US 2004/0171614 A1 · Novel gamma secretase inhibitors

Abstract

This invention discloses novel gamma secretase inhibitors of the formula: 1 wherein: R1 is a substituted aryl or substituted heteroaryl group; R2 is an R1 group, alkyl, —XC(O)Y, alkylene-XC(O)Y, cycloalkylene-X-C(O)—Y, —CH—X—C(O)—NR3—Y or —CH—X—C(O)—Y, wherein X and Y are as defined herein; each R3 and each R3A are independently H, or alkyl; R11 is aryl, heteroaryl, alkyl, cycloalkyl, arylalkyl, arylcycloalkyl, heteroarylalkyl, heteroarylcycloalkyl, arylheterocycloalkyl, or alkoxyalkyl. Also disclosed is a method of treating Alzheimer's Disease using one or more compounds of the invention.

A compound of the formula

438
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
(A) R1 is selected from the group consisting of:
(1) unsubstituted aryl;
(2) aryl substituted with one or more R5 groups;
(3) unsubstituted heteroaryl;
and
(4) heteroaryl substituted with one or more R5 groups,
(B) R2 is selected from the group consisting of:
(1) alkyl;
(2) —XC(O)Y;
(3) —(C1-C6)alkylene-XC(O)Y;
(4) —(C0-C6)alkylene-(C3-C6)cycloalkylene-(C0-C6)alkylene-XC(O)Y;
(5) aryl;
(6) aryl substituted with one or more R5 groups;
(7) heteroaryl;
(8) heteroaryl substituted with one or more R5 groups;
(9) cycloalkylene-X-C(O)—Y;
(10) —CH2—X—C(O)—NR3—Y;
(11) —CH2—X—C(O)—Y;
and
(12) —CH2—X—C(O)—NR3—Y,
(C) Each R3 is independently selected from the group consisting of:
(1) H;
and
(2) alkyl,
(D) Each R3A and R3B is independently selected from the group consisting of:
(1) H;
and
(2) alkyl;
(E) R5 is independently selected from the group consisting of:
(1) halo;
(2) —CF3;
(3) —OH;
(4) —O-alkyl;
(5) —OCF3;
(6) —CN;
(7) —NH2;
(8) —C(O)2alkyl;
(9) —C(O)NR6R7;
(10) -alkylene-NR6R7;
(11) —NR6C(O)alkyl;
(12) —NR6C(O)aryl;
(13) —NR6C(O)heteroaryl;
and
(14) —NR6C(O)NR6R7;
(F) X is selected from the group consisting of:
(1) —O—;
(2) —NH—;
(3) —N-alkyl;
and
(4) —O-alkylene;
(G) Y is selected from the group consisting of:
(1) —NR6R7;
(2) —N(R3)(CH2)bNR6R7 wherein b is 2-6;
(3) unsubstituted aryl;
(4) unsubstituted heteroaryl;
(5) -alkyl;
(6) -cycloalkyl,
(7) unsubstituted arylalkyl;
(8) unsubstituted arylcycloalkyl;
(9) unsubstituted heteroarylalkyl;
(10) unsubstituted heteroarylcycloalkyl;
(11) unsubstituted arylheterocycloalkyl;
(12) substituted aryl;
(13) substituted heteroaryl;
(14) substituted arylalkyl;
(15) substituted arylcycloalkyl;
(16) substituted heteroarylalkyl;
(17) substituted heteroarylcycloalkyl;
and
(18) substituted arylheterocycloalkyl;
(19) substituted heterocycloalkyl alkyl;
(20) unsubstituted heteroaryl alkyl;
(21) unsubstituted aryl alkyl heterocycloalkyl;
(22) unsubstituted heterocycloalkyl;
and
(23) unsubstituted cycloalkyl,
wherein the aryl moiety in said substituted groups (12), (14), (15), (18), and (21) of said Y group, and the heteroaryl moiety in said substituted groups (13), (16), (17) and (20) of said Y group, are substituted with one or more substituents independently selected from the group consisting of:
(a) halo;
(b) —CF3;
(c) —OH;
(d) —O-alkyl;
(e) —OCF3;
(f) —CN;
(g) —NH2;
(h) —C(O)2(C1-C6)alkyl;
(i) —C(O)NR6R7;
(j) —(C1-C6)alkylene-NR6R7;
(k) —NR6C(O)alkyl;
(l) —NR6C(O)aryl;
(m) —NR6C(O)heteroaryl;
(n) —NR6C(O)NR6R7;
and
(o) alkyl,
or Y is selected from the group consisting of:
439
(H) R6 and R7 are independently selected from the group consisting of:
(1) H;
(2) alkyl;
(3) cycloalkyl;
(4) arylalkyl;
(5) heteroarylalkyl;
(6)
(7)
440
(8) heterocycloalkyl,
(I) Each R8 is independently selected from the group consisting of:
(1) alkyl;
(2) alkyl substituted with 1 to 4 hydroxy groups;
and
(3) —OH,
(J) Each R9 is independently selected from the group consisting of:
(1) H;
(2) alkyl;
(3) alkyl substituted with 1 to 4 hydroxy groups;
(4) cycloalkyl;
(5) cycloalkyl substituted with 1 to 4 hydroxy groups;
(6) arylalkyl;
(7) heteroarylalkyl;
(8) —C(O)O-alkyl;
(9) alkylene-O-alkylene-OH;
(10) aryl substituted with one or more R5 groups;
(11) heteroaryl substituted with one or more R5 groups;
(12) unsubstituted heteroaryl;
(13) unsubstituted aryl;
(14) -alkylene-C(O)O-alkyl;
and
(15) hydroxyalkyl-O-alkyl,
(K) Each R10 is independently selected from the group consisting of:
(1) H;
and
(2) alkyl,
(L) R11 is selected from the group consisting of:
