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US 2006/0135762 A1Published application
Cyclic malonamides as inhibitors of Abeta protein protection
AssigneeBristol-Myers Squibb Pharma Company
InventorsRichard Olson, Michael Yang
Life of this patent
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Abstract
This invention relates to novel cyclic malonamides 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.
Claims23
A process of preparing a compound of Formula (I);
- or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
- L is —NR26C(═O)—, —C(—O)NR26—, —NR26C(═O)O—, —OC(═O)NR26, or —NR26C(═O)NR26—;
- R3 is —(CR7R7a)n—R4,
- —(CR7R7a)l—S—(CR7R7a)m—R4,
- —(CR7R7a)l—O—(CR7R7a)m—R4,
- —(CR7R7a)l—N(R7b)—(CR7R7a)m—R4,
- —(CR7R7a)l—S(═O)—(CR7R7a)m—R4,
- —(CR7R7a)l—S(═O)2—(CR7R7a)m—R4,
- —(CR7R7a)l—C(═O)—(CR7R7a)m—R4,
- —(CR7R7a)l—N(R7b)C(═O)—(CR7R7a)m—R4,
- —(CR7R7a)l—C(═O)N(R7b)—(CR7R7a)m—R4,
- —(CR7R7a)l—N(R7b)S(═O)2(CR7R7a)m—R4, or
- (CR7R7a)l—S(═O)2N(R7b)—(CR7R7a)m—R4;
- n is 0, 1, 2, or 3;
- m is 0, 1, 2, or 3;
- l is 1, 2, or 3;
- Ring C is a 3 to 8 membered carbocycle,
- wherein the carbocycle is saturated or partially saturated;
- optionally, the carbocycle contains a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, and
- —N(R20)—;
- and
- wherein the carbocycle is substituted with 0-4 R21;
- R4 is H, OH, OR14a,
- 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, NR15R16, CF3,
- 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—;
- 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 selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, C1-C4 alkyl, phenyl substituted with 0-5 R7c;
- R7a, at each occurrence, is independently selected from H, Cl, F, Br, I, CN, CF3, and C1-C4 alkyl;
- R7b is independently selected from H and C1-C4 alkyl;
- R7c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, CF3, C1-C4 alkoxy, and C1-C4 alkyl;
- B is a 5 to 10 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 an additional heteroatom selected from —O—, —S—, —S(═O)—,
- —S(═O)2—, —N═, —NH—, and —N(R10)—;
- R10 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 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 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, MR15R16, CF3, aryl substituted with 0-4 R10b;
- C3-C10 carbocycle substituted with 0-3 R10b, 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 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 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, 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 3 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—;
- additionally, two R1l 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 R13;
- additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R13;
- additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical;
- wherein said benzo fused radical is substituted with 0-4 R13;
- 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 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, 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 and 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 1-3 R12;
- C2-C4 alkenyl substituted with 1-3 R12;
- C2-C4 alkynyl substituted with 1-3 R12;
- C1-C8 alkyl substituted with 0-3 R12a;
- C2-C4 alkenyl substituted with 0-3 R12a;
- C2-C4 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;
- R12, at each occurrence, is independently selected from C6-C10 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;
- 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, and C1-C4 haloalkyl-S—;
- 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, X, CN, NO2, NR15R16, and CF3;
- R14 is H, phenyl substituted with 0-4 R14b, benzyl substituted with 0-4 R14b, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
- R14a is H, C6-C10 aryl, benzyl, heterocycle, or C1-C4 alkyl;
- R14b, at each occurrence, is independently selected from H, OR, 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—;
- R15, at each occurrence, is independently selected from H, C1-C6 alkyl, aryl-(C1-C6 alkyl)- wherein the aryl is substituted with 0-4 R15b, (C1-C6 alkyl)-C(═O)—, and (C1-C6 alkyl)-S(═O)2—;
- R15b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, 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—;
- 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, r, 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—;
- R20 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2R17;
- C1-C6 alkyl optionally substituted with 0-2 R20a;
- C6-C10 aryl substituted with 0-4 R20b;
- C3-C10 carbocycle substituted with 0-3 R20b;
- 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 R20b;
- R20a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, F, ═O, CN, NO2, NR15R16, CF3, aryl substituted with 0-4 R20b, and heterocycle substituted with 0-4 R20b;
- R20b, 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—;
- R21, 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 R21a;
- aryl substituted with 0-3 R21b;
- C3-C10 carbocycle substituted with 0-3 R21b;
- 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 R21b;
- R21a, 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 R21b;
- C3-C6 cycloalkyl substituted with 0-3 R21b;
- and
- 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 0-3 R21b;
- R21b, 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—;
- additionally, two R21 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 R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
- additionally, two R21 substituents on adjacent atoms may be combined to form a benzo fused radical;
- wherein said benzo fused radical is substituted with 0-4 R23;
- 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;
- R26 is H;
- C1-C6 alkyl substituted with 0-3 R26a;
- C3-C10 carbocycle substituted with 0-3 R26b;
- or
- C6-C10 aryl substituted with 0-3 R26b;
- R26a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, aryl and CF3;
- and
- R26b, 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.
