Substituted thienopyrimidinones as a mitotic kinesin inhibitor
View Patent ↗The present invention relates to thienopyrimidinone compounds that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.
1. A compound of the formula:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
one of W, Y and Z is S and the other two of W, Y and Z are CH;
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
n is 0 to 2;
u is 2, 3, 4 or 5;
R 1 is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 2 -C 10 alkenyl,
3) C 2 -C 10 alkynyl,
4) C 1 -C 6 perfluoroalkyl,
5) C 1 -C 6 aralkyl,
8) C 3 -C 8 cycloalkyl, and
9) heterocyclyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
R 2 selected from: C 2 -C 6 alkyl, aryl and aryl C 1 -C 6 alkylene;
R 2 ′ is selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 -C 10 alkenyl,
5) (C═O) a O b C 2 -C 10 alkynyl,
6) CO 2 H,
7) C 1 -C 6 perfluoroalkyl,
8) (C═O) a O b C 3 -C 8 cycloalkyl,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ; or
R 2 and R 2 ′ are combined to form —(CH 2 ) u — wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O) m , —NC(O)—, and —N(R b )—, and wherein the ring formed when R 2 and R 2 ′ are combined is optionally substituted with one, two or three substituents selected from R 5 ;
R 3 and R 3 ′ are independently selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 -C 10 alkenyl,
5) (C═O) a O b C 2 -C 10 alkynyl,
6) CO 2 H,
7) C 1 -C 6 perfluoroalkyl,
8) (C═O) a O b C 3 -C 8 cycloalkyl,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
or R 3 and R 3 ′ along with the nitrogen to which they are attached are combined to form ring
which is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R 5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;
R 4 is independently selected from:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) (C═O) a O b C 2 -C 10 alkenyl,
4) (C═O) a O b C 2 -C 10 alkynyl,
5) CO 2 H,
6) halo,
7) OH,
8) O b C 1 -C 6 perfluoroalkyl,
9) (C═O) a NR 7 R 8 ,
10) CN,
11) (C═O) a O b C 3 -C 8 cycloalkyl,
12) (C═O) a O b heterocyclyl,
13) SO 2 NR 7 R 8 , and
14) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
R 5 is:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) C 2 -C 10 alkenyl,
4) C 2 -C 10 alkynyl,
5) (C═O) a O b heterocyclyl,
6) CO 2 H,
7) halo,
8) CN,
9) OH,
10) O b C 1 -C 6 perfluoroalkyl,
11) O a (C═O) b NR 7 R 8 ,
12) oxo,
13) CHO,
14) (N═O)R 7 R 8 , or
15) (C═O) a O b C 3 -C 8 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R 6 ;
R 6 is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1,
2) O r (C 1 -C 3 )perfluoroalkyl, wherein r is 0 or 1,
3) (C 0 -C 6 )alkylene-S(O) m R a , wherein m is 0, 1, or 2,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O) r O s (C 2 -C 10 )alkenyl,
9) (C═O) r O s (C 2 -C 10 )alkynyl,
10) (C═O) r O s (C 3 -C 6 )cycloalkyl,
11) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
13) (C═O) r O s (C 0 -C 6 )alkylene-N(R b ) 2 ,
14) C(O)R a ,
15) (C 0 -C 6 )alkylene-CO 2 R a ,
16) C(O)H,
17) (C 0 -C 6 )alkylene-CO 2 H, and
18) C(O)N(R b ) 2 ,
said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6 alkyl, oxo, and N(R b ) 2 ;
R 7 and R 8 are independently selected from:
1) H,
2) (C═O)O b C 1 -C 10 alkyl,
3) (C═O)O b C 3 -C 8 cycloalkyl,
4) (C═O)O b aryl,
5) (C═O)O b heterocyclyl,
6) C 1 -C 10 alkyl,
7) aryl,
8) C 2 -C 10 alkenyl,
9) C 2 -C 10 alkynyl,
10) heterocyclyl,
11) C 3 -C 8 cycloalkyl,
12) SO 2 R a , and
13) (C═O)NR b 2 ,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 6 , or
R 7 and R 8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R 6 ;
R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl; and
R b is H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6 alkyl,
(C═O)C 1 -C 6 alkyl or S(O) 2 R a .
