IAP binding compounds
IAP binding molecules and compositions including these are disclosed. The IAP binding molecules interact with IAPs (inhibitor of apoptosis proteins) in cells and may be used to modify apoptosis in cells treated with such molecules. Embodiments of these compounds have a K d of less that 0.1 micromolar. Methods of using these IAP binding molecules for therapeutic, diagnostic, and assay purposes are also disclosed.
1. A compound represented by formula (3):
or a pharmaceutically acceptable salt thereof
where A 1 is H, lower alkyl, or optionally-substituted lower alkyl; R 1a and R 1b are separately H, lower alkyl, optionally-substituted lower alkyl, lower alkylene, optionally substituted lower alkylene; or A 1 together with either R 1a or R 1b form an optionally substituted heterocycloalkyl of 3 to 6 atoms;
Y is H, an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, aryl, heteroaryl, arylalkyl, optionally-substituted versions of these groups, hydroxy substituted versions of these groups, or Y together with Z, M, G, or R 10 forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Y is linked to Z, M, G, or R 10 ;
Z is H, alkyl, hydroxy, amino, alkylamino, diakylamino, alkoxy, cycloalkyl, cycloalkyloxy, aryl, heteroaryl, aryloxy, or heteroaryloxy; or Z together with Y, M, G, or R 10 form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Z is linked to Y, M, G, or R 10 ;
M is an optionally-substituted alkyl, alkenyl, or alkynyl; an optionally-substituted alkyl, alkenyl, or alkynyl of 1 to 5 carbon atoms; an optionally-substituted alkylene, alkenylene, or alkynylene; or an optionally-substituted alkylene, alkenylene, or alkynylene of 1 to 5 carbon atoms;
G is a bond, a heteroatom, —(C═O)—; —S(O) t — where t=0,1, or 2; —NR 18 —; —NCOR 18 —; or —NS(O) x R 18 — where x=0, 1, or 2, and R 18 is lower alkyl, optionally-substituted lower alkyl, or cycloalkyl or R 18 is contained within a carbocyclic, or heterocyclic ring containing 1 to 5 heteroatoms, where R 18 is linked to Z, M, or R 10 ; and
R 10 is any one of structures (4a), or (4b):
where independently R 11 , R′ 11 , or any of R 14-17 is H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14-17 is H, optionally-substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy;
or independently R 11 , R′ 11 , or any of R 14-17 is acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , or any of R 14-17 is contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z, M, G, R 11 , R′ 11 , or any of R 14-17 .
2. A compound represented by formula (5)
or a pharmaceutically acceptable salt thereof
where A 1 is H, or lower alkyl, or A 1 and R 1b together form a ring of 3-5 atoms;
R 1a is H; R 1b is lower alkyl, or together with A 1 forms a ring of 3 to 5 atoms;
Y is an alkyl group, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, hydroxy substituted versions of these groups, or Y together with Z 1a , Z 1b , or R 10 forms a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Y is linked to Z 1a , Z 1b , or R 10 ;
Z 1a and Z 1b are independently an H, hydroxy, amino, alkylamino, diakylamino, alkoxy, aryloxy, or heteroaryloxy; or Z 1a , Z 1b , together with Y or R 10 form a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, where Z 1a or Z 1b , is linked to Y or R 10 ;
M is an optionally-substituted alkyl or an optionally-substituted alkylene of 1 to 5 carbon atoms;
G is a bond, a heteroatom, —(C═O)—; —NR 18 —; —NCOR 18 —; or —NS(O) x R 18 — where x=0, 1, or 2, and R 18 is lower alkyl, optionally-substituted lower alkyl; and
R 10 is anyone of structures (4a), or (4b):
where independently R 11 , R′ 11 , any of R 14-17 are H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14-17 are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , or any of R 14-17 are contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z 1a , Z 1b , M, G, R 11 , R′ 11 , or any of R 14-17 .
