Read-through compound prodrugs suppressing premature nonsense mutations

1. A compound according to Formula Ia:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

W is —NR a R b , —C(O)OR 4 , —C(O)NR a R b , or -HetAr;

A is a bond from C(O) to W, —(CH 2 ) f CH(R 1 )(CH 2 ) g —, —(CH 2 ) f C(R a R b )(CH 2 ) g —, —(CH 2 CH 2 O) h (CH 2 ) t —, —(CH 2 ) t (OCH 2 CH 2 ) h —, —(CH 2 ) t N(R e )CH 2 CH 2 Z, or

 or A and W combine to form

R 1 is —H, —(CH 2 ) n CH 3 , —CH(CH 3 )CH 2 CH 3 , —CF 3 , —CH 2 (Ar), —CH 2 (HetAr), —CH 2 S(O) m CH 3 , —CH 2 CH 2 S(O) m CH 3 , —CH 2 (CH 2 ) n NR c R d , —CH 2 OH, —CH(CH 3 )OH, or —(CH 2 ) t COOH;

R 2 is —H, —CH 3 , —OH, or —CF 3 ;

each of R a and R b is independently R e ; or, in the alternative, R a and R b , together with the nitrogen or carbon atom to which they are attached, combine to form a 4 to 7-membered heterocyclic ring, optionally containing heteroatoms selected from O, NR g , and S(O)m;

R c is —H, —CH 3 , —(CH 2 ) n CH 3 , —CH(R 2 )CH 3 , —CH 2 -pyridyl, or CH 2 -imidazolyl;

R d is —H, —CH 3 , or —(CH 2 ) n CH 3 ; or, in the alternative, R c and R d , together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic ring optionally containing heteroatoms selected from O, NR e , and S(O) m ;

each R e is independently —H, —(CH 2 ) n CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —(CH 2 CH 2 O) p R 3 , or —CH 2 HetAr;

each R g is independently —H, —(CH 2 ) n CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —(CH 2 CH 2 O) p R 3 , —CH 2 -phenyl or —CH 2 -phenyl optionally substituted with F, Cl, —CH 3 , —OCH 3 , —OCF 3 , or -HetAr;

each R 3 is independently —H, —CH 3 , —CH 2 CH 2 —OH, or —CF 3 ;

each R 4 is independently —H or —(CH 2 ) n NR c R d ;

each HetAr is independently a heteroaryl group;

D is CH or N;

Q is —O—, —NR a —, —S(O) m —, or —CHW—;

each k is independently 1, 2, 3 or 4;

each u is independently 1, 2 or 3;

each v is independently 1, 2 or 3;

each p is independently 1 or 2;

each f is independently 0, 1 or 2;

each g is independently 0, 1 or 2;

each h is independently 1 or 2;

each n is independently 0, 1, 2, 3, or 4;

each m is independently 0, 1 or 2;

each of q 1 and q 2 is independently 0, 1, 2 or 3;

each s is independently 0, 1, 2 or 3; and

each t is independently 0, 1, 2 or 3.

2. The compound of any of the above claim 1 , with the proviso that when D is CH, then Q is not —O—;and with the proviso that when D is N and Q is —NR a —, then u and v are not both equal to 1.

3. The compound of claim 1 , wherein the compound is a compound of Formula Ib:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

4. The compound any of claim 1 , wherein the compound is a compound of Formula II:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

5. The compound of claim 1 , wherein the compound is a compound of Formula III:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

6. The compound of claim 5 , wherein R x is —CH 3 , -iPr, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 COOH, —CH 2 CH 2 COOH,

7. The compound of claim 1 , wherein the compound is a compound of Formula IV:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and wherein ring G is a 5 to 6-membered heterocyclic ring.

8. The compound of claim 7 , wherein ring G is

9. The compound of claim 1 , wherein the compound is a compound of Formula V:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Y is —OR 4 or —NR a R b .

10. The compound of any one of claims 1 - 5 , wherein W is —NH 2 , —NHCH 3 ,

N(CH 3 ) 2 ,

11. The compound of any of claims 1 - 5 , wherein A is —(CH 2 ) f CH(R 1 )(CH 2 ) g —.

12. The compound of claim 1 , wherein W is HetAr.

13. The compound of claim 1 , wherein A is

14. The compound of claim 1 , wherein A is —(CH 2 CH 2 O) h (CH 2 ) t — or —(CH 2 ) t (OCH 2 CH 2 ) h —.

15. The compound of claim 1 , wherein the compound is a compound of Formula VI:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer-thereof.