2. A compound of the formula:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
n is 0 to 2;
u is 2, 3, 4 or 5;
R 1 is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 2 -C 10 alkenyl,
5) C 2 -C 10 alkynyl,
6) C 1 -C 6 perfluoroalkyl,
7) C 1 -C 6 aralkyl,
8) C 3 -C 8 cycloalkyl, and
9) heterocyclyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
R 2 is selected from: C 2 -C 6 alkyl, aryl and aryl C 1 -C 6 alkylene;
R 2 is selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 -C 10 alkenyl,
5) (C═O) a O b C 2 -C 10 alkynyl,
6) CO 2 H,
7) C 1 -C 6 perfluoroalkyl,
8) (C═O) a O b C 3 -C 8 cycloalkyl,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ; or
R 2 and R 2 ′ are combined to form —(CH 2 ) u — wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O) m , —NC(O)—, and —N(R b )—, and wherein the ring formed when R 2 and R 2 ′ are combined is optionally substituted with one, two or three substituents selected from R 5 ;
R 3 and R 3 ′ are independently selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 -C 10 alkenyl,
5) (C═O) a O b C 2 -C 10 alkynyl,
6) CO 2 H,
7) C 1 -C 6 perfluoroalkyl,
8) (C═O) a O b C 3 -C 8 cycloalkyl,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
or R 3 and R 3 ′ along with the nitrogen to which they are attached are combined to form ring
which is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R 5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;
R 4 is independently selected from:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) (C═O) a O b C 2 -C 10 alkenyl,
4) (C═O) a O b C 2 -C 10 alkynyl,
5) CO 2 H,
6) halo,
7) OH,
8) O b C 1 -C 6 perfluoroalkyl,
9) (C═O) a NR 7 R 8 ,
10) CN,
11) (C═O) a O b C 3 -C 8 cycloalkyl,
12) (C═O) a O b heterocyclyl,
13) SO 2 NR 7 R 8 , and
14) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
R 5 is:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) C 2 -C 10 alkenyl,
4) C 2 -C 10 alkynyl,
5) (C═O) a O b heterocyclyl,
6) CO 2 H,
7) halo,
8) CN,
9) OH,
10) O b C 1 -C 6 perfluoroalkyl,
11) O a (C═O) b NR 7 R 8 ,
12) oxo,
13) CHO,
14) (N═O)R 7 R 8 , or
15) (C═O) a O b C 3 -C 8 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R 6 ;
R 6 is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1,
2) O r (C 1 -C 3 )perfluoroalkyl, wherein r is 0 or 1,
3) (C 0 -C 6 )alkylene-S(O) m R a , wherein m is 0, 1, or 2,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O) r O s (C 2 -C 10 )alkenyl,
9) (C═O) r O s (C 2 -C 10 )alkynyl,
10) (C═O) r O s (C 3 -C 6 )cycloalkyl,
11) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
13) (C═O) r O s (C 0 -C 6 )alkylene-N(R b ) 2 ,
14) C(O)R a ,
15) (C 0 -C 6 )alkylene-CO 2 R a ,
16) C(O)H,
17) (C 0 -C 6 )alkylene-CO 2 H, and
18) C(O)N(R b ) 2 ,
said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6 alkyl, oxo, and N(R b ) 2 ;
R 7 and R 8 are independently selected from:
1) H,
2) (C═O)O b C 1 -C 10 alkyl,
3) (C═O)O b C 3 -C 8 cycloalkyl,
4) (C═O)O b aryl,
5) (C═O)O b heterocyclyl,
6) C 1 -C 10 alkyl,
7) aryl,
8) C 2 -C 10 alkenyl,
9) C 2 -C 10 alkynyl,
10) heterocyclyl,
11) C 3 -C 8 cycloalkyl,
12) SO 2 R a , and
13) (C═O)NR b 2 ,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 6 , or
R 7 and R 8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one or more substituents selected from R 6 ;
R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl; and
R b is H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6 alkyl,
(C═O)C 1 -C 6 alkyl or S(O) 2 R a .
