US 2002/0055501 A1 · Succinoylamino carbocycles and heterocycles as inhibitors of a-beta protein production

Abstract

This invention relates to novel carbocycles and heterocycles having drug and bio-affecting properties, their pharmaceutical compositions and 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.

A compound of Formula (I):

198
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is —OR1 or -NR1R2;
ring B is selected from the group consisting of:
a carbocyclic group of 3 to 8 carbon atoms wherein the carbocyclic group is saturated, partially saturated or unsaturated;
a heterocycle of 3 to 8 atoms containing a heteroatom selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—,and —N(R10)—;
a bicyclic ring system selected from the group consisting of:
199
a tricyclic ring system selected from the group consisting of:
200
and
a tetracyclic ring system selected from the group consisting of:
201
s is 0, 1, 2, 3, 4, 5, or 6;
R1, at each occurrence, is independently selected from:
H;
C1-C6 alkyl substituted with 0-3 R1a;
C2-C6 alkenyl substituted with 0-3 R1a;
C3-C10 carbocycle substituted with 0-3 R1b;
C6-C10 aryl substituted with 0-3 R1b;
and
5 to 10 membered heterocycle substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3;
C3-C10 carbocycle substituted with 0-3 RIb;
C6-CI0 aryl substituted with 0-3 RIb;
and
5 to 6 membered heterocycle substituted with 0-3 R1b;
R1b, 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;
R2 is independently selected from H, NH2, OH, C1-C6 alkyl, C1-C6 alkoxy, phenoxy, benzyloxy, C3-C10 carbocycle, C6-C10 aryl and 5 to 10 membered heterocycle;
R3 is —(CR7R7a)n—R4,
—(CR7R7a)n—S—(CR7R7a)m—R4,
—(CR7R7a)n—O—(CR7R7a)m—R4,
—(CR7R7a)n—N(R7b)—(CR7R7a)m—R4,
—(CR7R7a)n—S(═O)—(CR7R7a)m—R4,
—(CR7R7a)n—S(═O)2—(CR7R7a)m—R4,
—(CR7R7a)n—C(═O)—(CR7R7a)m—R4,
—(CR7R7a)n—N(R7b)C(═O)—(CR7R7a)m—R4,
—(CR7R7a )n—C(═O)N(R7b)—(CR7R7a)m—R4,
—(CR7(CR7R7a )n—N(R7b)S(═O)2—(CR7R7a)m—R4, or
—(CR7R7a)n—S(═O)2N(R7b)—(CR7R7a)m—R4;
n is0, 1,2, or 3;
m is 0, 1, 2, or 3;
R3a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyloxy;
alternatively, R3 and R3a may be combined to form a 3-7 membered carbocyclic moiety;
wherein said 3-7 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-7 membered carbocyclic moiety may optionally contain a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)2—, —N=, —NH—, and —N(R20)—, and
wherein said 3-7 membered carbocyclic moiety is substituted with 0-4 R4;
additionally, two R4 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 R4 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 R4 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R4 is H, OH, OR14a,
C1-C6 alkyl substituted with 0-3 R4a,
C2-C6 alkenyl substituted with 0-3 R4a,
C2-C6 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 substituted with 0-3 R4b;
R4a, at each occurrence, is independently selected from is H, F, Cl, Br, I, CF3,
C3-C10 carbocycle substituted with 0-3 R4b,
C6-C10 aryl substituted with 0-3 R4b, or
5 to 10 membered heterocycle 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 halothioalkoxy;
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 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c;
or
5 to 10 membered heterocycle substituted with 0-3R5c;
R5a is H, OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, or C2-C4 alkenyloxy;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c;
or
5 to 10 membered heterocycle 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 halothioalkoxy;
alternatively, R5 and R5a may be combined to form a 3-7 membered carbocyclic ring substituted with 0-3 R5c;
optionally the carbocyclic ring formed by combining R5 and R5a may be benzo fused, wherein the benzo fused ring may be substituted with 0-3 R5c;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b;
or
C6-C10 aryl substituted with 0-3R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, phenyl or 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, and C1-C4 alkyl;
R7a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, aryl and C1-C4 alkyl;
R7b is independently selected from H and C1-C4 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, Cl, —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 is0, 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—, —NR19bS(═O)—, —S(═O)NR19b—, —C(═O)O—, or —OC(═O)—;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C4 alkenyl substituted with 0-3 R12a;
C2-C4 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12a;
C3-C10 carbocycle substituted with 0-4 R12a;
or
5 to 10 membered heterocycle substituted with 0-3 R12a;
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—,
C1-C3 alkyl substituted with 0-1 R12c;
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—;
R12c, at each occurrence, is independently selected from
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;
R10 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, S(═O)2RI7;
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 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, NR15RI6, CF3, or aryl substituted with 0-4 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 halothioalkoxy;
alternatively, R10 may be —W—X—Y—Z;
R11, at each occurrence, is independently selected from
H, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR18R19, C(═O)R17, C(═O)OR17, C(═O)NR18R19, S(═O)2NR18R19, CF3;
C1-C6 alkyl 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 substituted with 0-3 R11b;
alternatively, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle or a benzo fused radical;
wherein said benzo fused radical is substituted with 0-4 R13;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or phenyl 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 halothioalkoxy;
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, or C2-C6 alkoxyalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(CI-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
R17 is H, aryl, aryl-CH2—, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
and
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C1-C6 alkyl) and —S(═O)2—(C1-C6 alkyl);
and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl;
additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 7 membered heterocyclic ring;
R20 is H, C(═O)R17, C(═O)OR17, C(═O)NR18R19,
S(═O)2NR18R19, S(═O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R20a;
or
C6-C10 aryl substituted with 0-4 R20b;
R20a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, ═O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R20b;
R20b, 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-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-S—;
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.

166 more elements

Succinoylamino carbocycles and heterocycles as inhibitors of a-beta protein production

Life of this patent

Succinoylamino carbocycles and heterocycles as inhibitors of a-beta protein production

Life of this patent

Abstract

Claims13