US 2011/0034483 A1 · 2-AMINOIMIDAZOLE BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE

Abstract

The present invention is directed to 2-aminoimidazole compounds of formula (I) which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.

A compound of formula (I)

wherein
R1 is —C1-6alkyl, wherein said alkyl is optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C1-6 alkyl,
(e) —C2-6 alkenyl,
(f) —C3-6 cycloalkyl,
(g) —NO2,
(h) —O—C1-6 alkyl,
(i) phenyl, and
R2 is hydrogen, or
R1 and R2 may be linked together to form a carbocyclic ring having from four to nine ring carbon atoms wherein one or more of the ring carbon atoms may be replaced with an oxygen, nitrogen or sulfur, wherein said carbocyclic ring is optionally substituted with one or more
(a) halogen,
(b)—C1-6 alkyl, or
(c) —OC1-6 alkyl;
R3 is selected from the group consisting of
(1) —C1-6 alkyl,
(2) —C1-6 alkenylene-C6-10 aryl,
(3) —(CH2)n—C6-10 aryl, or
(4) —(CH7)n heteroaryl, wherein said heteroaryl is an aromatic cyclic group having 5 to 12 ring atoms, at least one of which is O, N or S,
wherein said alkyl, alkenylene, aryl, or heteroaryl R2 moiety is optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —NO2,
(e) —C1-6 alkyl
(f) —C2-6 alkenyl
(g) —C3-6 cycloalkyl,
(h) —O—C1-6 alkyl,
(i) —O—CH2-aryl,
(j) —C6-10 aryl,
(k) heteroaryl, wherein said heteroaryl is an aromatic cyclic group having 5 to 12 ring atoms, at least one of which is O, N or S,
(l) —NR6AR6B,
(m) —NR6AC(═O)R6B,
(n) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen,
(o) —SO2C1-3 alkyl,
(p) —SO2NR6AR6B, and
(q) —CONR6AR6B,
wherein said alkyl, alkenyl, cycloalkyl, aryl and heteroaryl moiety is optionally substituted with one or more
(I) halo,
(II) —C1-6 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(III) —O—C1-6 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(IV) —NHSO2R9, or
(V) OH;
R4 is selected from the group consisting of:
(1) hydrogen, or
(2) —C1-6 alkyl,
wherein said alkyl is optionally substituted with one or more
(a) halogen
(b) hydroxyl,
(c) —C6-10 aryl,
(d) heteroaryl, wherein said heteroaryl is an aromatic cyclic group having 5 to 12 ring atoms, at least one of which is O, N or S,
(e) —OC1-4 alkyl, or
(f) —C(═O)OR9,
and wherein said alkyl, aryl or heteroaryl is optionally substituted with one or more
(I) hydroxy,
(II) fluoro,
(III) —C1-4 alkyl, optionally substituted by fluoro;
or
(IV) —OC1-4 alkyl;
R5 is selected from the group consisting of
(1) hydrogen,
(2) —C1-6 alkyl, or
(3) a heterocyclic group having 4 to 8 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen,
wherein said alkyl or heterocyclyl is optionally substituted with one or more
(a) halogen
(b) hydroxyl,
(c) —C6-10 aryl,
(d) heteroaryl, wherein said heteroaryl is an aromatic cyclic group having 5 to 12 ring atoms, at least one of which is O, N or S,
(e) a heterocyclic group having 4 to 8 ring atoms, wherein at least one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur and oxygen,
(f) —OC1-4 alkyl,
(g) —CN, or
(h) —C(═O)—OR9,
wherein said alkyl, aryl, heteroaryl or heterocyclic group is optionally substituted with one or more
(I) hydroxy,
(II) fluoro,
(III) —C1-4 alkyl, optionally substituted by fluoro,
(IV) —OC1-4 alkyl,
(V) —(CH2)n—C6-10 aryl,
(VI) heteroaryl, or
(VII) —C(═O)OR9;
R6A, R6B and R6C are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6alkyl,
(4) O—C1-6alkyl,
(5) —NO2,
(6) cyano
(7) OH
(8) —(CH2)maryl
(9) —NR7R8, wherein R7 and R8 are selected from the group consisting of
(I) hydrogen,
(II) —C1-6 alkyl,
(III) —C3-6 cycloalkyl,
or R7 and R8 are linked together with the nitrogen to which they are both attached to form a 2-6 membered carbocyclic ring, wherein one or two of the ring carbon atoms is replaced by a nitrogen, oxygen or sulfur,
wherein said R6A, R6B or R6C alkyl or aryl moiety is optionally substituted with one or more
(a) halo,
(b)—C1-6 alkyl,
(c) —O—C1-6 alkyl, and
(d)-aryl,
wherein said wherein said alky or aryl is optionally substituted with one or more halo;
R9 is selected from the group consisting of:
(1) hydrogen,
(2) C1-4alkyl, or
(3) —C3-8 cycloalkyl,
n is 1 or 1;
m is 0, 1, 2 or 3;
provided that when R2, R4 and R5 are each hydrogen, then R1 is not 4-methoxyphenyl and R3 is not (1-methoxy-4-nitrophenyl)methylene;
or a pharmaceutically acceptable salt thereof.

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2-aminoimidazole beta-secretase inhibitors for the treatment of alzheimer's disease

Life of this patent

2-aminoimidazole beta-secretase inhibitors for the treatment of alzheimer's disease

Life of this patent

Abstract

Claims18