US 2003/0166636 A1Published application

Hydroxyalkanoylaminolactams and related structures as inhibitors of A-beta 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): 1 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.

Claims45

Dependent claims

A compound of the formula (I):

62
or a pharmaceutically acceptable salt form or prodrug thereof, wherein:
Q is Q1,
(C1-C3 alkyl) —O-Q1,
(C1-C3 alkyl)-S-Q1,
(C1-C3 alkyl)-S(═O)-Q1,
(C1-C3 alkyl)-S(═O)2-Q1, or
(C1-C3 alkyl)-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;
C6-C10 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 alkynyl substituted with 0-3 R5b;
C3-C10 cycloalkyl substituted with 0-3 R5c;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 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;
C6-C10 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;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 cycloalkyl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb;
or 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 alkynyl substituted with 0-2 R12;
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;
Ring B is a 6, 7, or 8 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 a heteroatom selected from —N═, —N+(—O−)═, —NH—, —N(R10)—, —O—, —S—, —S(═O)—, and —S(═O)2—;
additionally, two R11 substituents on adjacent atoms may be combined to form C3-C6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical,
wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, O, and S;
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;
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 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—;
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 substituted with 0-1 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-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.

125 more elements

A compound of selected from:

3-(2 (R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-(4-fluoro-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Benzyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Isopropyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-(3,5-difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-(3,5-difluorophenoxy)butyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-(4-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Methyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Methyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenoxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Benzyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Cyclopentylmethyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isopropyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Methoxy-3(S)-hydroxyl-1-oxo-4-(4-trifluoromethylbenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-4-(2,4-difluorobenzyloxy)butyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Vinyl-3(S)-hydroxyl-1-oxo-4-benzyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Methyl-3(S)-hydroxyl-1-oxo-4-cyclohexyloxybutyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-3-cyclopropylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(R)-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-nonyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Isobutyl-3(S)-hydroxyl-1-oxo-4-phenylbutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Methyl-3(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Methyl-3 (S)-hydroxyl-1-oxo-6-phenylhexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-butyl)amino-1-methyl 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Isobutyl-3(S)-hydroxyl-1-oxo-octyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Methyl-3(S)-hydroxyl-1-oxo-heptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-3-phenylpropyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-5,5-dimethyl-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2(R)-Methyl-3(S)-hydroxyl-1-oxo-hexyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2 (R)-Methyl-3(S)-hydroxyl-1-oxo-3-(4-propoxyphenyl)propyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
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-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(azapan-1-yl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3(S)-hydroxyl -1-oxopentyl)amino-1-methyl-5-(pyridn-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-methoxyphenyl)1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-methoxyphenyl)-1-methyl-2,3-dihydro -1H-1,4-benxodiazepin-2-one;
3-(S)-(4-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl -1-oxobutyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6-enyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxohept-6-enyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-dimethylisoxazol-4-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-(pyridin-2-yl)-2,3-dihydro-1H-1,4 benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifouoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5-(thiophen-2-yl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)3—(S)-hydroxyl -1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro -1H-1,4-benzodiazepin-2-one;
3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-cyclopropylmethyl-5-(3,5-difluorophenyl)-3-(S)-hydroxy-1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(3-(S)-hydroxyl-2-(R)-(thiophen-2-yl)methyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-7-methoxy-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-(3,5-difluorobenzyl)-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydor-1H-1,4-benzodiaxepin-2-one;
3-(S)-(2-(R)— (furan-2-yl)methyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxl-1-oxo-5-pheylpentyl)amino-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-benzodiazepin -2-one;
3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-iso-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxo-5-phenylpentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-5-(furan-2-yl)-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxooctyl)amino -1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxononyl)amino -1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl(pyridin-2-yl))-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclobutylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino -1-methyl-5-(40trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopentylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridiyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-methyl-2-pyridyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxobutyl)amino -1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-(3-butenyl)-3-(S)-hydroxyl-1-oxoheptyl)amino -1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-(3-methylbutyl)3—(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-ethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-propyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1,4-benzodiazepin-2-one;
3-(S)-(2-(R)-butyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(4-(S)-amino-3-(R)-hydroxyl-2-(R)-methyl-1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl -2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(4-(S)-(tert-butoxycarbonylamino-3-(R)-hydroxyl-2-(R)-methyl -1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(3-(tert-butoxycarbonylpyrrolidin-2-(R)-yl)-3-(R)-hydroxyl -2-(R)-methyl-1-oxopropyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(3-(R)-hydroxyl-2-(R)-methyl-1-oxo-3-(pyrrolidin-2-(R)-yl)propyl)-amino -7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(4-benzyloxy-3-(R)-hydroxyl-2-(R)-iso-propyl-1-oxobutyl-amino -7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
2-(4-(S)-amino-3-(S)-hydroxyl-2-(S)-methyl-1-oxo-5-phenylpentyl) amino-7-chloro-5-(2-flourophenyl)-1-methyl -2,3-dihydro-1H-1,4-benzodiazepin-2-one;
2-(4-(S)-(tert-butoxycarbonylamino-3-(S)hydroxyl-2-(S)-methyl -1-oxo-5-phenylpentyl)amino-7-chloro-5-(2-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl) amino-1-methyl-5-(thiazol-2-yl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-cyclopropylmethyl-5-(thiazol-2-yl)-2,3-dihydro-1H-1,4benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-cyclopropylmethyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-phenoxybenzyl)-5-(4-trifluoromethyl-phenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethyl)-5-(4-trifluoromethyl-phenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(S)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(R)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-3-(S)-methyl-1-oxoheptyl)amino-1-methyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-phenoxybenzyl)-5-methyl-2,3-dihydro -1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmehtyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(3-(S)-acetoxy-2-(R)-iso-butyl-1-oxoheptyl)amino-5-(4-fluorophenyl)-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(S)-(5-cyclopentyl-2-(R)-cyclopropylmethyl-3-(S)-methoxy -1-oxopentyl)amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
1-(1-hydroxypentyl)cyclohexanecarboxylic acid(5-(4-fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-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;
2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-heptanoic acid (2-oxo-1-(3-phenylamino-benzyl)azapan-3-(S)-yl) amide;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-cyclopentyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-benzyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-benzyl-1-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-5-cycloheptyl-1-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cycloropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino -1-benzyl-5-cycloheptyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-butyl-5-cycloheptyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-pyridinylmethyl)-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(3-pyridinylmethyl)-5-(2-fluorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(S)-cyclopropylmethyl-3-(S)-hydroxyl-1-oxopentyl)amino-1-(3-pyridinylmethyl)-5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-1(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-(N,N-dibutylamino)-2,3-dihydro -1H-1,4-benzodiazepin-2-one;
3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-n-butyl-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-oxo-3,3-dimethylbutyl)-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-benzyl-5-t-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-Cyclopropylmethyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-(2-picolyl)-5-n-butyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-Isobutyl-3-(S)-hydroxyl-1-oxoheptyl)amino-1-methyl-5-homopiperidino-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
3-(2-(R)-cyclopropylmethyl-1,3-dioxoheptyl)amino-1-methyl -5-(4-trifluoromethylphenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one;
and
1-pentyrylcyclohexanecarboxylic acid (5-(4-fluorophenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl) amide.

