Tetrazolylpropionamides as inhibitors of Aβ protein production

A compound of Formula (I):

• or a pharmaceutically acceptable salt or prodrug thereof, wherein:
• R1 is H,
• C1–C6 alkyl optionally substituted with 0–2 R2a;
• C2–C6 alkenyl optionally substituted with 0–2 R2a;
• or
• C2–C6 alkynyl optionally substituted with 0–2 R2a;
• R2a, at each occurrence, is independently selected from
• H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1–C4 alkyl, C1–C4 alkoxy, C1–C4 haloalkyl, C1–C4 haloalkoxy, C1–C4 haloalkyl-S—;
• phenyl substituted with 0–3 R2b;
• C3–C6 cycloalkyl substituted with 0–3 R2b;
• and
• 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0–3 R2b;
• R2b, at each occurrence, is independently selected from
• H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1–C4 alkyl,
• C1–C4 alkoxy, C1–C4 haloalkyl, C1–C4 haloalkoxy, and C1–C4 haloalkyl-S—;
• R3 is H, NH2, NR25R26,
• C1–C6 alkyl substituted with 0–3 R4;
• C2–C6 alkenyl substituted with 0–3 R4;
• or
• C2–C6 alkynyl substituted with 0–3 R4;
• R3a is H, C1–C6 alkyl, or C2–C6 alkenyl;
• alternatively, R3 and R3a are combined to form a 3–6 membered carbocyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl;
• wherein said 3–6 membered carbocyclic group is substituted with 0–2 R4;
• additionally, two R4 substituents on adjacent atoms may be combined to form a benzo fused radical;
• wherein said benzo fused radical is substituted with 0–4 R23;
• additionally, two R4 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S;
• wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0–3 R23;
• additionally, two R4 substituents on the same or adjacent carbon atoms may be combined to form a C3–C6 carbocyclic group substituted with 0–3 R23;
• R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, NR15R16, C1–C4 alkyl, C2–C4 alkenyl, C2–C4 alkynyl, C1–C4 alkoxy, C1–C4 haloalkyl, C1–C4 haloalkoxy, and C1–C4 haloalkyl-S—, C3–C6 carbocycle, aryl, and a
• 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
• R5 is H;
• C1–C6 alkyl substituted with 0–2 R5b;
• C2–C6 alkenyl substituted with 0–2 R5b;
• C2–C6 alkynyl substituted with 0–2 R5b;
• C3–C6 carbocycle substituted with 0–3 R5c;
• phenyl substituted with 0–3 R5c;
• or
• 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0–3 R5c;
• R5a is H, C1–C4 alkyl, or C2–C4 alkenyl;
• alternatively, R5 and R5a may be combined to form a 3–6 membered carbocyclic moiety selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl;
• R5b, at each occurrence, is independently selected from:
• H, C1–C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
• C3–C6 carbocycle substituted with 0–3 R5c;
• phenyl substituted with 0–3 R5c;
• or
• 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0–3 R5c;
• R5c, at each occurrence, is independently selected from
• H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1–C4 alkyl, C1–C3 alkoxy, C1–C3 haloalkyl, C1–C3 haloalkoxy, and C1–C3 haloalkyl-S—;
• R6 is H or C1–C6 alkyl;
• Ring B is a 7 membered lactam,
• wherein the lactam is saturated, partially saturated or unsaturated;
• wherein each additional lactam carbon is substituted with 0–2 R11;
• and,
• optionally, the lactam contains an additional heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, —N═, —NH—, and —N(R10)—;
• additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical;
• wherein said benzo fused radical is substituted with 0–4 R13;
• additionally, two R11 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S;
• wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0–3 R13;
• additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3–C6 carbocyclic radical substituted with 0–3 R13;
• R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
• C1–C6 alkyl optionally substituted with 0–3 R10a;
• C6–C10 aryl substituted with 0–4 R10b;
• C3–C10 carbocycle substituted with 0–3 R10b;
• or
• 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0–3 R10b;
• R10a, at each occurrence, is independently selected from
• H, C1–C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3,
• phenyl substituted with 0–3 R10b;