3. The Compound of claim 2 represented by the general formula (5)
or a pharmaceutically acceptable salt thereof
where A 1 is H, or lower alkyl;
R 1a is H; R 1b is lower alkyl;
Y is an alkyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, hydroxy substituted versions of these groups;
Z 1a and Z 1b are independently an H, hydroxy, alkoxy, aryloxy, or heteroaryloxy;
M is an optionally-substituted alkyl or an optionally-substituted alkylene of 1 to 5 carbon atoms;
G is a bond, a heteroatom, or —NCOR 18 — and R 18 is lower alkyl, optionally-substituted lower alkyl; and
R 10 is anyone of structures (4a), or (4b):
where independently R 11 , R′ 11 , or any of R 14-17 are H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14-17 are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , or any of R 14-17 are contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z 1a , Z 1b , M, G, R 11 , R′ 11 , or any of R 14-17 .
4. The compound of claim 2 represented by formula (5)
or a pharmaceutically acceptable salt thereof
where A 1 is H, or methyl;
R 1a is H; R 1b is methyl or ethyl;
Y is an alkyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, or hydroxy substituted versions of these groups;
Z 1a and Z 1b are independently an H, hydroxy, or alkoxy;
M is a methyl;
G is a bond; and
R 10 is any one of structures (4a) or (4b):
where independently R 11 , R′ 11 , or any of R 14-17 are H, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14-17 are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups; or groups R 11 , R′ 11 , or any of R 14-17 are contained within a carbocyclic ring, or a heterocyclic ring containing 1 to 5 heteroatoms, and linked to groups at position Y, Z 1a , Z 1b , M, G, R 11 , R′ 11 , or any of R 14-17 .
5. The compound of 4 or a pharmaceutically acceptable salt thereof, in which R 10 is:
6. The compound of claim 2 or a pharmaceutically acceptable salt thereof where R 10 is anyone of structures (4a), or (4b):
where independently R 11 , R′ 11 , or any of R 14-17 is H, halogen, alkyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14-17 are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy; independently R 11 , R′ 11 , or any of R 14 - 17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups.
7. The compound of claim 2 or a pharmaceutically acceptable salt thereof where R 10 has the structure of formula (4a):
where independently R 11 , or any of R 14 - 17 is H, or optional substituents including halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, alkyloxyalkyl, sulfonate, aryloxy or heteroaryloxy independently R 11 , or any of R 14-17 are H, optionally-substituted alkyl, aryl, alkenyl, alkynyl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkyloxyalkyl, aryloxy, or heteroaryloxy;
independently R 11 , R′ 11 , or any of R 14-17 are acyl or acetyl groups, carboxylate, sulfonate, sulfone, imine, or oxime groups.
8. The compound of claim 2 or a pharmaceutically acceptable salt thereof that has a K d for IAP of less than about 1 micromolar.
9. The compound of claim 2 or a pharmaceutically acceptable salt thereof where A 1 is H, methyl, or ethyl.
10. The compound of claim 2 or a pharmaceutically acceptable salt thereof where R 1a is H; R 1b is methyl or ethyl.
11. The compound of claim 2 or a pharmaceutically acceptable salt thereof where Y is an alkyl group of 1 to 10 carbon atoms, a branched alkyl group of 1 to 10 carbon atoms, an alkynyl group, a cycloalkyl group of 3 to 7 carbon atoms, optionally substituted versions of these groups, hydroxy substituted versions of these groups.
12. The compound of claim 2 or a pharmaceutically acceptable salt thereof where Z 1a and Z 1b are independently an H, hydroxy, amino, alkylamino, dialkylamino, alkoxy, aryloxy, or heteroaryloxy.
13. The compound of claim 2 or a pharmaceutically acceptable salt thereof where M is an alkyl or an alkylene of 1 to 5 carbon atoms.
14. The compound of claim 2 or a pharmaceutically acceptable salt thereof that has a K d for IAP of less than about 0.1 micromolar.
15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition of claim 16 comprising a compound of claim 3 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 16 comprising a compound of claim 4 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 16 comprising a compound of claim 5 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
20. The compound of claim 16 selected from the group consisting of