Methods and compositions for modulating splicing
Described herein are small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded by genes, pharmaceutical compositions comprising the same, and methods of use of the small molecule splicing modulator compounds for modulating splicing and treating diseases and conditions.
1. A method of treating or ameliorating Huntington's disease in a subject, comprising administering to the subject a compound of Formula (Id) or Formula (IId), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:
wherein,
in Formula (Id),
X is —NR 3 —, —O—, —S—,
in Formula (IId),
X is
E is —NR;
R A is hydrogen, deuterium, F, Cl, —CN, —OR 1 , —SR 1 , —S(═O)R 1 , —S(═O) 2 R 1 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 4 cycloalkyl, or substituted or unsubstituted C 2 -C 3 heterocycloalkyl;
ring Q is ortho hydroxy substituted aryl or ortho-hydroxy substituted bicyclic heteroaryl, wherein the aryl or bicyclic heteroaryl is optionally further substituted;
W is substituted or unsubstituted C 2 -C 3 alkylene, or substituted or unsubstituted C 2 -C 3 alkenylene;
R is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 5 heterocycloalkyl;
each R 1 is independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, —CD 3 , substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, —CD 3 , or substituted or unsubstituted C 1 -C 4 haloalkyl;
R 3 is hydrogen, —CN, substituted or unsubstituted C 1 -C 4 alkyl, —CD 3 , substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, or —C 1 -C 4 alkylene-OR 1 ;
each R 4 is independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, —CD 3 , substituted or unsubstituted C 1 -C 4 haloalkyl, or substituted or unsubstituted C 1 -C 4 heteroalkyl;
each R 16 and R 17 is independently selected from the group consisting of hydrogen, deuterium, F, —OR 1 , substituted or unsubstituted C 1 -C 4 alkyl, a substituted or unsubstituted C 1 -C 4 fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl; and
R 15 and R 18 are each independently selected from the group consisting of hydrogen, deuterium, F, —OR 1 , substituted or unsubstituted C 1 -C 4 alkyl, a substituted or unsubstituted C 1 -C 4 fluoroalkyl, and substituted or unsubstituted C 1 -C 4 heteroalkyl.
2. The method of claim 1 , wherein the compound of Formula (Id) has the structure of Formula (If):
3. The method of claim 1 , wherein ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
4. The method of claim 3 , wherein ring Q is 2-hydroxy-phenyl substituted with substituted or unsubstituted heteroaryl, wherein if heteroaryl is substituted then it is substituted with 1 or 2 substituents independently selected from:
deuterium, halogen, —OH, —NO 2 , —CN, —SR 1 , —S(═O)R 1 , —S(═O) 2 R 1 , —N(R 1 ) 2 , —C(═O)R 1 , —OC(═O)R 1 , —C(═O)OR 1 , —C(═O)N(R 1 ) 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 3 -C 7 cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl; wherein
each R 1 is independently hydrogen, deuterium, substituted or unsubstituted C 1 -C 4 alkyl, —CD 3 , substituted or unsubstituted C 1 -C 4 haloalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
5. The method of claim 1 , wherein:
ring Q is
wherein each R Q is independently selected from hydrogen, deuterium, —F, —Cl, —CN, —OH, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —OCH 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , —OCH 2 CH 2 CH 3 , and —OCH(CH 3 ) 2 ; and ring P is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
6. The method of claim 5 , wherein ring P is substituted or unsubstituted heteroaryl.
7. The method of claim 6 , wherein ring P is heteroaryl selected from the group consisting of:
wherein,
each R B is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 alkyl, —CD 3 , substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, deuterium substituted C 1 -C 6 alkoxy, —OCD 3 , substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, —CD 3 , substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl; and
m is 2 or 3.
8. The method of claim 1 , wherein ring Q is ortho-hydroxy substituted bicyclic heteroaryl; wherein if the bicyclic heteroaryl is further substituted, then it is substituted with one or more substituents each independently selected from D, halogen, —CN, —NH 2 , —OH, ═O, —NH(CH 3 ), —N(CH 3 ) 2 , —NH(cyclopropyl), —CH 3 , —CH 2 CH 3 , —CF 3 , —OCH 3 , and —OCF 3 .
9. The method of claim 1 , wherein ring Q is selected from the group consisting of:
wherein ring Q is optionally substituted with 1, 2, 3, 4, or 5 R B , wherein each R B is independently selected from deuterium, halogen, hydroxy, cyano, substituted or unsubstituted C 1 -C 6 alkyl, —CD 3 , substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 alkoxy, deuterium substituted C 1 -C 6 alkoxy, —OCD 3 , substituted or unsubstituted C 3-7 cycloalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
10. The method of claim 1 , wherein ring Q is selected from the group consisting of:
wherein
R B1 is selected from hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, —CD 3 , substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3-7 cycloalkyl, and substituted or unsubstituted C 2 -C 7 heterocycloalkyl.
11. The method of claim 1 , wherein W is substituted or unsubstituted C 2 -C 3 alkylene.
12. The method of claim 11 , wherein W is —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —.
13. The method of claim 1 , wherein R is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 5 cycloalkyl, or substituted or unsubstituted C 2 -C 4 heterocycloalkyl.
14. The method of claim 1 , wherein R 16 is F and R 17 is hydrogen; or wherein R 16 is hydrogen and R 17 is F.
15. The method of claim 1 , wherein X is —NR 3 — and R 3 is hydrogen, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 F, —CHF 2 , or —CF 3 .
16. The method of claim 1 , wherein R 15 and R 18 are both hydrogen or —CH 3 .
17. The method of claim 1 , wherein R 15 is hydrogen and R 18 is —CH 3 ; or wherein R 15 is —CH 3 and R 18 is hydrogen.
18. The method of claim 1 , wherein at least one of R 16 , R 17 , and R 18 is or comprises a fluorine.