• C3–C7 cycloalkyl substituted with 0–3 R10b;
• and
• 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0–3 R10b;
• R10b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1–C6 alkyl, C1–C4 alkoxy, C1–C4 haloalkyl, C1–C4 haloalkoxy, and C1–C4 haloalkyl-S—;
• R11, at each occurrence, is independently selected from
• H, C1–C4 alkoxy, Cl, F, Br, I, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
• C1–C6 alkyl optionally substituted with 0–3 R11a;
• C6–C10 aryl substituted with 0–3 R11b;
• C3–C10 carbocycle substituted with 0–3 R11b;
• or
• 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0–3 R11b;
• R11a, at each occurrence, is independently selected from
• H, C1–C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
• phenyl substituted with 0–3 R11b;
• C3–C7 cycloalkyl substituted with 0–3 R11b;
• and
• 5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0–3 R11b;
• R11b, at each occurrence, is independently selected from
• H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C1–C6 alkyl, C1–C4 alkoxy, C1–C4 haloalkyl, C1–C4 haloalkoxy, and C1–C4 haloalkyl-S—;
• W is a bond, —CH2—, —CH2CH2—;
• X is a bond, -phenyl-, -pyridyl-, -cyclohexyl-, or -piperidinyl-;
• Y is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —NH—, —N(CH3)—, or —N(CH2CH3)—;
• Z is H;
• C1–C8 alkyl substituted with 0–3 R12a;
• C2–C6 alkenyl substituted with 0–3 R12a;
• C2–C6 alkynyl substituted with 0–3 R12a;
• C6–C10 aryl substituted with 0–4 R12b;
• C3–C10 carbocycle substituted with 0–4 R12b;
• or
• 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0–3 R12b;
• R12a, at each occurrence, is independently selected from
• H, OH, Cl, F, Br, I, CN, NO2, NR15R16, —C(═O)NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3,
• C1–C6 alkyl, C1–C4 alkoxy, C1–C4 haloalkyl, C1–C4 haloalkoxy, C1–C4 haloalkyl-S—, C6–C10 aryl substituted with 0–4 R12b;
• C3–C10 carbocycle substituted with 0–4 R12b;
• or
• 5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0–3 R12b;
• R12b, at each occurrence, is independently selected from
• H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C3–C6 cycloalkyl,
• C1–C6 alkyl, C1–C4 alkoxy, C1–C4 haloalkyl, C1–C4 haloalkoxy, C1–C4 haloalkyl-S, and aryl substituted with 0–3 R12c;
• R12c, at each occurrence, is independently selected from
• H, methyl, ethyl, propyl, methoxy, ethoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, —N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(═O)CH3, CO2H, CO2CH3, and C1–C3 haloalkyl;
• R13, at each occurrence, is independently selected from
• H, OH, C1–C6 alkyl, C1–C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
• R14 is H, phenyl, benzyl, C1–C6 alkyl, C2–C6 alkoxyalkyl, or C3–C6 cycloalkyl;
• R15, at each occurrence, is independently selected from H, and C1–C6 alkyl;
• R16, at each occurrence, is independently selected from
• H, C1–C6 alkyl, benzyl, phenethyl, (C1–C6 alkyl)-C(═O)—, and (C1–C6 alkyl)-S(═O)2—;
• R17 is H, C1–C6 alkyl, C2–C6 alkoxyalkyl, aryl substituted by 0–4 R17a, or —CH2-aryl substituted by 0–4 R17a;
• R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, —OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, —NH2, —N(CH3)2, or C1–C4 haloalkyl;
• R18, at each occurrence, is independently selected from
• H, C1–C6 alkyl, phenyl, benzyl, phenethyl, (C1–C6 alkyl)-C(═O)—, and (C1–C6 alkyl)-S(═O)2—;
• R19, at each occurrence, is independently selected from
• H, OH, C1–C6 alkyl, phenyl, benzyl, phenethyl, (C1–C6 alkyl)-C(═O)—, and (C1–C6 alkyl)-S(═O)2—;
• additionally, R18 and R19, when substituents on the same atom, may be combined to form a 5 to 7 membered nitrogen containing heterocyclic ring;
• R23, at each occurrence, is independently selected from
• H, OH, C1–C6 alkyl, C1–C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
• R25, at each occurrence, is independently selected from H, and C1–C6 alkyl;
• and
• R26, at each occurrence, is independently selected from
• H, C1–C6 alkyl, C3–C4 alkenyl, C3–C4 alkynyl, (C1–C6 alkyl)-C(═O)—, (C1–C6 alkyl)-S(═O)2—, aryl(C1–C4 alkyl)-, C3–C6 cycloalkyl, and C3–C6 cycloalkyl(C1–C4 alkyl)-.