected from halo and —OR9;
• each R16 is independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R17, —C(O)OR7, —C(O)OR17, —OC(O)OR17, -NR6C(O)R7, —C(O)NR6R7, —NR8R7, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, —(CH2)m(C6-C10 aryl), and —(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein said aryl and heteroaryl subsituents are optionally substituted by 1 or 2 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)R17, —C(O)OR17, —C(O)OR17, —OC(O)OR17, —NR6C(O)R7, —C(O)NR6R7, —NR6R7, hydroxy, C1-C6 alkyl, and C1-C8 alkoxy;
• each R17 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)m(C6-C10 aryl), and —(CH2)m(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4;
• with the proviso that R8 is not H where R3 is —CH2S(O)nR8;
• which comprises treating a compound of the formula
• 33
• wherein R1 and R4 are as defined above, with a compound of the formula HOR8, HSR8 or HNR15R8, wherein n, R15 and R8 are as defined above, wherein if said compound of formula HSR8 is used the resulting R3 group of formula —CH2SR8 is optionally oxidised to —CH2S(O)R8 or —CH2S(O)2R8.

A compound of the formula

• 35
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is H, hydroxy or methoxy;
• and,
• R4 is H, —C(O)R9, —C(O)OR9, (O)NR9R10 or a hydroxy protecting group;
• and,
• each R9 and R10 is independently H or C1-C6 alkyl.

A compound of the formula

• 36
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is H, hydroxy or methoxy;
• and,
• R4 is H, C(O)R9, C(O)OR9, —C(O)NR9R10 or a hydroxy protecting group;
• and,
• each R9 and R10 is independently H or C1-C6 alkyl.