IP Library › Granted Patent US 7,256,186

Granted Patent B2

US 7,256,186 · App. 10/941,440 · Granted Aug 14, 2007

Gamma secretase inhibitors

Assignee: Schering Corporation

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Quick Facts

Patent No.: US 7,256,186
App. No.: 10/941,440
Granted: Aug 14, 2007
Kind: B2

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Abstract

This invention discloses novel gamma secretase inhibitors of the formula: wherein: R 1 is a substituted aryl or substituted heteroaryl group; R 2 is an R 1 group, alkyl, —XC(O)Y, alkylene-XC(O)Y, cycloalkylene-X—C(O)—Y, —CH—X—C(O)—NR 3 —Y or —CH—X—C(O)—Y, wherein X and Y are as defined herein; each R 3 and each R 3A are independently H, or alkyl; R 11 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.

Claims (694)

1. A compound of the formula

or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:

(A) R 1 is selected from the group consisting of:

(1) unsubstituted aryl;

(2) aryl substituted with one or more R 5 groups;

(B) R 2 is selected from the group consisting of:

(1) alkyl;

(2) —XC(O)Y;

(3) —(C 1 –C 6 )alkylene-XC(O)Y;

(4) —(C 0 –C 6 )alkylene-(C 3 –C 6 )cycloalkylene-(C 0 –C 6 )alkylene-XC(O)Y;

(5) aryl;

(6) aryl substituted with one or more R 5 groups;

(7) heteroaryl;

(8) heteroaryl substituted with one or more R 5 groups;

(9) cycloalkylene-X—C(O)—Y;

(10) —CH 2 —X—C(O)—NR 3 —Y;

(11) —CH 2 —X—C(O)—Y; and

(12) —CH 2 —X—C(O)—NR 3 —Y,

(1) H;

(2) alkyl;

(3) —OH;

(4) —O—alkyl;

(5) Acyl;

(6) Aroyl;

(7) the moiety (R 3 ) 2 , together with the ring carbon atom to which it is shown attached in formula I, defines a carbonyl group, —C(O)—, with the proviso that when m is an integer greater than 1, at most one carbonyl group is present in the ring shown in formula I;

(8) halo,

(D) Each R 3A and R 3B is independently selected from the group consisting of:

(1) H; and

(2) alkyl;

(E) R 5 is independently selected from the group consisting of:

(1) halo;

(2) —CF 3 ;

(3) —OH;

(4) —O-alkyl;

(5) —OCF 3 ;

(6) —CN;

(7) —NH 2 ;

(8) —C(O) 2 alkyl;

(9) —C(O)NR 6 R 7 ;

(10) -alkylene-NR 6 R 7 ;

(11) —NR 6 C(O)alkyl;

(12) —NR 6 C(O)aryl;

(13) —NR 6 C(O)heteroaryl; and

(14) —NR 6 C(O)NR 6 R 7 ;

(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) —NR 6 R 7 ;

(2) —N(R 3 ) (CH 2 ) b NR 6 R 7 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) —CF 3 ;

(d) —O-alkyl;

(e) —OCF 3 ;

(f) —CN;

(g) —NH 2 ;

(h) —C(O) 2 (C 1 –C 6 )alkyl;

(i) —C(O)NR 6 R 7 ;

(j) —(C 1 –C 6 )alkylene-NR 6 R 7 ;

(k) —NR 6 C(O)alkyl;

(l) —NR 6 C(O)aryl;

(m) —NR 6 C(O)heteroaryl;

(n) —NR 6 C(O)NR 6 R 7 ; and

(o) alkyl,

or Y is selected from the group consisting of:

(H) R 6 and R 7 are independently selected from the group consisting of:

(1) H;

(2) alkyl;

(3) alkyl substituted with 1 to 4 hydroxy groups, with the proviso that one of the hydroxy groups are bonded to a carbon to which a nitrogen is also bonded;

(4) cycloalkyl;

(5) arylalkyl;

(6) heteroarylalkyl;

(7)

(8)

(9) heterocycloalkyl,

(I) Each R 8 is independently selected from the group consisting of:

(1) H;

(2) alkyl;

(3) alkyl substituted with 1 to 4 hydroxy groups;

(4) aryl;

(5) —OH;

(6) —O-alkyl;

(7) —C(O)O-alkyl;

(8) if r is greater than 1, at least two R 8 groups, together with the ring carbon atom or atoms to which they are attached define a ring, wherein one or more carbon atoms of said ring may be replaced independently of each other by —O— or —C(O)O—, and said ring may be substituted with 1 to 4 hydroxy groups,