130 more elements

A compound of Formula (Ib)

81
wherein:
Ring B is selected from:
82
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;
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;
C6-C10 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 —(CHR8)p—;
p is 0 or 1;
R8 is H, methyl, or ethyl;
X is a bond;
phenyl substituted with 0-2 RXb;
C5-C6 cycloalkyl substituted with 0-3 RXb;
or
5 to 6 membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is 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, —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 alkynyl substituted with 0-2 R12;
C6-C10 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, at each occurrence, is independently selected from
H, ═O, 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—;
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-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.

79 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/287,117Filed 4 Nov 2002
Priority: 13 Sep 2000
Published: 4 Sep 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 223/18
Condensed with carbocyclic rings or ring systems: dibenzazepines; Hydrogenated dibenzazepines
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
C07D 223/10
Oxygen atoms: attached in position 2

Family

Application09/661,008Continuation in part · filed 13 Sep 2000
Application09/805,645Division · filed 14 Mar 2001
Application10/287,117Division · filed 4 Nov 2002
Application10/287,117Continuation in part · filed 4 Nov 2002
US 2002/0052360 A1Published application
US 6,503,902 B2Related patent
US 6,960,576 B2Related patent
US 2003/0166636 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula (I):

62
or a pharmaceutically acceptable salt form or prodrug thereof, wherein:
Q is Q1,
(C1-C3 alkyl) —O-Q1,
(C1-C3 alkyl)-S-Q1,
(C1-C3 alkyl)-S(═O)-Q1,
(C1-C3 alkyl)-S(═O)2-Q1, or
(C1-C3 alkyl)-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;
C6-C10 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 alkynyl substituted with 0-3 R5b;
C3-C10 cycloalkyl substituted with 0-3 R5c;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 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;
C6-C10 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;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 cycloalkyl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb;
or 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 alkynyl substituted with 0-2 R12;
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;
Ring B is a 6, 7, or 8 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 a heteroatom selected from —N═, —N+(—O−)═, —NH—, —N(R10)—, —O—, —S—, —S(═O)—, and —S(═O)2—;
additionally, two R11 substituents on adjacent atoms may be combined to form C3-C6 carbocycle fused radical, a benzo fused radical, or a 5 to 6 membered heteroaryl fused radical,
wherein said 5 to 6 membered heteroaryl fused radical comprises 1-2 heteroatoms selected from N, O, and S;
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;
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 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—;
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 substituted with 0-1 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-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.

125 more elements

Facts

Application

10/287,117Filed 4 Nov 2002

Priority

13 Sep 2000

Published

4 Sep 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 223/18
Condensed with carbocyclic rings or ring systems: dibenzazepines; Hydrogenated dibenzazepines
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
C07D 223/10
Oxygen atoms: attached in position 2

Family

Application09/661,008Continuation in part · filed 13 Sep 2000

Application09/805,645Division · filed 14 Mar 2001

Application10/287,117Division · filed 4 Nov 2002

Application10/287,117Continuation in part · filed 4 Nov 2002

US 2002/0052360 A1Published application

US 6,503,902 B2Related patent

US 6,960,576 B2Related patent

US 2003/0166636 A1This patent

From the US filing history. Foreign family members aren’t listed.