(1) unsubstituted aryl;
(2) substituted aryl;
(3) unsubstituted heteroaryl,
(4) alkyl;
(5) cycloalkyl;
(6) unsubstituted arylalkyl;
(7) unsubstituted arylcycloalkyl,
(8) unsubstituted heteroarylalkyl;
(9) unsubstituted heteroarylcycloalkyl;
(10) unsubstituted arylheterocycloalkyl;
(11) alkoxyalkyl;
(12) substituted heteroaryl;
(13) substituted arylalkyl;
(14) substituted arylcycloalkyl;
(15) substituted heteroarylalkyl;
and
(16) substituted arylheterocycloalkyl,
wherein the aryl moiety in said substituted groups (2), (13), (14) and (16) of said R11 group, and the heteroaryl moiety in said substituted groups (12) and (15) of said R11 group, are substituted with one or more substituents independently selected from the group consisting of:
(a) halo;
(b) —CF3;
(c) —OH;
(d) —O-alkyl;
(e) —OCF3;
(f) —CN;
(g) —NH2;
(h) —C(O)2(C1-C6)alkyl;
(i) —C(O)NR6R7;
(j) —(C1-C6)alkylene-NR6R7;
(k) —NR6C(O)alkyl;
(l) —NR6C(O)aryl;
(m) —NR6C(O)heteroaryl;
and
(n) —NR6C(O)NR6R7;
(M) (1) m is 0 to 3, and if m is greater than 1, m moieties can be the same or different from one another;
(2) n is 0 to 3, and if n is greater than 1, n moieties can be the same or different from one another;
(3) o is 0 to 3, and if o is greater than 1, o moieties can be the same or different from one another;
such that m+n+o is 1, 2, 3 or 4,
(N) p is 0 to 4, and if greater than 1, p moieties can be the same or different from one another;
(O) r is 0 to 4, and if greater than 1, r moieties can be the same or different from one another;
(P) s is 0 to 3, and if greater than 1, s moieties can be the same or different from one another;
and
(Q) Z is selected from the group consisting of:
(1) unsubstituted heterocycloalkyl;
(2) substituted heterocycloalkyl;
(3) —NH2;
(4) —NH(alkyl);
(5) —N(alkyl)2 wherein each alkyl is the same or different;
(6) —NH(unsubstituted cycloalkyl);
(7) —NH(substituted cycloalkyl);
(8) —N(alkyl)(unsubstituted cycloalkyl);
(9) —N(alkyl)(substituted cycloalkyl);
(10) —NH(unsubstituted aralkyl);
(11) —NH(substituted aralkyl);
(12) —N(alkyl)(aralkyl);
(13) —NH(unsubstituted heterocycloalkyl);
(14) —NH(substituted heterocycloalkyl);
(15) —N(alkyl)(unsubstituted heterocycloalkyl),
(16) —N(alkyl)(substituted heterocycloalkyl);
(17) —NH(unsubstituted heteroaralkyl);
(18) —NH(substituted heteroaralkyl);
(19) —NH-alkylene-(unsubstituted cycloalkyl);
(20) —NH-alkylene-(substituted cycloalkyl);
(21) —N(alkyl)alkylene-(unsubstituted cycloalkyl);
(22) —N(alkyl)alkylene-(substituted cycloalkyl);
(23) —NHalkylene-(unsubstituted heterocycloalkyl);
(24) —NHalkylene-(substituted heterocycloalkyl);
(25) —N(alkyl)alkylene-(unsubstituted heterocycloalkyl);
(26) —N(alkyl)alkylene-(substituted heterocycloalkyl);
(27) unsubstituted benzofused heterocycloalkyl;
and
(28) substituted benzofused heterocycloalkyl;
(29) H;
and
(30) —N(hydroxyalkyl)2, wherein each alkyl may be the same or different,
wherein said substituted heterocycloalkyl moiety of substituents (2), (14), (16), (24), (26) and (27) of group Z, and said substituted cycloalkyl moiety of substituents (7), (9), (20) and (22) of group Z, and said substituted aryl moiety of substituent (11) of group Z, and said substituted heteroaryl moiety of substituent (18) of group Z, are substituted with 1 to 3 groups independently selected from the group consisting of:
(a) alkyl;
(b) —OH;
(c) —Oalkyl;
(d) —OC(O)alkyl;
(e) —OC(O)aryl;
(f) —NH2;
(g) —NH(alkyl);
(h) —N(alkyl)2 wherein each alkyl is the same or different;
(i) —NHC(O)alkyl;
(j) —N(alkyl)C(O)alkyl;
(k) —NHC(O)aryl;
(l) —N(alkyl)C(O)aryl;
(m) —C(O)alkyl;
(n) —C(O)aryl;
(o) —C(O)NH2;
(p) —C(O)NH(alkyl);
(q) —C(O)N(alkyl)2 wherein each alkyl is the same or different;
(r) —C(O)2alkyl;
(s) -alkylene-C(O)Oalkyl;
(t) piperidinyl;
(u) pyrrolidinyl;
(v) 1,1-ethylenedioxy;
(w) aryl;
(x) heteroaryl;
and
(y) —O—CH2CH2—O-wherein both oxygen atoms are bound to the same carbon atom, and provided that the aryl and heteroaryl moieties of said Z group are not substituted with said —O—CH2CH2—O-group.

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Novel gamma secretase inhibitors

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Novel gamma secretase inhibitors

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Abstract

Claims31