Substituted cycloalkyls as inhibitors of a beta protein production
AssigneeDuPont Pharmaceuticals Company
InventorsMichael G Yang, Hong Liu
Life of this patent
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Abstract
This invention relates to novel lactams having the Formula (I): to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer's disease and Down's Syndrome.
Claims30
A compound of Formula (I):
- or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
- Q is
- —(CR7R7a)m—R4,
- —(CR7R7a)m—CH(OH)—R4,
- —(CR7R7a)m—NHC(O)—R4,
- —(CR7R7a)n—S—R4,
- —(CR7R7a)n—O—R4,
- —(CR7R7a)n—N(R7b)—R4,
- —(CR7R7a)n—S (═O)—R4, or
- —(CR7R7a)n—C(═O)—R4;
- m is 1, 2, or 3;
- n is 0, 1, or 2;
- R4 is H,
- C1-C8 alkyl substituted with 0-3 R4a,
- C2-C8 alkenyl substituted with 0-3 R4a,
- C2-C8 alkynyl substituted with 0-3 R4a,
- C3-C10 carbocycle substituted with 0-3 R4b, aryl substituted with 0-3 R4b, 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 R4b;
- R4a, at each occurrence, is independently selected from H, OH, F, Cl, Br, I, CF3, C1-C3 alkyl,
- C3-C10 carbocycle substituted with 0-3 R4b, aryl substituted with 0-3 R4b, and
- 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 R4b;
- R4b, 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—;
- R5 and R5a are 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 the heteroatom —O—;
- and
- wherein said 3-8 membered carbocyclic moiety is substituted with 0-2 R5b;
- R5b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, methyl, ethyl, methoxy, ethoxy, allyl, —OCF3, and —SCF3;
- 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 and 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;
- R7, at each occurrence, is independently H or C1-C4 alkyl;
- R7a, at each occurrence, is independently H or C1-C4 alkyl;
- R7b is H, C1-C4 alkyl, or (C1-C4 alkyl)OC(═O)—;
- Ring B is
- 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;
- aryl substituted with 0-3 R11b;
- C3-C10 carbocycle substituted with 0-3 R11b;
- and
- 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)0, 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;
- R9 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 haloalkyl-S—,
- aryl substituted with 0-4 R12b;
- C3-C10 carbocycle substituted with 0-4 R12b;
- and
- 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, aryl, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
- 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, OH, 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, aryl, aryl-CH2—, aryl-CH2CH2—, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- R19, at each occurrence, is independently selected from Ii, OH, C1-C6 alkyl, aryl, aryl-CH2—, aryl-CH2CH2—, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- and
- R19b, at each occurrence, is independently is H or C1-C4 alkyl;
- provided when Q is —(CR7R7a)n—N(R7b)—R4 and R7b is (C1-C4 alkyl)OC(═O)—, then n is 1 or 2;
- and
- provided when Q is —(CR7R7a)n—N(R7b)—R4 and n is 0, then R4 does not contain a —C(═O)— adjacent to —N(R7b)—.
A method for the treatment of Alzheimer's Disease comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim.
Dependencies are inferred from the claim text.