Inhibitor of apoptosis protein (IAP) antagonists
View Patent ↗Provided herein are compounds that modulate the activity of inhibitor of apoptosis proteins (IAPs), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
1. A compound having the structure of Formula C-I, pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:
wherein,
R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
X 1 is N—R A ;
X 2 is CR 2c R 2d ;
X 3 is CR 2a R 2b ;
R A is H, C 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
W 1 is O, S, N—R a , or C(R 8a )(R 8b );
W 2 is O, S, N—R a , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
R 2a , R 2b , R 2c , and R 2d are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), and —C(═O)R B ;
R B is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), or —NR D R E ;
R D and R E are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), and —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
m is 0, 1, or 2;
—U— is —NHC(═O)—, —C(═O)NH—, —NHS(═O) 2 —, —S(═O) 2 NH-, —NHC(═O)NH—, —NH(C═O)O-, —O(C═O)NH-, or —NHS(═O) 2 NH-;
R 3 is C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl;
R 4 is —NHR 5 , —N(R 5 ) 2 , —N + (R 5 ) 3 , or —OR 5 ;
each R 5 is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);
or:
R 3 and R 5 together with the atoms to which they are attached form a substituted or unsubstituted 5-7 membered ring;
or:
R 3 is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
R 6 is —NHC(═O)R 7 , —C(═O)NHR 7 , —NHS(═O) 2 R 7 , —S(═O) 2 NHR 7 ; —NHC(═O)NHR 7 , —NHS(═O) 2 NHR 7 , -(C 1 -C 3 alkyl)-NHC(═O)R 7 , -(C 1 -C 3 alkyl)-C(═O)NHR 5 , -(C 1 -C 3 alkyl)-NHS(═O) 2 R 7 , -(C 1 -C 3 alkyl)-S(═O) 2 NHR 7 ; -(C 1 -C 3 alkyl)-NHC(═O)NHR 7 , -(C 1 -C 3 alkyl)-NHS(═O) 2 NHR 7 , substituted or unsubstituted C 2 -C 10 heterocycloalkyl, or substituted or unsubstituted heteroaryl;
each R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, a substituted or unsubstituted C 3 -C 10 cycloalkyl, a substituted or unsubstituted C 2 -C 10 heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 10 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), —(CH 2 ) P —CH(substituted or unsubstituted aryl) 2 , —(CH 2 ) P —CH(substituted or unsubstituted heteroaryl) 2 , —(CH 2 ) P —CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), and -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
p is 0, 1, or 2;
R 8a , R 8b , R 8c , and R 8d are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy, and substituted or unsubstituted aryl;
or:
R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
or:
R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1-3 heteroatoms selected from S, O, and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1-3 heteroatoms selected from S, O, and N;
or:
R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatoms selected from S, O, and N;
or:
R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatoms selected from S, O, and N;
where each substituted alkyl, fused ring, spirocycle, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 1-3 R 9 ;
each R 9 is independently selected from halogen, —OH, —SH, (C═O), CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl) 2 , —C(═O)OH, —C(═O)NH 2 , —C(═O)C 1 -C 3 alkyl, —S(═O) 2 CH 3 , —NH(C 1 -C 4 alkyl)-OH, —NH(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O(C 1 -C 4 alkyl)-NH 2 , —O(C 1 -C 4 alkyl)-NH—(C 1 -C 4 alkyl), and —O(C 1 -C 4 alkyl)-N—(C 1 -C 4 alkyl) 2 ; or two R 9 together with the atoms to which they are attached form a methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C 1 -C 3 alkyl;
where each heterocycloalkyl is independently selected from a monocyclic, fused bicyclic, and bridged bicyclic ring, where the heterocycloalkyl has from 2 to 10 carbons in the ring and heteroatoms selected from O, N, or S; and
where each heteroaryl is independently selected from a monocyclic and fused bicyclic ring, where the heteroaryl is a 5- to 14-membered ring system comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of O, N, or S.
2. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, having the structure of Formula C-III-1:
wherein,
X 1 is N—R A ;
X 2 is CR 2c R 2d ; and
X 3 is CR 2a R 2b .
3. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein,
X 1 is N—R a ;
X 2 is CR 2c R 2d ;
X 3 is CR 2a R 2b ;
—U— is —NHC(═O)— or —C(═O)NH—;
R 3 is C 1 -C 3 alkyl;
R 4 is —NHR 5 , —N(R 5 ) 2 , or —N + (R 5 ) 3 ; and
each R 5 is independently selected from H, C 1 -C 3 alkyl and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl).
4. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein,
5. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein,
6. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein,
X 1 is N—R A ;
X 2 is CH 2 ; and
X 3 is CR 2a R 2b .
7. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, having the structure of Formula C-VIII-2:
8. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, having the structure of Formula C-XII:
wherein,
X 1 is N—R A ; and
X 2 is CR 2c R 2d .
9. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R 2a , R 2b R 2c , and R 2d , are independently H or C 1 -C 3 alkyl; and R 1 is H or methyl.
10. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R 1 is H.
11. The compound claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein R 6 is —C(═O)NHR 7 .
12. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof, wherein the compound of Formula C-I has the structure of C-XXI, or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:
wherein,
W 2 is O, S, or C(R 8c )(R 8d );
R 1 is H or C 1 -C 6 alkyl;
X 1 is N—R A ;
R A is H, C 1 -C 6 alkyl, —C(═O)C 1 -C 6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2a and R 2b are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, and —C(═O)R b ;
R B is substituted or unsubstituted C 1 -C 6 alkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), or —NR D R E ;
R D and R E are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
R 3 is C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl;
each R 5 is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);
each R 7 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, a substituted or unsubstituted C 3 -C 10 cycloalkyl, a substituted or unsubstituted C 2 -C 10 heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 10 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 10 heterocycloalkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), —(CH 2 ) P —CH(substituted or unsubstituted aryl) 2 , —(CH 2 ) P —CH(substituted or unsubstituted heteroaryl) 2 , —(CH 2 ) P —CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), and -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
p is 0, 1, or 2;
R 8a and R 8b are independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl;
R 8C and R 8d are independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl;
where each substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 1-3 R 9 ; and
each R 9 is independently selected from halogen, —OH, —SH, (C═O), CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl) 2 , —C(═O)OH, —C(═O)NH 2 , —C(═O)C 1 -C 3 alkyl, —S(═O) 2 CH 3 , —NH(C 1 -C 4 alkyl)-OH, —NH(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O(C 1 -C 4 alkyl)-NH 2 , —O(C 1 -C 4 alkyl)-NH—(C 1 -C 4 alkyl), and —O(C 1 -C 4 alkyl)-N—(C 1 -C 4 alkyl) 2 ; or two R 9 together with the atoms to which they are attached form a methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C 1 -C 3 alkyl;
where each heterocycloalkyl is independently selected from a monocyclic, fused bicyclic, and bridged bicyclic ring, where the heterocycloalkyl has from 2 to 10 carbons in the ring and heteroatoms selected from O, N, or S; and
where each heteroaryl is independently selected from a monocyclic and fused bicyclic ring, where the heteroaryl is a 5- to 14-membered ring system comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of O, N, or S.
13. The compound of claim 12 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein:
W 2 is C(R 8c )(R 8d );
R 1 is H;
R 2a and R 2b are independently selected from H and C 1 -C 3 alkyl;
and
R 8a , R 8b , R 8c , R 8d are independently selected from H and C 1 -C 3 alkyl.
14. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein,
R 7 is selected from
15. The compound of claim 1 or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, selected from:
16. A pharmaceutical composition comprising a compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.