3. The compound according to claim 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
n is 0 to 2;
R 1 is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 1 -C 6 aralkyl,
5) C 3 -C 8 cycloalkyl, and
6) heterocyclyl,
said alkyl, aryl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;
R 2 is selected from: C 2 -C 6 alkyl, aryl and aryl C 1 -C 6 alkylene;
R 2 is selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) CO 2 H,
5) C 1 -C 6 perfluoroalkyl,
6) (C═O) a O b C 3 -C 8 cycloalkyl, and
7) (C═O) a O b heterocyclyl,
said alkyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;
R 3 and R 3 ′ are independently selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 -C 10 alkenyl,
5) (C═O) a O b C 2 -C 10 alkynyl,
6) CO 2 H,
7) C 1 -C 6 perfluoroalkyl,
8) (C═O) a O b C 3 -C 8 cycloalkyl,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;
or R 3 and R 3 ′ along with the nitrogen to which they are attached are combined to form ring
which is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to three R 5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;
R 4 is independently selected from:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) CO 2 H,
4) halo,
5) OH,
6) O b C 1 -C 6 perfluoroalkyl,
7) (C═O) a NR 7 R 8 ,
8) CN,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;
R 5 is:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) C 2 -C 10 alkenyl,
4) C 2 -C 10 alkynyl,
5) (C═O) a O b heterocyclyl,
6) CO 2 H,
7) halo,
8) CN,
9) OH,
10) O b C 1 -C 6 perfluoroalkyl,
11) O a (C═O) b NR 7 R 8 ,
12) oxo,
13) CHO,
14) (N═O)R 7 R 8 , or
15) (C═O) a O b C 3 -C 8 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 6 ;
R 6 is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1,
2) O r (C 1 -C 3 )perfluoroalkyl, wherein r is 0 or 1,
3) oxo,
4) OH,
5) halo,
6) CN,
7) (C 2 -C 10 )alkenyl,
8) (C 2 -C 10 )alkynyl,
9) (C═O) r O s (C 3 -C 6 )cycloalkyl,
10) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
11) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
12) (C═O) r O s (C 0 -C 6 )alkylene-N(R b ) 2 ,
13) C(O)R a ,
14) (C 0 -C 6 )alkylene-CO 2 R a ,
15) C(O)H,
16) (C 0 -C 6 )alkylene-CO 2 H, and
17) C(O)N(R b ) 2 ,
said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6 alkyl, oxo, and N(R b ) 2 ;
R 7 and R 8 are independently selected from:
1) H,
2) (C═O)O b C 1 -C 10 alkyl,
3) (C═O)O b C 3 -C 8 cycloalkyl,
4) (C═O)O b aryl,
5) (C═O)O b heterocyclyl,
6) C 1 -C 10 alkyl,
7) aryl,
8) C 2 -C 10 alkenyl,
9) C 2 -C 10 alkynyl,
10) heterocyclyl,
11) C 3 -C 8 cycloalkyl,
12) SO 2 R a , and
13) (C═O)NR b 2 ,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one, two or three substituents selected from R 6 , or
R 7 and R 8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocylcic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 6 ;
R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl; and
R b is H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6 alkyl,
(C═O)C 1 -C 6 alkyl or S(O) 2 R a .
4. The compound according to claim 3 , or the pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is benzyl, optionally substituted with one to three substituents selected from R 5 ; R 2 is C 2 -C 6 -alkyl and R 2 ′ is H.
5. A compound of the formula
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
n is 0 to 2;
u is 2, 3, 4 or 5;
R 1 is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 2 -C 10 alkenyl,
5) C 2 -C 10 alkynyl,
6) C 1 -C 6 perfluoroalkyl,
7) C 1 -C 6 aralkyl,
8) C 3 -C 8 cycloalkyl, and
9) heterocyclyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
R 2 is selected from: C 2 -C 6 alkyl, aryl and aryl C 1 -C 6 alkylene;
R 2 is selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 -C 10 alkenyl,
5) (C═O) a O b C 2 -C 10 alkynyl,
6) CO 2 H,
7) C 1 -C 6 perfluoroalkyl,
8) (C═O) a O b C 3 -C 8 cycloalkyl,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ; or
R 2 and R 2 ′ are combined to form —(CH 2 ) u — wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O) m , —NC(O)—, and —N(R b )—, and wherein the ring formed when R 2 and R 2 ′ are combined is optionally substituted with one, two or three substituents selected from R 5 ;
