Spirocyclic compounds
View Patent ↗The present invention relates to a novel class of substituted spirocyclic compounds. These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the compounds of the instant invention and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of these compounds in vivo.
1. A compound represented by the following structural Formula:
wherein
A is O, B is CR 1 2 or C(O) and D is NR 1a ;
E is a bond;
G is CR 1 2 ;
R is selected from NH 2 and OH;
- - - - is an optional double bond;
is an aryl or heteroaryl, optionally substituted with from 1 to 3 substituents selected from R 7 ;
is an aryl or heteroaryl;
R 1 is independently selected from
1) hydrogen,
2) C 1 -C 6 alkyl,
3) (CR 6 2 ) n R 10 ,
4) (CR 6 2 ) n C(O)R 4 ,
5) (CR 6 2 ) n C(O)OR 4 ,
6) (CR 6 2 ) n C(O)NR 5 2 ,
7) (CR 6 2 ) n S(O) 2 R 4 ,
8) (CR 6 2 ) n OH, and
9) halo;
R 1a is independently selected from
1) hydrogen,
2) C 1 -C 6 alkyl,
3) (CR 6 2 ) n R 10 ,
4) (CR 6 2 ) n C(O)R 4 ,
5) (CR 6 2 ) n C(O)OR 4 ,
6) (CR 6 2 ) n C(O)NR 5 2 , and
7) (CR 6 2 ) n S(O) 2 R 4 ;
L 1 is a bond;
R 3 is selected from
H,
unsubstituted or substituted C 1 -C 6 alkyl,
unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl
halo,
CN,
amide,
carboxyl,
C 1 -C 7 alkoxy,
C 1 -C 7 haloalkyl,
C 1 -C 7 haloalkyloxy,
C 1 -C 7 hydroxyalkyl,
C 1 -C 7 alkenyl,
C 1 -C 7 alkynyl,
C 1 -C 7 alkyl-C(═O)O—,
C 1 -C 7 alkyl-C(═O)—,
hydroxyalkoxy,
C 1 -C 7 alkyl-NHSO 2 —,
C 1 -C 7 alkyl-SO 2 NH—,
C 1 -C 7 alkylsulfonyl,
C 1 -C 7 alkylamino,
di(C 1 -C 7 )alkylamino, and
-L 2 -R 12 ;
R 4 is independently selected from
1) H,
2) C 1 -C 6 alkyl,
3) aryl, and
3) heterocyclyl,
wherein alkyl, aryl or heterocyclyl may be optionally substituted;
R 5 is independently selected from
1) hydrogen,
2) C 1 -C 6 alkyl, and
3) aryl,
which may be optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, aryl, heteroaryl and halo;
R 6 is independently selected from
1) hydrogen,
2) C 1 -C 6 alkyl,
3) aryl,
4) OR 11 ,
5) halo, and
6) NR 11 2 ;
wherein the alkyl or aryl may be optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, aryl, heteroaryl and halo;
R 7 is independently selected from hydrogen, OH, NR 11 2 , nitro, CN, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl-C(═O) O—, C 1 -C 7 alkyl-C(═O)—, C 1 -C 7 alkynyl, halo group, amide, hydroxyalkoxy, C 1 -C 7 alkyl-NR 11 SO 2 —, C 1 -C 7 alkyl-SO 2 NR 11 —, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R 10 is independently selected from
1) aryl, and
2) heterocyclyl,
which may be optionally substituted;
R 11 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, and unsubstituted or substituted aryl;
L 2 is selected from
1) a bond,
2) C 1 -C 4 alkylene,
3) C 1 -C 4 alkynyl,
4) C 1 -C 4 alkenyl,
5) —O—,
6) —S—,
7) —NH—,
8) —C(═O)NH—,
9) —NHC(═O)—,
10) —NHC(═O)NH—,
11) —SO 2 NH—,
12) —NHSO 2 —,
13) —SO 2 —,
14) —C(═O)— and
15) —C(═O)O—;
R 12 is selected from:
1) substituted or unsubstituted heteroaryl,
2) substituted or unsubstituted heterocyclyl,
3) substituted or unsubstituted aryl, and
4) substituted or unsubstituted C 3 -C 8 cycloalkyl;
m is 1;
n is independently selected from 0, 1, 2, 3 and 4;
p is 1;
q is 1, 2, 3, or 4;
s is 0 or 1;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , represented by Formula II:
wherein
A is O, B is CR 1 2 or C(O) and D is NR 1a ;
E is a bond;
- - - - is an optional double bond;
is an aryl or heteroaryl, optionally substituted with from 1 to 3 substituents selected from R 7 ;
is an aryl or heteroaryl;
R 1 is independently selected from
1) hydrogen,
2) C 1 -C 6 alkyl,
3) (CR 6 2 ) n R 10 ,
4) (CR 6 2 ) n C(O)R 4 ,
5) (CR 6 2 ) n C(O)OR 4 ,
6) (CR 6 2 ) n C(O)NR 5 2 ,
7) (CR 6 2 ) n S(O) 2 R 4 ,
8) (CR 6 2 ) n OH, and
9) halo;
R 1a is independently selected from
1) hydrogen,
2) C 1 -C 6 alkyl,
3) (CR 6 2 ) n R 10 ,
4) (CR 6 2 ) n C(O)R 4 ,
5) (CR 6 2 ) n C(O)OR 4 ,
6) (CR 6 2 ) n C(O)NR 5 2 , and
7) (CR 6 2 ) n S(O) 2 R 4 ;
L 1 is a bond;
R 3 is selected from
H,
unsubstituted or substituted C 1 -C 6 alkyl,
unsubstituted or substituted aryl,
