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US 6,960,576 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.
Claims54
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 alkynyl substituted with 0-3 R1a;
- C3-C10 cycloalkyl substituted with 0-3 R1b;
- C3-C10 carbocycle substituted with 0-3 R1b;
- C6-C10 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;
- 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 alkynyl 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 0-3R5c;
- 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 alkynyl, 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 alkynyl 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 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, 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 alkynyl 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
- R11 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 substituted with 0-1 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-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;
- 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, C1-C4 haloalkyl-S—, benzyl, benzoyl, C(═O)CH3, t-butoxycarbonyl, and 3,5-dimethyl-isoxazole-S(═O)2—;
- 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 piperidinyl, 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.
105 more elements
A compound or a pharmaceutically acceptable salt form thereof selected from:
- 2-(R)-cyclopropylmethyl-3-(S)-hydroxylheptanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl) amide;
- 2(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3-(S)-hydroxypentanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl)amide;
- 4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxybutanoic acid (2-oxo-1-(3-phenoxybenzyl)azapan-3-(S)-yl) amide;
- 2-(R)-cyclopropylmethyl-3-(S)-hydroxyheptanioc acid (1-(5-bromo-3-pyridinyl)methyl-2-oxo-azapan-3-(S)-yl) amide;
- 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-methyl-5H, 7H-dibenzo[b,d]azepin-6-one;
- 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino-5-methyl-5H, 7H-dibenzo[b,d]azepin-6-one;
- 3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino-5-methyl-5H, 7H-dibenzo[b,d]azepin-6-one;
- 3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-5-methyl-5H, 7H-dibenzo[b,d]azepin-6-one;
- and
- 2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-heptanoic acid (2-oxo-1-(3-phenylamino-benzyl)azapan-3-(S)-yl) amide.
7 more elements
A compound of Formula (Ib)
- or a pharmaceutically acceptable salt form thereof
- wherein:
- Ring B is
- Q1 is C1-C6 alkyl substituted with 0-3 R1a;
- C2-C6 alkenyl substituted with 0-3 R1a;
- C2-C6 alkynyl 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 alkynyl 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 a bond;
- X is a bond;
- Y is a bond;
- Z is H,
- C1-C4 alkyl substituted with 0-2 R12;
- C2-C4 alkenyl substituted with 0-2 R12;
- C2-C4 alkynyl 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;
- R11 is selected from
- H, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
- C1-C6 alkyl substituted with 0-1 R11a;
- phenyl substituted with 0-3 R11b;
- C3-C6 carbocycle substituted with 0-3 R11b;
- or
- 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;
- wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
- R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, ═O, NR15R16, CF3;
- phenyl substituted with 0-3 R11b;
- C3-C6 carbocycle substituted with 0-3 R11b;
- or
- 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;
- wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
- R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(═O)CH3, S(═O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
- 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.
69 more elements
A compound, according to claim 26, of Formula (If);
- or a pharmaceutically acceptable salt form thereof.
Dependencies are inferred from the claim text.