R 3 and R 3 ′ are independently selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 -C 10 alkenyl,
5) (C═O) a O b C 2 -C 10 alkynyl,
6) CO 2 H,
7) C 1 -C 6 perfluoroalkyl,
8) (C═O) a O b C 3 -C 8 cycloalkyl,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
or R 3 and R 3 ′ along with the nitrogen to which they are attached are combined to form ring
which is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R 5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;
R 4 is independently selected from:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) (C═O) a O b C 2 -C 10 alkenyl,
4) (C═O) a O b C 2 -C 10 alkynyl,
5) CO 2 H,
6) halo,
7) OH,
8) O b C 1 -C 6 perfluoroalkyl,
9) (C═O) a NR 7 R 8 ,
10) CN,
11) (C═O) a O b C 3 -C 8 cycloalkyl,
12) (C═O) a O b heterocyclyl,
13) SO 2 NR 7 R 8 , and
14) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R 5 ;
R 5 is:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) C 2 -C 10 alkenyl,
4) C 2 -C 10 alkynyl,
5) (C═O) a O b heterocyclyl,
6) CO 2 H,
7) halo,
8) CN,
9) OH,
10) O b C 1 -C 6 perfluoroalkyl,
11) O a (C═O) b NR 7 R 8 ,
12) oxo,
13) CHO,
14) (N═O)R 7 R 8 , or
15) (C═O) a O b C 3 -C 8 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R 6 ;
R 6 is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1,
2) O r (C 1 -C 3 )perfluoroalkyl, wherein r is 0 or 1,
3) (C 0 -C 6 )alkylene-S(O) m R a , wherein m is 0, 1, or 2,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C═O) r O s (C 2 -C 10 )alkenyl,
9) (C═O) r O s (C 2 -C 10 )alkynyl,
10) (C═O) r O s (C 3 -C 6 )cycloalkyl,
11) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
12) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
13) (C═O) r O s (C 0 -C 6 )alkylene-N(R b )
14) C(O)R a ,
15) (C 0 -C 6 )alkylene-CO 2 R a ,
16) C(O)H,
17) (C 0 -C 6 )alkylene-CO 2 H, and
18) C(O)N(R b ) 2 ,
said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6 alkyl, oxo, and N(R b ) 2 ;
R 7 and R 8 are independently selected from:
1) H,
2) (C═O)O b C 1 -C 10 alkyl,
3) (C═O)O b C 3 -C 8 cycloalkyl,
4) (C═O)O b aryl,
5) (C═O)O b heterocyclyl,
6) C 1 -C 10 alkyl,
7) aryl,
8) C 2 -C 10 alkenyl,
9) C 2 -C 10 alkynyl,
10) heterocyclyl,
11) C 3 -C 8 cycloalkyl,
12) SO 2 R a , and
13) (C═O)NR b 2 ,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R 6 , or
R 7 and R 8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R 6 ;
R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl; and
R b is H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6 alkyl,
(C═O)C 1 -C 6 alkyl or S(O) 2 R a .
6. The compound of claim 5 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
a is 0 or 1;
b is 0 or 1;
m is 0, 1, or 2;
n is 0 to 2;
R 1 is selected from:
1) H,
2) C 1 -C 10 alkyl,
3) aryl,
4) C 1 -C 6 aralkyl,
5) C 3 -C 8 cycloalkyl, and
6) heterocyclyl,
said alkyl, aryl, cycloalkyl, aralkyl and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;
R 2 is selected from: C 2 -C 6 alkyl, aryl and aryl C 1 -C 6 alkylene;
R 2 is selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) CO 2 H,
5) C 1 -C 6 perfluoroalkyl,
6) (C═O) a O b C 3 -C 8 cycloalkyl, and
7) (C═O) a O b heterocyclyl,
said alkyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;
R 3 and R 3 ′ are independently selected from:
1) H,
2) (C═O) a O b C 1 -C 10 alkyl,
3) (C═O) a O b aryl,
4) (C═O) a O b C 2 -C 10 alkenyl,
5) (C═O) a O b C 2 -C 10 alkynyl,
6) CO 2 H,
7) C 1 -C 6 perfluoroalkyl,
8) (C═O) a O b C 3 -C 8 cycloalkyl,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;
or R 3 and R 3 ′ along with the nitrogen to which they are attached are combined to form ring
which is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R 5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring;
R 4 is independently selected from:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) CO 2 H,
4) halo,
5) OH,
6) O b C 1 -C 6 perfluoroalkyl,
7) (C═O) a NR 7 R 8 ,
8) CN,
9) (C═O) a O b heterocyclyl,
10) SO 2 NR 7 R 8 , and
11) SO 2 C 1 -C 10 alkyl,
