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US 7,112,583 B2Granted
Hydroxyalkanoylaminolactams and related structures as inhibitors of Aβ protein production
AssigneeBristol-Myers Squibb Pharma Company
InventorsRichard E. Olson, Hong Liu, Lorin A. Thompson
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.
Claims39
A compound of the formula (I):
- or a pharmaceutically acceptable salt form thereof, wherein:
- Q is Q1,
- (C1–C3 alkylene)-O-Q1,
- (C1–C3 alkylene)-S-Q1,
- (C1–C3 alkylene)-S(═O)-Q1,
- (C1–C3 alkylene)-S(═O)2-Q1, or
- (C1–C3 alkylene)-N(R20)-Q1;
- Q1 is C1–C8 alkyl substituted with 0–3 R1a;
- C2–C8 alkenyl substituted with 0–3 R1a;
- C2–C8 alkenyl substituted with 0–3 R1a;
- C3–C10 cycloalkyl substituted with 0–3 R1b;
- C3–C10 carbocycle substituted with 0–3 R1b;
- aryl substituted with 0–3 R1b;
- 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 R1b;
- R1a, at each occurrence, is independently selected from H, C1–C6 alkyl, OR14, Cl, F, Br, I, NR15R16, CF3;
- C3–C10 carbocycle substituted with 0–3 R1b;
- aryl substituted with 0–3 R1b;
- 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 R1b;
- R1b, 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, C1–C4 haloalkyl-S—, and (C1–C6 alkyl)-O—C(═O)—;
- R2 is H, methyl, ethyl, propyl, or butyl;
- R3 is H, C1–C6 alkyl, —C(═O)(C1–C6 alkyl), —C(═S)(C1–C6 alkyl), or —C(═O)NR21R22;
- alternatively, R2 and OR3 are combined to form C═O or C═N—OH;
- R5 is H, OR14;
- C1–C6 alkyl substituted with 0–3 R5b;
- C1–C6 alkoxy substituted with 0–3 R5b;
- C2–C6 alkenyl substituted with 0–3 R5b;
- C2–C6 alkenyl substituted with 0–3 R5b;
- C3–C10 cycloalkyl substituted with 0–3 R5c;
- 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;
- alternatively, R5 and R5a may be combined to form a 3–7 membered cycloalkyl ring substituted with 0–3 R5c;
- optionally the cycloalkyl ring formed by combining R5 and R5a may be benzo fused, wherein the benzo fused ring may be substituted with 0–3 R5c;
- R5b, at each occurrence, is independently selected from:
- H, C1–C6 alkyl, CF3, OR14 , Cl, F, Br, I, O, CN, NO2, NR15R16, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, C2–C6 alkenyl, C2–C6 alkenyl, C1–C4 alkoxy, C1–C4 haloalkyl, C1–C4 haloalkoxy, C1–C4 haloalkyl-S—,
- C3–C10 cycloalkyl substituted with 0–3 R5c;
- C3–C10 carbocycle substituted with 0–3 R5c;
- aryl substituted with 0–3 R5c;
- 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 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—;
- R6 is H or C1–C6 alkyl;
- W is —(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 alkenyl and C3–C8 cycloalkyl;
- X is a bond;
- aryl substituted with 0–3 RXb;
- C3–C10 cycloalkyl 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 haloalkyl-S—;
- Y is a bond or —(CR9R9a)t—V—(CR9R9a)u—;
- t is 0, 1, 2, or 3;
- u is 0, 1, 2, or 3;
- 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—, —C(═O)O—, or —OC(═O)—;
- Z is H;
- C1–C8 alkyl substituted with 0–2 R12;
- C2–C4 alkenyl substituted with 0–2 R12;
- C2–C4 alkenyl substituted with 0–2 R12;
- 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;
- Ring B is selected from:
- wherein said benzo fused radical or 5 to 6 membered heteroaryl fused radical is 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 substituted with 0–2 R10a;
- 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 optionally 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;
- 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 optionally substituted with 0–3 R10b;
- R10b, at each occurrence, is independently selected from H, OH, C1–C6 alkyl, C1–C4 alkoxy, 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—;
- R12 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, and 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, 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, at each occurrence, is independently selected from H, phenyl, benzyl, C1–C6 alkyl, and C2–C6 alkoxyalkyl;
- R14a is H, phenyl, benzyl, or C1–C6 alkyl;
- R15, at each occurrence, is independently selected from H, C1–C6 alkyl, phenyl, benzyl, phenethyl, (C1–C6 alkyl)-C(═O)—, (C1–C6 alkyl)-O—C(═O)— and (C1–C6 alkyl)-S(═O)2—;
- R16, at each occurrence, is independently selected from H, OH, C1–C6 alkyl, phenyl, benzyl, phenethyl, (C1–C6 alkyl)-C(═O)—, (C1–C6 alkyl)-O—C(═O)— and (C1–C6 alkyl)-S(═O)2—;
- alternatively, —NR15R16 may be a heterocyclic ring selected from the group piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
- R17 is H, C1–C6 alkyl, or C2–C6 alkoxyalkyl, aryl substituted by 0–4 R17a, or
- aryl-CH2— wherein said aryl is substituted by 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, S(═O)2CH3, —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—;
- alternatively, —NR18R19 may be a heterocyclic ring selected from the group:
- piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, homopiperidinyl, piperazinyl, and N-methylpiperizinyl;
- wherein said heterocyclic ring is substituted with 0–3 R11b;
- 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—;
- R19b, at each occurrence, is independently selected from H and C1–C6 alkyl;
- R20 is H, OH, C1–C4 alkyl, phenyl, benzyl, or phenethyl;
- R21, at each occurrence, is independently selected from H, C1–C6 alkyl, phenyl, benzyl, and phenethyl;
- and
- R22, at each occurrence, is independently selected from H, C1–C6 alkyl, phenyl, benzyl, and phenethyl.
