Azalides and methods of making same

A compound of Formula 1:

• or a pharmaceutically acceptable salt or solvates thereof, wherein:
• X is —N(Ra)CH2—, 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, and Ra is 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;
• R1 is straight-chain or alpha-branched C1-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may be substituted by one or more hydroxyl groups;
• a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, either of which may be substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halo atoms;
• or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated, and which may be substituted by one or more C1-C4 alkyl groups or halo atoms or a group of the formula SRb, wherein Rb is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C1-C4 alkyl, C1-C4 alkoxy or halo or a 3 to 6 membered oxygen or sulfur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may be substituted by one or more C1-C4 alkyl groups or halo atoms;
• or R1 is phenyl which may be substituted with at least one substituent selected from C1-C4 alkyl, C1-C4 alkoxy and C1-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano;
• or R1 is of the formula
• wherein Z1 is O, S or —CH2—, and a, b, c, and d is each independently an integer ranging from0 to 2 and a+b+c+d#5;
• R2 is H or OH;
• R3 is H or —C(O)NRcRd, wherein each of Rc and Rd is independently H, C1-C10 alkyl, C2-C20 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 each of the foregoing Rc and Rd groups, except H, may be substituted by 1 to 3 Q groups;
• or wherein Rc and Rd may be taken together to form a 4-7 membered saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings may include 1 or 2 heteroatoms selected from O, S and N, in addition to the nitrogen to which Rc and Rd are attached, and said saturated ring may include 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings may be substituted by 1 to 3 Q groups;
• or R2 and R3 taken together form a carbonate ring;
• R4 is H, OH, O(C1-C10 alkyl);
• R5 is H, —C(O)Re, —C(O)ORe, —C(O)NReRf, or a hydroxy protecting group, and Re and Rf is each independently H or C1-C6 alkyl;
• R6 is H or OH;
• R7 is H or OH;
• R8 is C1-C10 alkyl, C2-C20 alkenyl, C2-C10 alkynyl, cyano, —CH2S(O)nRg wherein n is an integer ranging from 0 to 2, —CH2ORg, —CH2N(ORh)Rg, —CH2NRgRi, —(CH2)m(C6-C12 aryl), or —(CH2)m(5-10 membered heteroalkyl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R8 groups may be substituted by 1 to 3 Q groups;
• each Rg is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CH2)qCRg(1)Rg(2)(CH2)rNRg(3)Rg(4) wherein q and r is 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 Rg groups, except H, may be substituted by 1 to 3 Q groups;
• each of Rg(1), Rg(2), R3(3) and Rg(4) is independently selected from H, C1-C10 alkyl, —(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 Rg(1), Rg(2), Rg(3) and Rg(4) groups, except H, may be substituted by 1 to 3 Q groups;
• or Rg(1) and Rg(3) 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 may include 1 or 2 carbon-carbon double or triple bonds;
• or Rg(3) and Rg(4) 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 may include 1 or 2 heteroatoms selected from O, S and N, in addition to the nitrogen to which Rg(3) and Rg(4) are attached, said saturated ring may include 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings may be substituted by 1 to 3 Q groups;
• Rh is H or C1-C6 alkyl;
• Ri is H, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl, wherein the foregoing Ri group may be substituted by 1 to 3 substituents independently selected from halo, OH, and O(C1-C6 alkyl);
• and if R8 is —CH2NRgRi, then Rg and Ri may be taken together to form a 4-10 membered saturated monocyclic or polycycic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings may include 1 or 2 heteroatoms selected from O, S and N, in addition to the nitrogen to which Rg and Ri are attached, said saturated ring may include 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings may be substituted by 1 to 3 Q groups;
• or R7 and R8 are taken together to form an oxazolyl ring as shown below
• wherein Z2 is —SRg, —(CH2)nC(O)Rg 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 Z2 groups may be substituted by 1 to 3 Q groups;
• each Q is independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)Q1, —OC(O)Q1, —C(O)OQ1, —OC(O)OQ1, —NQ2C(O)Q3, —C(O)NQ2Q3, —NQ2Q3, hydoxy, 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 substituents may be substituted by 1 or 2 subsfituents independently selected from halo, cyano, nitro, trifluoromethyl, azide, —C(O)Q1, —C(O)OQ1, —OC(O)OQ1, —NQ2C(O)Q3, —C(O)NQ2Q3, —NQ2Q3, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each Q1, Q2 and Q3 is independently selected from H, OH, C1-C10 alkyl, C1-C6 alkoxy, 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;
• R9 is H or CH3;
• and
• R10 is H or CH3.