said alkyl, aryl, cycloalkyl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R 5 ;
R 5 is:
1) (C═O) a O b C 1 -C 10 alkyl,
2) (C═O) a O b aryl,
3) C 2 -C 10 alkenyl,
4) C 2 -C 10 alkynyl,
5) (C═O) a O b heterocyclyl,
6) CO 2 H,
7) halo,
8) CN,
9) OH,
10) O b C 1 -C 6 perfluoroalkyl,
11) O a (C═O) b NR 7 R 8 ,
12) oxo,
13) CHO,
14) (N═O)R 7 R 8 , or
15) (C═O) a O b C 3 -C 8 cycloalkyl,
said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one, two or three substituents selected from R 6 ;
R 6 is selected from:
1) (C═O) r O s (C 1 -C 10 )alkyl, wherein r and s are independently 0 or 1,
2) O r (C 1 -C 3 )perfluoroalkyl, wherein r is 0 or 1,
3) oxo,
4) OH,
5) halo,
6) CN,
7) (C 2 -C 10 )alkenyl,
8) (C 2 -C 10 )alkynyl,
9) (C═O) r O s (C 3 -C 6 )cycloalkyl,
10) (C═O) r O s (C 0 -C 6 )alkylene-aryl,
11) (C═O) r O s (C 0 -C 6 )alkylene-heterocyclyl,
12) (C═O) r O s (C 0 -C 6 )alkylene-N(R b ) 2 ,
13) C(O)R a ,
14) (C 0 -C 6 )alkylene-CO 2 R a ,
15) C(O)H,
16) (C 0 -C 6 )alkylene-CO 2 H, and
17) C(O)N(R b ) 2 ,
said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from R b , OH, (C 1 -C 6 )alkoxy, halogen, CO 2 H, CN, O(C═O)C 1 -C 6 alkyl, oxo, and N(R b ) 2 ;
R 7 and R 8 are independently selected from:
1) H,
2) (C═O)O b C 1 -C 10 alkyl,
3) (C═O)O b C 3 -C 8 cycloalkyl,
4) (C═O)O b aryl,
5) (C═O)O b heterocyclyl,
6) C 1 -C 10 alkyl,
7) aryl,
8) C 2 -C 10 alkenyl,
9) C 2 -C 10 alkynyl,
10) heterocyclyl,
11) C 3 -C 8 cycloalkyl,
12) SO 2 R a , and
13) (C═O)NR b 2 ,
said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one, two or three substituents selected from R 6 , or
R 7 and R 8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from R 6 ;
R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, or heterocyclyl; and
R b is H, (C 1 -C 6 )alkyl, aryl, heterocyclyl, (C 3 -C 6 )cycloalkyl, (C═O)OC 1 -C 6 alkyl,
(C═O)C 1 -C 6 alkyl or S(O) 2 R a .
7. The compound according to claim 6 , or the pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is benzyl, optionally substituted with one to three substituents selected from R 5 ; R 2 is C 2 -C 6 -alkyl and R 2 ′ is H.
8. A compound selected from:
N-[1-(3-Benzyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)propyl]-4-bromo -N-[2-(dimethylamino)ethyl]benzamide
N-[1-(3-benzyl-5,6-dibromo-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide
N-[1-(3-benzyl-6-bromo-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo -N-[2-(dimethylamino)ethyl]benzamide
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo -N-(2-methoxyethyl)benzamide
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo -N-[2-(methylamino)ethyl]benzamide
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo -N-(2-hydroxyethyl)benzamide
N-(2-aminoethyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromobenzamide
ethyl N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-N-(4-bromobenzoyl)-beta-alaninate
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-N-(4-bromobenzoyl)-beta-alanine
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo -N-[3-(dimethylamino)propyl]benzamide
N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromobenzamide
N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-fluorobenzamide
N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-chlorobenzamide
N-(2-aminoethyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-fluorobenzamide
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2-methylpropyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2-methylpropyl]-N-[2-(dimethylamino)ethyl]-4-methylbenzamide
N-(2-aminoethyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-chlorobenzamide
3-benzyl-2-(1-{(4-bromobenzyl)[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-bromobenzyl)[2-(methylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
2-{1-[(3-aminopropyl)(4-bromobenzyl)amino]propyl}-3-benzylthieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-chlorobenzyl)[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-{1-[[2-(dimethylamino)ethyl](4-fluorobenzyl)amino]propyl}thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(3,4-difluorobenzyl)[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(2,4-difluorobenzyl)[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