16. The compound of claim 1 , wherein A and W combine to form

17. The compound of claim 1 , wherein the compound is a compound of Formula 8, Formula 12, Formula 16, Formula 20, Formula 22:

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

18. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt.

19. A pharmaceutical composition comprising:

a compound, or a pharmaceutically acceptable salt thereof, in an amount effective for treating or ameliorating a medical condition associated with premature termination codons (PTCs) in RNA, wherein the compound is a compound according to claim 1 ; and

a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier.

20. A compound according to Formula (9001):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

R is

W is —NR a R b , —COOH, -HetAr;

A is A 1 , A 2 or A 3 ;

A 1 is —(CH 2 ) f —CH(R 1 R 2 )—(CH 2 ) g —;

R 1 is —H, —(CH 2 ) n CH 3 , —CH(CH 3 )CH 2 CH 3 , —CF 3 , —CH(Ar), —CH(HetAr), —CH 2 S(O) m CH 3 , —CH 2 CH 2 S(O) m CH 3 , —CH 2 (CH 2 ) n —NR c R d , —CH 2 OH, —CH(CH 3 )OH, or —(CH 2 ) t —COOH;

R c is —H, —CH 3 , —(CH 2 ) n CH 3 , —CH(R 2 )CH 3 , —CH 2 -pyridyl, or —CH 2 -Imidazolyl;

R d is —H, —(CH 2 ) n CH 3 ; or R c and R d taken together form a 4-7 membered ring optionally containing O, NR e , or S(O) m ;

R e is —H, —(CH 2 ) n CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —(CH 2 CH 2 O) p R 2 , or —CH 2 -HetAr;

f is 0-2;

g is 0-2;

n is 0-4;

p is 1-2;

m is 0-2;

R 2 is —H, —CH 3 , —OH, —CF 3 , or R 1 and R 2 taken together can form a 4-7 membered ring optionally containing O, NR f , or S(O) m ;

R f is —H, —(CH 2 ) n CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —(CH 2 CH 2 O)pR 2 , a 4-7 member carbocyclic ring, or a 4-7 member heterocyclic ring;

or wherein —C(O)—A—W of Formula 9001 is of Formula 9002:

A 2 is

q1 and q2 are independently 0-3;

s is 0-3;

t is 1-3;

A 3 is —(CH 2 CH 2 —O) h —(CH 2 ) t —, —(CH 2 ) t —(O—CH 2 CH 2 ) h —, —(CH 2 ) t —N(R e )—CH 2 CH 2 —Z;

h is 1-2; or

A-W′ are taken together as Formula 9004:

wherein P is —CH— or —N—;

Q is —O—, NR a , S(O) m , or —CH—W;

k is 1-4;

u is 1-3;

v is 1-3;

with the proviso that when P is —CH, Q cannot be —O—, and u and v each cannot be 1 when P is —N— and Q is —NR a ;

R a or R b can independently be R e , or R a and R b together with the nitrogen atom to which they are attached, form a 4-7 membered ring which can optionally contain a O, NR g , or S(O) m ;

R g is —H, —(CH 2 ) n CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —(CH 2 CH 2 O) p R 2 , —(CH 2 )phenyl or —(CH 2 )phenyl optionally substituted with —F, —Cl, —CH 3 , —OCH 3 , —OCF 3 , or heteroaromatics; and

HetAr is pyridyl, pyrimidyl, C-imidazolyl, or N-imidazolyl.

21. A composition, comprising at least one compound or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound is a compound according to claim 20 .

22. The composition of claim 21 , comprising two compounds, wherein each of the two compounds is according to claim 20 .

23. The composition of claim 21 , further comprising a pharmaceutically acceptable carrier.

24. The compound of claim 1 , wherein each HetAr is independently pyridyl, pyrimidyl, C-imidazolyl or N-imidazolyl.

25. The compound of claim 20 , wherein Rf is cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxetane, tetrahydrofurane, dioxane, oxepine, azetidine, pyrrolidine, piperidine, thioxetane, tetrahydrofurane, or a corresponding sulfoxide or sulfone thereof.