Lactams substituted by cyclic succinates as inhibitors of Aβ protein production

A Compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Q is —NR1R2;
• R1 is H, C1-C4 alkyl, phenyl, benzyl, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)methyl-;
• R2 is H, C1-C4 alkyl, OH, C1-C4 alkoxy, phenyl, benzyl, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)methyl-;
• R3 and R3a may be combined to form a 3-8 membered carbocyclic moiety;
• wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
• wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, —N═, —NH—, and —N(R20)—, and
• wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 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 carbocycle substituted with 0-3 R23;
• alternatively, R3 is H;
• 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;
• and R3a is H, C1-C6 alkyl, or C2-C6 alkenyl;
• 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, OR14a, C1-C4 alkyl, C2-C6 alkenyl, 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 alkoxy;
• C1-C6 alkyl substituted with 0-3 R5b;
• C2-C6 alkenyl substituted with 0-3 R5b;
• C2-C6 alkynyl substituted with 0-3 R5b;
• C3-C10 carbocycle substituted with 0-3 R5c;
• aryl substituted with 0-3 R5c;
• 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 R5c;
• R5a is H, C1-C4 alkyl, or C2-C4 alkenyl;
• R5b, at each occurrence, is independently selected from:
• H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
• C3-C10 carbocycle substituted with 0-3 R5c;
• aryl substituted with 0-3 R5c;
• 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 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-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
• alternatively, R5 and R5a may be combined to form a 3-8 membered carbocyclic moiety;
• wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
• wherein said 3-8 membered carbocyclic moiety may optionally contain a hesteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, —N═, —NH—, and —N(R20)—, and
• wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R5c;
• provided at least:
• 1) R3 and R3a are combined to form a 3-8 membered carbocyclic moiety;
• or
• 2) R5 and R5a are combined to form a 3-8 membered carbocyclic moiety;
• or
• 3) R3 and R3a are combined to form a 3-8 membered carbocyclic moiety and R5 and R5a are combined to form a 3-8 membered carbocyclic moiety;
• R6 is H;
• C1-C6 alkyl substituted with 0-3 R6a;
• C3-C10 carbocycle substituted with 0-3 R6b;
• or
• aryl substituted with 0-3 R6b;
• R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, aryl or CF3;
• R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
• Ring B is
• R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, ═O, 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;
• 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-C6 cycloalkyl substituted with 0-3 R11b;
• and
• 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 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 or —(CR8R8a)p—;
• p is 0, 1, 2, 3, or 4;
• R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
• X is a bond;
• aryl substituted with 0-3 RXb;
• C3-C10 carbocycle substituted with 0-3 RXb;
• or
• 5 to 10 membered heterocycle substituted with 0-2 RXb;
• RXb, 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 halothioalkoxy;
• Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
• t is 0, 1, or 2;
• u is 0, 1, or 2;
• 9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
• V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, —N(R19)—, —C(═O)NR19b—, —NR19bC(═O)—, —NR19bS(═O)2—, —S(═O)2NR19b—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
• 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;
• 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 helloalkyl-S—, 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;
• R14a is H, phenyl, benzyl, or C1-C4 alkyl;
• R15, 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—;
• 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 3 to 6 membered heterocyclic ring;
• R19b, at each occurrence, is independently is H or C1-C4 alkyl;
• R20 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 R20a;
• or aryl substituted with 0-4 R20b;
• R20a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R20b;
• R20b, 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—;
• 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.