Beta-secretase modulators and methods of use

A compound of Formula I:

• or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative or prodrug thereof, wherein
• A is C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, R1—C1- 10-alkyl-, R1—C2-10-alkenyl- or R1—C2-10-alkynyl-, wherein
• 1, 2 or 3 carbon atoms of (1) said C1-C10 alkyl, C1-C10 alkenyl, C1-C10 ( alkynyl or (2) said C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl of R1—C1-10-alkyl-, R1—C2-10-alkenyl- or R1—C2-10-alkynyl-, is optionally replaced with a heteroatom selected from O, S, S(O), S(O)2 and
• N, and optionally substituted independently with one or more substitutents of R9;
• and
• R1 is a fully saturated or a partially or fully unsaturated 4-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms and optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said ring system is substituted independently with one or more substitutents of oxo, R7, R8, R9, NR7R7, NR7R8, OR7, SR7, OR8, SR8, C(O)R7, OC(O)R7, COOR7, C(O)R8, OC(O)R8, COOR8, C(O)NR7R7, C(S)NR7R7, NR7C(O)R7, NR7C(S)R7, NR7C(O)NR7R7, NR7C(S)NR7R7, NR7(COOR7), OC(O)NR7R7, C(O)NR7R8, C(S)NR7R8, NR7C(O)R8, NR7C(S)R8, NR7C(O)NR7R8, NR7C(S)NR7R8, NR7(COOR8), OC(O)NR7R8, S(O)2NR7R7, NR7S(O)2NR7R7, NR7S(O)2R7, S(O)2R8, S(O)2NR7R8, NR7S(O)2NR7R8 or NR7S(O)2R8;
• W is —C(═O)—, —OC(═O)—, —NHC(═O)—, —S(═O)b— or —NHS(═O)b—, wherein b is 1 or 2;
• B is R2—(CR2aR2a)h—, R2—O—(CR2aR2a)h—, R2—S—(CR2aR2a)h— or R2—N(R2a)—(CR2aR2a)h—, wherein
• R2 is C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkenyl, C1-C10 alkynyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl is optionally substituted independently with one or more substitutents of R9, and said ring system is optionally substituted independently with one or more substitutents of oxo, R7, R8, R9, NR7R7, NR7R8, OR7, SR7, OR8, SR8, C(O)R7, OC(O)R7, COOR7, C(O)R8, OC(O)R8, COOR8, C(O)NR7R7, C(S)NR7R7, NR7C(O)R7, NR7C(S)R7, NR7C(O)NR7R7, NR7C(S)NR7R7, NR7(COOR7), OC(O)NR7R7, C(O)NR7R8, C(S)NR7R8, NR7C(O)R8, NR7C(S)R8, NR7C(O)NR7R8, NR7C(S)NR7R8, NR7(COOR8), OC(O)NR7R8, S(O)2NR7R7, NR7S(O)2NR7R7, NR7S(O)2R7, S(O)2R8, S(O)2NR7R8, NR7S(O)2NR7R8 or NR7S(O)2R8;
• each R2a, independently, is H, OH, NO2, CN, NH2, C1-C10 alkyl, C1-C10 alkoxyl or haloalkyl;
• and
• h is 0, 1, 2 or 3;
• i is 1, 2 or 3;
• j is 0, 1 or 2;
• each R3, independently, is H, haloalkyl, CN, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl or C4-10-cycloalkenyl, each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl and C4-10-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-5 substitutents of R8 or R9;
• R4 is H, haloalkyl, CN, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl or C4-10-cycloalkenyl, each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl and C4-10-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-5 substitutents of R8 or R9;
• wherein X1 is CR12, O, S or NR12;
• each X2, independently, is CR12R12;
• each of Y1, Y2 and Y3, independently, is CR12R12, O, S or NR12;
• m is 0, 1 or 2;
• and
• o is 0, 1, 2, 3, 4 or 5;
• provided that (a) no more than two of Y1, Y2 and Y3 is O, S or NR12 and (b) when o is 0, then each of Y1 and Y2 is CR12R12;
• R7 is H, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl or C4-10-cycloalkenyl, each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl and C4-10-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-5 substitutents of NR8R9, NR9R9, OR8, SR8, OR9, SR9, C(O)R8, OC(O)R8, COOR8, C(O)R9, OC(O)R9, COOR9, C(O)NR8R9, C(O)NR9R9, NR9C(O)R8, NR9C(O)R9, NR9C(O)NR8R9, NR9C(O)NR9R9, NR9(COOR8), NR9(COOR9), OC(O)NR8R9, OC(O)NR9R9, S(O)2R8, S(O)2NR8R9, S(O)2R9, S(O)2NR9R9, NR9S(O)2NR8R9, NR9S(O)2NR9R9, NR9S(O)2R8, NR9S(O)2R9, R8 or R9;
• R8 is a partially or fully saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substitutents of R9, oxo, NR9R9, OR9;
• SR9, C(O)R9 or a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substitutents of R9;
• R9 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substitutents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-thioalkoxyl, benzyl or phenyl;
• R10 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substitutents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-thioalkoxyl, benzyl or phenyl;
• R11 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1 -alkoxyl, C1-10-thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substitutents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-thioalkoxyl, benzyl or phenyl;
• alternatively, R10 and R11 taken together with the carbon or nitrogen atoms to which they are attached form a partially or fully saturated or unsaturated 5-6 membered second ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, the second ring optionally substituted independently with 1-5 substitutents of R2, R13, R14 or R15 and optionally fused to a 4-7 membered third ring, the third ring formed of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substitutents of R2, R13, R14 or R15;
• R12 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, oxo, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10 -cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substitutents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-thioalkoxyl, benzyl, phenyl or R14;
• R13 is NR14R15, NR15R15, OR14, SR14, OR15, SR15, C(O)R14, OC(O)R14, COOR14, C(O)R15, OC(O)R15, COOR15C(O)NR14R15, C(O)NR15R15, NR14C(O)R14, NR15C(O)R14, NR14C(O)R15, NR15C(O)R15, NR15C(O)NR14R15, NR15C(O)NR15R15, NR15(COOR14), NR15(COOR15), OC(O)NR14R15, OC(O)NR15R15, S(O)2R14, S(O)2R15, S(O)2NR14R15, S(O)2NR15R15, NR14S(O)2NR14R15, N15S(O)2NR15R15, NR14S(O)2R14 or NR15S(O)2R15;
• R14 is a partially or fully saturated or unsaturated 5-8 membered or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substitutents of R15;
• and
• R15 is H, halo, haloalkyl, CN, OH, NO2, NH2, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-thioalkoxyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substitutents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl.