Phosphate Derivatives of Substituted Benzoxazoles

A compound of Formula I, having the structure:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R1 is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N, S, —NO2, NR5R6, —N(R5)COR6, —CN, —CHFCN, CF2CN, alkynyl of 2-7 carbon atoms, alkenyl of 2-7 carbon atoms;
• wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, —COR5, —CO2R5, —NO2, CONR5R6, NR5R6, or N(R5)COR6;
• R2 and R2a are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms;
• wherein the alkyl, alkenyl, or alkynyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, —COR5, —CO2R5, —NO2, CONR5R6, NR5R6, or N(R5)COR6;
• R3 and R3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms;
• wherein the alkyl, alkenyl, or alkynyl moieties are optionally substituted with hydroxyl, —CN, halogen, trifluoroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, —COR5, —CO2R5, —NO2, CONR5R6, NR5R6, NR5R6 or N(R5)COR6;
• R4 is hydrogen, halogen, or alkyl of 1-6 carbon atoms provided that when R4 is hydrogen, R1, R2, R2a, R3, and R3a, cannot all be hydrogen;
• R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms;
• X is O, S, or NR7;
• R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, —COR5, —CO2R5 or SO2R5;
• A and A′ are each independently hydrogen or —P(O)(OR8)(OR9);
• wherein at least one of A and A′ is —P(O)(OR8)(OR9);
• R8 and R9 are each independently selected from H, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C5-10 heteroaryl, C3-12 heterocycloalkyl, C8-20 arylalkyl, C8-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, wherein each of the C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C5-10 heteroaryl, C3-12 heterocycloalkyl, C6-20 arylalkyl, C6-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, is optionally substituted by 1, 2, 3, 4 or 5 R10;
• each R10 is independently halo, C1-6 alkyl, C1-6 haloalkyl, C6-13 aryl, C3-8 cycloalkyl, C5-10 heteroaryl, C3-12 heterocycloalkyl, C6-20 arylalkyl, C6-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, CN, NO2, ORa, SRa, C(═O)Rb, C(═O)NRcRd, C(═O)ORa, OC(═O)Rb, OC(═O)NRcRd, NRcRd, NRcC(═O)Rb, NRcC(═O)ORa, NRcS(═O)2Rb, S(═O)Rb, S(═O)NRcRd, S(═O)2Rb, or S(═O)2NRcRd;
• each Ra is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C6-10 heteroaryl, C3-12 heterocycloalkyl, C6-20 arylalkyl, C6-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, wherein each of said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C5-10 heteroaryl, C3-12 heterocycloalkyl, C6-20 arylalkyl, C6-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, is optionally substituted by OH, C1-6 alkoxy, C1-6 haloalkoxy, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C6-20 arylalkyl, C5-10 heteroaryl, C6-20 heteroarylalkyl, C3-8 cycloalkyl or C3-12 heterocycloalkyl;
• each Rb is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C6-10 heteroaryl, C3-12 heterocycloalkyl, C6-20 arylalkyl, C6-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, wherein each of said C1-6 alkyl, C1-6 haloalkyl, C2-5 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-8 cycloalkyl, heteroaryl, C3-12 heterocycloalkyl, C6-20 arylalkyl, C6-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, is optionally substituted by OH, C1-6 alkoxy, C1-6 haloalkoxy, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C6-20 arylalkyl, C-5-10 heteroaryl, C6-20 heteroalkyl, C3-8 cycloalkyl or C3-12 heterocycloalkyl;
• and
• Rc and Rd are each, independently, selected from H, C1-10 alkyl, C1-6, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C5-10 heteroaryl, C3-12 heterocycloalkyl, C6-20 arylalkyl, C6-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, wherein each of said C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-8 cycloalkyl, C5-10 heteroaryl, C3-12 heterocycloalkyl, C6-20 arylalkyl, C6-20 heteroarylalkyl, C3-20 cycloalkylalkyl and C3-20 heterocycloalkylalkyl, is optionally substituted by OH, C1-6 alkoxy, C1-6 haloalkoxy, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, C6-20 arylalkyl, C5-10 heteroaryl, C6-20 heteroarylalkyl, C3-8 cycloalkyl or C3-12 heterocycloalkyl;
• or
• Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.