(J) Each R 9 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 R 5 groups;

(11) heteroaryl substituted with one or more R 5 groups;

(12) unsubstituted heteroaryl;

(13) unsubstituted aryl;

(14) -alkylene-C(O)O-alkyl; and

(15) hydroxyalkyl-O-alkyl,

(K) Each R 10 is independently selected from the group consisting of:

(1) H; and

(2) alkyl,

(L) R 11 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 R 11 group, and the heteroaryl moiety in said substituted groups (12) and (15) of said R 11 group, are substituted with one or more substituents independently selected from the group consisting of:

(a) halo;

(b) —CF 3 ;

(d) —O-alkyl;

(e) —OCF 3 ;

(f) —CN;

(g) —NH 2 ;

(h) —C(O) 2 (C 1 –C 6 )alkyl;

(i) —C(O)NR 6 R 7 ;

(j) —(C 1 –C 6 )alkylene-NR 6 R 7 ;

(k) —NR 6 C(O)alkyl;

(l) —NR 6 C(O)aryl;

(m) —NR 6 C(O)heteroaryl; and

(n) —NR 6 C(O)NR 6 R 7 ;

(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) —NH 2 ;

(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;

(d) —OC(O)alkyl;

(e) —OC(O)aryl;

(f) —NH 2 ;

(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)NH 2 ;

(p) —C(O)NH(alkyl);

(q) —C(O)N(alkyl) 2 wherein each alkyl is the same or different;

(r) —C(O) 2 alkyl;

(s) -alkylene-C(O)Oalkyl;

(t) piperidinyl;

(u) pyrrolidinyl;

(v) 1,1-ethylenedioxy;

(w) aryl;

(x) heteroaryl; and

(y) —O—CH 2 CH 2 —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—CH 2 CH 2 —O— group.

2. The compound of claim 1 wherein:

(A) R 1 is aryl substituted with one or more R 5 groups;

(B) n is 0 or 1 and m is 1, 2 or 3 such that m+n is 3;

(D) R 2 is —XC(O)Y, —(C 1 –C 6 )alkylene-XC(O)Y or —(C 0 –C 6 )alkylene-(C 3–C 6 )cycloalkylene-(C 0 –C 6 )alkylene-XC(O)Y.

3. The compound of claim 2 wherein:

(A) R 1 is phenyl substituted with one or more R 5 groups; and

(B) n is 0 and m is 3.

4. The compound of claim 1 , wherein R 2 is

5. The compound of claim 3 wherein R 1 is phenyl substituted with one or more halo atoms.

6. The compound of claim 1 wherein:

(A) R 1 is aryl substituted with one or more R 5 groups;

(B) n is 0 or 1 and m is 1, 2 or 3 such that m+n is 3;

(D) R 2 is —XC(O)Y, —(C 1 –C 6 )alkylene-XC(O)Y or —(C 0 –C 6 )alkylene-(C 3–C 6 )cycloalkylene-(C 0 –C 6 )alkylene-XC(O)Y;

(E) X is O;

(F) Y is —NR 6 R 7 ; or Y is selected from the group consisting of:

(G) R 6 and R 7 are independently selected from the group consisting of: H, methyl, ethyl, —(C 3 –C 8 )cycloalkyl, -aryl(C 1 –C 6 )alkyl, 4-pyridylmethyl, and

7. The compound of claim 6 wherein:

(A) R 1 is phenyl substituted with one or more R 5 groups;

(B) n is 0 and m is 3;

is a group of the formula:

(D) said group

is a group of the formula:

(E) R 11 is selected from the group consisting of: —(C 1 –C 6 )alkyl, (C 3 –C 8 )-cycloalkyl, aryl, aryl(C 1 –C 6 )alkyl and —(C 1 –C 6 )alkoxyalkyl.

8. The compound of claim 7 wherein said R 11 is selected from the group consisting of: methyl, ethyl, cyclohexyl, phenyl, benzyl, —(CH 2 ) 2 phenyl, and —CH 2 OCH 3 .

9. The compound of claim 7 wherein R 1 is phenyl substituted with one or more halo atoms.

10. The compound of claim 8 wherein R 11 is phenyl substituted with one or more halo atoms.

11. The compound of claim 6 wherein Y is selected from the group consisting of:

12. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.

13. A compound selected from the group consisting of:

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 13 , or a pharmaceutically acceptable salt, ester or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier.

15. A compound of the following formula