104 more elements
A compound of Formula (Ib) or pharmaceutically acceptable salt thereof:
- wherein:
- Ring B is selected from:
- Q1 is C1–C6 alkyl substituted with 0–3 R1a;
- C2–C6 alkenyl substituted with 0–3 R1a;
- C2–C6 alkenyl substituted with 0–3 R1a;
- C3–C10 cycloalkyl substituted with 0–3 R1b;
- C3–C10 carbocycle substituted with 0–3 R1b;
- aryl substituted with 0–3 R1b;
- 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 R1b;
- R1a, at each occurrence, is independently selected, from H, C1–C6 alkyl, OR14, Cl, F, Br, I, NR15R16, CF3;
- C3–C10 carbocycle substituted with 0–3 R1b;
- aryl substituted with 0–3 R1b;
- 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 R1b;
- R1b, 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, C1–C4 haloalkyl-S—, and (C1–C6 alkyl)-O—C(═O)—;
- R5 is OR14;
- C1–C6 alkyl substituted with 0–3 R5b;
- C2–C6 alkenyl substituted with 0–3 R5b;
- or
- C2–C6 alkenyl substituted with 0–3 R5b;
- R5a is H, methyl, ethyl, propyl, butyl, or C2–C4 alkenyl;
- alternatively, R5 and R5a may be combined to form a C4–C7 cycloalkyl ring;
- R5b, at each occurrence, is independently selected from:
- H, methyl, ethyl, propyl, butyl, CF3, OR14, Cl, F, Br, I, ═O, NR15R16,
- C3–C7 cycloalkyl substituted with 0–3 R5c;
- C3–C7 carbocycle substituted with 0–3 R5c;
- phenyl substituted with 0–3 R5c;
- 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 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–C2 haloalkyl, and C1–C2 haloalkoxy;
- W is —(CHR8)p—;
- p is 0 or 1;
- R8 is H, methyl, or ethyl;
- X is a bond;
- Y is a bond, —V—, —CH2—V—, —V—CH2—, or —CH2—V—CH2—;
- V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)2—, or —N(R19)—;
- Z is H, F, Cl, Br,
- C1–C4 alkyl substituted with 0–2 R12;
- C2–C4 alkenyl substituted with 0–2 R12;
- C2–C4 alkenyl substituted with 0–2 R12;
- aryl substituted with 0–4 R12b;
- C3–C6 carbocycle substituted with 0–4 R12b;
- 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 R12b;
- R10 is C(═O)R17, C(═O)NR18R19, S(═O)2R17;
- C1–C6 alkyl substituted with 0–2 R10a;
- phenyl substituted with 0–3 R10b;
- 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 optionally 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, or aryl substituted with 0–3 R10b;
- R10b, at each occurrence, is independently selected from H, OH, C1–C6 alkyl, C1–C4 alkoxy, 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—;
- R12 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, and C1–C4 haloalkyl-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, 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, at each occurrence, is independently selected from H, phenyl, benzyl, C1–C4 alkyl, and C2–C4 alkoxyalkyl;
- R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
- R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, CH3CH2C(═O)—, CH3C(═O)—, CH3CH2OC(═O)—, CH3OC(═O)—, CH3CH2S(═O)2— and CH3S(═O)2—;
- R17 is H, phenyl, benzyl, C1–C4 alkyl, or C2–C4 alkoxyalkyl;
- R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
- and
- R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, and butyl.
63 more elements
Dependencies are inferred from the claim text.