unsubstituted or substituted heteroaryl
halo,
CN,
amide,
carboxyl,
C 1 -C 7 alkoxy,
C 1 -C 7 haloalkyl,
C 1 -C 7 haloalkyloxy,
C 1 -C 7 hydroxyalkyl,
C 1 -C 7 alkenyl,
C 1 -C 7 alkynyl,
C 1 -C 7 alkyl-C(═O)O—,
C 1 -C 7 alkyl-C(═O)—,
hydroxyalkoxy,
C 1 -C 7 alkyl-NHSO 2 —,
C 1 -C 7 alkyl-SO 2 NH—,
C 1 -C 7 alkylsulfonyl,
C 1 -C 7 alkylamino,
di(C 1 -C 7 )alkylamino, and
-L 2 -R 12 ,
R 4 is independently selected from
1) H,
2) C 1 -C 6 alkyl,
3) aryl, and
3) heterocyclyl,
wherein alkyl, aryl or heterocyclyl may be optionally substituted;
R 5 is independently selected from
1) hydrogen,
2) C 1 -C 6 alkyl, and
3) aryl,
which may be optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, aryl, heteroaryl and halo;
R 6 is independently selected from
1) hydrogen,
2) C 1 -C 6 alkyl,
3) aryl,
4) OR 11 ,
5) halo, and
6) NR 11 2 ;
wherein the alkyl or aryl may be optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, aryl, heteroaryl and halo;
R 7 is independently selected from hydrogen, OH, NR 11 2 , nitro, CN, carboxyl, C 1 -C 7 alkoxy, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkyloxy, C 1 -C 7 hydroxyalkyl, C 1 -C 7 alkenyl, C 1 -C 7 alkyl-C(═O)O—, C 1 -C 7 alkyl-C(═O)—, C 1 -C 7 alkynyl, halo group, amide, hydroxyalkoxy, C 1 -C 7 alkyl-NR 11 SO 2 —, C 1 -C 7 alkyl-SO 2 NR 11 —, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylamino and di(C 1 -C 7 )alkylamino;
R 10 is independently selected from
1) aryl, and
2) heterocyclyl,
which may be optionally substituted;
R 11 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, and unsubstituted or substituted aryl;
L 2 is selected from
1) a bond,
2) C 1 -C 4 alkylene,
3) C 1 -C 4 alkynyl,
4) C 1 -C 4 alkenyl,
5) —O—,
6) —S—,
7) —NH—,
8) —C(═O)NH—,
9) —NHC(═O)—,
10) —NHC(═O)NH—,
11) —SO 2 NH—,
12) —NHSO 2 —,
13) —SO 2 —,
14) —C(═O)— and
15) —C(═O)O—;
R 12 is selected from:
1) substituted or unsubstituted heteroaryl,
2) substituted or unsubstituted heterocyclyl,
3) substituted or unsubstituted aryl, and
4) substituted or unsubstituted C 3 -C 8 cycloalkyl;
m is 1;
n is independently selected from 0, 1, 2, 3 and 4;
p is 1;
q is 1, 2, 3, or 4;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 , represented by Formula III:
wherein
X is CH or N;
and the remaining substituents are as described in claim 2 ;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 wherein:
A is O;
B is C(O);
D is NR 1a ;
E is a bond;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 selected from
N-[2-Amino-5-(2-thienyl)phenyl]-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)nicotinamide;
N-[2-amino-5-(3-thienyl)phenyl]-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)nicotinamide;
N-[2-amino-5-(2-thienyl)phenyl]-6-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)nicotinamide;
N-(4-aminobiphenyl-3-yl)-6-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)nicotinamide; and
N-(4-aminobiphenyl-3-yl)-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)nicotinamide;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.
7. The compound of claim 1 that is N-[2-amino-5-(2-thienyl)phenyl]-6-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)nicotinamide or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 7 , and a pharmaceutically acceptable carrier.
9. The compound of claim 1 that is N-[2-Amino-5-(2-thienyl)phenyl]-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)nicotinamide or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 that is
N-[2-amino-5-(3-thienyl)phenyl]-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)nicotinamide or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 9 , and a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 10 , and a pharmaceutically acceptable carrier.
13. The compound of claim 4 , wherein R 3 is H, unsubstituted or substituted phenyl or unsubstituted or substituted thienyl;
or a stereoisomer or a pharmaceutically acceptable salt thereof.
14. The compound of claim 4 , wherein R 3 is phenyl or thienyl optionally substituted with halo;
or a stereoisomer or a pharmaceutically acceptable salt thereof.