Prodrugs of aspartyl protease inhibitors

A compound of formula I:

• 123
• wherein:
• each R1 is independently selected from the group consisting of C(O)—, —S(O)2—, —C(O)—C(O)—, —O—C(O)—, —O—S(O)2, —NR2—S(O)2—, —NR2—C(O)— and —NR2—C(O)—C(O)—;
• each A is independently selected from the group consisting of 5-7 membered monocyclic heterocycles containing from 1-3 endocyclic heteroatoms, which may be optionally methylated at the point of attachment, optionally benzofused, optionally attached through a C1-C3 alkyl linker and optionally fused with a 5-7 membered monocyclic heterocycle containing from 1-2 endocyclic heteroatoms, and wherein unmethylated THF is expressly excluded;
• each Ht is independently selected from C3-C7 cycloalkyl;
• C5-C7 cycloalkenyl;
• C6-C10 aryl;
• or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), O, S and S(O)n;
• wherein said aryl or said heterocycle is optionally fused to Q;
• and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, —OR2, SR2, —R2, —N(R2)(R2), —R2—OH, —CN, —CO2R2, —C(O)—N(R2)2, —S(O)2—N(R2)2, —N(R2)—C(O)—R2, —C(O)—R2, —S(O)n—R2, —OCF3, —S(O)n—Q, methylenedioxy, —N(R2)—S(O)2(R2), halo, —CF3, —NO2, Q, —OQ, —OR7, —SR7, —R7, —N(R2)(R7) or —N(R7)2;
• each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system;
• or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n or N(R2);
• wherein Q is optionally substituted with one or more groups selected from oxo, —OR2, —R2, —N(R2)2, —N(R2)—C(O)—R2, —R2—OH, —CN, —CO2R2, —C(O)—N(R2)2, halo or —CF3;
• each R2 is independently selected from the group consisting of H and C1-C3 alkyl optionally substituted with Q;
• each x is independently 0 or 1;
• each R3 is independently selected from the group consisting of H, Ht, C1-C6 alkyl and C2-C6 alkenyl wherein any member of said R3, except H, may be optionally substituted with one or more substituents selected from the group consisting of —OR2, —C(O)—NH—R2, —S(O)n—N(R2)(R2), Ht, —CN, —SR2, —CO2R2, NR2—C(O)—R2;
• each n is independently 1 or 2;
• G, when present, is selected from H, R7 or C1-C4 alkyl, or, when G is C1-C4 alkyl, G and R7 are bound to one another either directly or through a C1-C3 linker to form a heterocyclic ring;
• or
• when G is not present (i.e., when x in (G)x is 0), then the nitrogen to which G is attached is bound directly to the R7 group on —OR7;
• each D and D′ is independently selected from the group consisting of Q;
• C1-C5 alkyl, which may be optionally substituted with one or more groups selected from C3-C6 cycloalkyl, —OR2, —R3, —O—Q, —S—Q and Q;
• C2-C4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, —OR2, R3, O—Q and Q;
• C3-C6 cycloalkyl, which may be optionally substituted with or fused with Q;
• and C5-C6 cycloalkenyl, which may be optionally substituted with or fused with R6;
• each E is independently selected from the group consisting of Ht;
• —O—Ht;
• Ht—Ht;
• —O—R3;
• —NR2R3;
• C1-C6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Ht;
• and C2-C6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Ht;
• C3-C6 saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht;
• or C5-C6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht;
• each R4 is independently selected from the group consisting of OR2, —C(O)—NHR2, S(O)2—NHR2, halo, NR2—C(O)—R2 and —CN;
• each R5 is independently selected from the group consisting of H and C1-C4 alkyl optionally substituted with aryl;
• and
• each R6 is independently selected from the group consisting of aryl, carbocycle and heterocycle, wherein said aryl, carbocycle or heterocycle may be optionally substituted with one or more groups selected from the group consisting of oxo, —OR5, —R5, N(R5)(R5), N(R5)—C(O)—R5, —R5—OH, —CN, CO2R5, C(O)—N(R5)(R5), halo and CF3;
• each R7 is independently selected from
• 124
• wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, —N(R2)4, C1-C12-alkyl, C2-C12-alkenyl, —R6;
• wherein 1 to 4 —CH2 radicals of the alkyl or alkenyl group, other than the —CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2);
• and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, —OR2, —R2, N(R2)2, N(R2)3, R2OH, —CN, —CO2R2, —C(O)—N(R2)2, S(O)2—N(R2)2, N(R2)—C(O)—R2, C(O)R2, —S(O)n—R2, OCF3, —S(O)n—R6, N(R2)—S(O)2(R2), halo, —CF3, or —NO2;
• M′ is H, C1-C12-alkyl, C2-C12-alkenyl, —R6;
• wherein 1 to 4 —CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2);
• and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, —OR2, —R2, —N(R2)2, N(R2)3, —R2OH, —CN, —CO2R2, —C(O)—N(R2)2, —S(O)2—N(R2)2, —N(R2)—C(O)—R2, —C(O)R2, —S(O)n—R2, —OCF3, —S(O)n—R6, —N(R2)—S(O)2(R2), halo, —CF3, or —NO2;
• Z is O, S, N(R2)2, or, when M is absent, H;
• Y is P or S;
• X is O or S;
• and
• R9 is C(R2)2, O or N(R2);
• and wherein when Y is S, Z is not S;
• and
• R6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system;
• wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O)n or N(R2);
• and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C1-C4 alkyl, O—C1-C4 alkyl or OC(O)C1-C4 alkyl.