2-{1-[(2-aminoethyl)(4-fluorobenzyl)amino]propyl}-3-benzylthieno[2,3-d]pyrimidin-4(3H)-one
2-{1-[(2-aminoethyl)(4-chlorobenzyl)amino]propyl}-3-benzylthieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-{1-[[2-(dimethylamino)ethyl](4-methylbenzyl)amino]propyl}thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{[2-(dimethylamino)ethyl][(2-methylpyrimidin-5-yl)methyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{[(6-chloropyridin-3-yl)methyl][2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{[2-(methylamino)ethyl][(2-methylpyrimidin-5-yl)methyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-bromobenzyl)[2-(dimethylamino)ethyl]amino}propyl)thieno[3,2-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-bromobenzyl)[(2-dimethylnitroryl)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo -N-[3-(dimethylnitroryl)propyl]-benzamide
3-benzyl-2-(1-{(4-chlorobenzyl)[(2-(dimethyl -nitroryl)ethyl]amino}propyl)thieno-[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-fluorobenzyl)[(2-(dimethyl-nitroryl)ethyl]amino}propyl) -thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-methylbenzyl)[(2-(dimethyl-nitroryl)ethyl]amino}propyl) -thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(3,4-difluorobenzyl)[(2-(dimethyl-nitroryl)ethyl]amino}propyl) -thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(6-chloro-pyridin-3-yl)methyl[(2-(dimethylnitroryl)ethyl]amino}-propyl)thieno[2,3-d]pyrimidin-4(3 H)-one
3-benzyl-2-(1-{[2-(dimethylnitroryl)ethyl][(2-methylpyrimidin-5-yl)methyl]amino}propyl)thieno-[2,3-d]pyrimidin-4(3H)-one
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2-methylpropyl]-4-brom-N-[2-(dimethylnitroryl)-ethyl]benzamide
N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2-methylpropyl]-N-[2-(dimethylnitroryl)ethyl]-4-methylbenzamide
or a pharmaceutically acceptable salt or stereoisomer thereof.
9. The compound according to claim 8 which is selected from:
3-benzyl-2-(1-{(4-bromobenzyl)[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-bromobenzyl)[2-(methylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-bromobenzyl)[(2-dimethylnitroryl)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one
3-benzyl-2-(1-{(4-chlorobenzyl)[(2-(dimethyl -nitroryl)ethyl]amino}propyl)thieno-[2,3-d]pyrimidin-4(3H)-one
or a pharmaceutically acceptable salt or stereoisomer thereof.
10. The compound according to claim 1 which is selected from:
N-(2-aminoethyl)-N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-chlorobenzamide HCl salt
2-{1-[(3-aminopropyl)(4-bromobenzyl)amino]propyl}-3-benzylthieno[2,3-d]pyrimidin-4(3H)-one TFA salt
2-{1-[(2-aminoethyl)(4-fluorobenzyl)amino]propyl}-3-benzylthieno[2,3-d]pyrimidin-4(3H)-one bis-HCl salt
2-{1-[(2-aminoethyl)(4-chlorobenzyl)amino]propyl}-3-benzylthieno[2,3-d]pyrimidin-4(3H)-one bis-HCl salt
3-benzyl-2-(1-{[2-(methylamino)ethyl][(2-methylpyrimidin-5-yl)methyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one TFA salt
3-benzyl-2-(1-{(3,4-difluorobenzyl)[(2-(dimethyl-nitroryl)ethyl]amino} propyl) -thieno[2,3-d [pyrimidin-4(3H)-one TFA salt
3-benzyl-2-(1-{(6-chloro-pyridin-3-yl)methyl[(2-(dimethylnitroryl)ethyl]amino}-propyl)thieno[2,3-d]pyrimidin-4(3H)-one TFA salt and
3-benzyl-2-(1-{[2-(dimethylnitroryl)ethyl][(2-methylpyrimidin-5-yl)methyl]amino}propyl)thieno-[2,3-d]pyrimidin-4(3H)-one TFA salt.
11. A compound which is selected from:
R 1
R 2
R 4
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
5-Cl
Bn
Et
6-Cl
Bn
H
Bn
H
Bn
H
Bn
Et
H
Bn
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
H
Bn
H
Bn
Et
6-F
Bn
Et
5-F
Et
H
Et
H
Et
H
Bn
Et
H
Bn
Et
H
Bn
Pr
H
Bn
Et
5-F
Bn
Et
6-Cl
Bn
Et
5-Cl
Et
H
Pr
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
6-F
Et
H
Et
H
Et
H
Et
H
Bn
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
Bn
Et
H
or a pharmaceutically acceptable salt or stereoisomer thereof.
12. A pharmaceutical composition that is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.