167 more elements
A process of preparing a compound of Formula (I):
- or a stereoisomer, pharmaceutically acceptable salt, wherein:
- L is —NR26C(═O)—, —C(═O)NR26—, —NR26C(═O)O—, —OC(═O)NR26, or —NR26C(═O)NR26—;
- R3 is —(CR7R7a)n—R4,
- —(CR7R7a)l—S—R4,
- —(CR7R7a)l—O—R4;
- (CR7R7a)l—N(R7b)—R4,
- —(CR7R7a)l—S(═O)—R4, or
- —(CR7R7a)l—S(═O)2—R4,
- n is 0, 1 or 2;
- l is 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,
- C6-C10 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, NR15R16, CF3,
- 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—;
- Ring C is a 3-8 membered carbocycle;
- wherein said 3-8 membered carbocycle is saturated or partially unsaturated;
- wherein said 3-8 membered carbocycle is substituted with 0-4 R21;
- and
- optionally, the carbocycle contains a heteroatom selected from —O— and —N(R20)—;
- additionally, two R21 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 R21 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 R21 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
- R21, 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, phenyl, and a
- 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
- R6 is H, methyl, or ethyl;
- 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 or C1-C4 alkyl;
- Ring B is selected from:
- R10 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 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 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 0-4 R10b;
- R10b, 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—;
- 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;
- 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, 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)2OH3,
- C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,
- C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
- W is a bond or —(CH2)p—;
- p is 1 or 2;
- X is a bond;
- phenyl substituted with 0-2 RXb;
- C3-C6 carbocycle substituted with 0-2 RXb;
- or
- 5 to 6 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-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 halothioalkoxy;
- Y 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,
- 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, 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, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl;
- R19b, at each occurrence, is independently is H or C1-C4 alkyl;
- R20 is H, C1-C4 alkyl, or C(═O)OR17;
- 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;
- and
- R26 is H or C1-C4 alkyl.
106 more elements
A process of preparing a compound selected from:
- {[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carboxamide;
- {[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
- [(N-butylcarbamoyl)cyclopentyl]-N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carboxamide;
- 2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}acetamide;
- 2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}acetamide;
- 2-(3,5-difluorophenyl)-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopropyl}acetamide;
- 3-cyclopentyl-N-{[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclohexyl}propanamide;
- 2-(3,5-difluorophenyl)-N-{4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl](4-piperidyl)}acetamide;
- phenyl 4-[2-(3,5-difluorophenyl)acetylamino]-4-[N-(1-methyl-2-oxo-5-phenyl((S)-3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]piperidinecarboxylate;
- 4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
- N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}{[(phenylmethoxy)carbonylamino]cyclopentyl}carboxamide;
- (2S)-N-{[(N-(1-{[3-(4-fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopropyl}-2-hydroxy-4-methylpentanamide;
- (2S)-N-{[N-(1-{[3-(4-fluorophenoxy)phenyl]methyl}-2-oxoazaperhydroepin-3-yl)carbamoyl]cyclopentyl}-2-hydroxy-3-methylbutanamide;
- 2,2-difluoro-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-4-phenylbutanamide;
- N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-(4-piperidyl)propanamide;
- (2S)-2-hydroxy-4-methyl-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
- 3-cyclopropyl-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
- (2R)-2-hydroxy-3-imidazol-2-yl-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
- 2-ethoxy-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
- 3-cyclopentyl-N-[(N-{1-methyl-2-oxo-S-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
- (2S)-2-hydroxy-3-methyl-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]butanamide;
- (2S)-2-cyclohexyl-2-hydroxy-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
- (2R)-2-cyclohexyl-2-hydroxy-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]acetamide;
- (2S)-2-amino-4-methyl-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
- [(cyclohexylcarbonylamino)cyclopentyl]-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
- {[N-(3-methylbutyl)carbamoyl]cyclopentyl}-N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carboxamide;
- 4-methyl-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
- (2S)-2-hydroxy-4-methyl-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]pentanamide;
- 3-methoxy-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]propanamide;
- (2S)-2-hydroxy-N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-3-phenylpropanamide;
- N-[(N-{1-methyl-2-oxo-5-[4-(trifluoromethyl)phenyl](3H-benzo[f]1,4-diazepin-3-yl)}carbamoyl)cyclopentyl]-2-(phenylmethoxy)acetamide;
- (2S)-2-hydroxy-3-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}butanamide;
- (2S)-2-hydroxy-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo [d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
- 3-cyclopentyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}propanamide;
- (2S)-2-cyclohexyl-2-hydroxy-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}acetamide;
- 3-cyclopropyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}propanamide;
- N-{[N-(1-butyl-5-cyclopentyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
- N-{[N-(5-cyclopentyl-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
- (2S)-2-hydroxy-3-methyl-N-({N-[2-oxo-1-benzyl(3H,4H,5H-benzo[f]azaperhydroepin-3-yl)]carbamoyl}cyclopentyl)butanamide;
- (2S)-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-2-[(propylsulfonyl)amino]pentanamide;
- (2S)-2-amino-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
- 2,2-difluoro-4-methyl-N-{[N-(5-methyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
- 4-methyl-N-{[N-(6-oxo(5H,7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}pentanamide;
- N-{(N-[5-(3,3-dimethyl-2-oxobutyl)-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
- 4-methyl-N-[(N-{6-oxo-5-[(3-phenoxyphenyl)methyl](7H-dibenzo[d,f]azaperhydroepin-7-yl)}carbamoyl)cyclopentyl]pentanamide;
- N-{[N-(5-butyl-6-oxo(7H-dibenzo[d,f]azaperhydroepin-7-yl))carbamoyl]cyclopentyl}-4-methylpentanamide;
- 4-methyl-N-({N-[6-oxo-5-benzyl(7H-dibenzo[d,f]azaperhydroepin-7-yl)]carbamoyl}cyclopentyl)pentanamide;
- N-({N-[5-(tert-butyl)-1-methyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
- N-({N-[5-(tert-butyl)-1-butyl-2-oxo(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide;
- and
- N-({N-[5-butyl-2-oxo-1-(2-pyridylmethyl)(3H-benzo[f]1,4-diazepin-3-yl)]carbamoyl}cyclopentyl)-4-methylpentanamide.
48 more elements
(canceled)
-24. (canceled)
Dependencies are inferred from the claim text.