Substituted RIG-I agonists: compositions and methods thereof

1. A compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

each X is independently selected from the group consisting of O, S, —CH 2 —, and —NH—;

each Y is independently selected from the group consisting of —OH, —SH,

and

each V is independently O, or S;

K is H, or

each W is independently N, —CH—, or —C(F)—;

each Z is independently N, or —CH—;

each R 1 is independently selected from the group consisting of H, halogen, —OH, —OC 1-6 alkyl, C 1-6 alkyl, —OC 1-3 haloalkyl, —OC 2-6 alkenyl, —OC 2-6 alkynyl, —NH 2 , and —OCH 2 C 5-6 heteroarylCH 2 R y , said alkyl, alkenyl, alkynyl and heteroaryl optionally substituted with 1 to 3 groups of R b ;

each R 2 is independently selected from the group consisting of H, halogen, —OH, —OC 1-6 alkyl, C 1-6 alkyl, —OC 1-3 haloalkyl;

or one or more adjacent R 1 and R 2 can combine to form ═CH 2 ;

each R 3 is independently H, halogen, C 1-6 alkyl, or C 2-6 alkynyl;

or R 1 and R 3 on a sugar moiety can be linked to form —CH 2 O, provided R 2 is hydrogen;

R 4 is selected from the group consisting of

—CH 2 OH,

R 5 is selected from the group consisting of H, C 1-6 alkyl, —(CH 2 CH 2 O) p CH 2 CH 3 , and —CH 2 CH(OH)CH 2 (O(CH 2 ) 2 ) n CH 2 NHC(O)R z ;

each R 6 is independently selected from H and NH 2 ;

R b is selected from C 1-6 alkyl, —OC 1-6 alkyl, halo, OH, CN, NO, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , SO 3 H, SO 4 , PO 4 , C 1-3 haloalkyl, C 1-3 haloalkoxy, carboxyl, oxo, and S(O) g alkyl;

R is H or —P(O)(OH) 2′ ;

Q is independently selected from the group consisting of O, CH 2 , and NH;

R s is NH 2 or —C(O)—;

R x is hydrogen or —C≡CH;

R y is —CH 2 (O(CH 2 ) 2 ) n (CH 2 ) k NHC(O)—R z , or —(CH 2 OCH 2 ) n CH 2 C(O)N((CH 2 ) k NHC(O)R z ) 2 ;

R z is cholesterol;

g is 1, 2, or 3;

k and n are independently selected from 1, 2, 3, 4, 5, and 6; and

p is an integer from 1 to 50.

2. A compound according to claim 1 of Formula Ia represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each X is independently selected from the group consisting of O, S, —CH 2 —, and —NH—;

each Y is independently selected from the group consisting of —OH, —SH,

and

each V is independently O, or S;

K is H, or

each W is independently N, —CH—, or —C(F)—;

each Z is independently N, or —CH—;

each R 1 is independently selected from the group consisting of H, halogen, —OH, —OC 1-6 alkyl, C 1-6 alkyl, —OC 1-3 haloalkyl, —OC 2-6 alkenyl, —OC 2-6 alkynyl, —NH 2 , and —OCH 2 C 5-6 heteroarylCH 2 R y , said alkyl, alkenyl, alkynyl and heteroaryl optionally substituted with 1 to 3 groups of R b ;

each R 2 is independently selected from the group consisting of H, halogen, —OH, —OC 1-6 alkyl, C 1-6 alkyl, —OC 1-3 haloalkyl;

or one or more adjacent R 1 and R 2 can combine to form ═CH 2 ;

each R 3 is independently H, halogen, C 1-6 alkyl, or C 2-6 alkynyl;

or R 1 and R 3 on a sugar moiety can be linked to form —CH 2 O, provided R 2 is hydrogen;

R 4 is selected from the group consisting of

—CH 2 OH,

R 5 is selected from the group consisting of H, C 1-6 alkyl, —(CH 2 CH 2 O) p CH 2 CH 3 , and —CH 2 CH(OH)CH 2 (O(CH 2 ) 2 ) n CH 2 NHC(O)R z ;

each R 6 is independently selected from H and NH 2 ;

R b is selected from C 1-6 alkyl, —OC 1-6 alkyl, halo, OH, CN, NO, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , SO 3 H, SO 4 , PO 4 , C 1-3 haloalkyl, C 1-3 haloalkoxy, carboxyl, oxo, and S(O) g alkyl;

R is H or —P(O)(OH) 2′ ;

Q is independently selected from the group consisting of O, CH 2 , and NH;

R y is —CH 2 (O(CH 2 ) 2 ) n (CH 2 ) k NHC(O)—R z , or —(CH 2 OCH 2 ) n CH 2 C(O)N((CH 2 ) k NHC(O)R z ) 2 ;

R z is cholesterol;

g is 1, 2, or 3;

k and n are independently selected from 1, 2, 3, 4, 5, and 6; and

p is an integer from 1 to 50.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein: any X is independently selected from O and S, any Y is independently selected from OH and SH, any V is independently selected from O and S, and any K is independently selected from H and

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein: any R 1 is selected from the group consisting of H, halogen, —OH, —OMe, Me, —OCF 3 , O(CH 2 ) 2 OCH 3 , NH 2 , and —OCH 2 C≡CH; any R 2 is independently selected from the group consisting of H, halogen, —OH, —OMe, Me, and —OCF 3 ; and Rx is hydrogen.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein: any X is independently selected from O and S; any Y is independently selected from OH and SH; any V is independently selected from O and S; K is H; any W and Z within a single nine membered bicycle is independently selected from W═N and Z═—CH—, W═—CH— and Z═N and W═—CH— and Z is CH; any R 1 selected from the group consisting of H, halogen, —OH, —OMe, Me, —OCF 3 , —O(CH 2 ) 2 OCH 3 , —NH 2 , and —OCH 2 C≡CH; any R 2 is independently selected from the group consisting of H, halogen, —OH, —OMe, -Me, and —OCF 3 ; R x is hydrogen; R s is NH 2 ; and any R 3 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, and —C≡CH.

6. A compound selected from Examples 1 through 838, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

8. The composition according to claim 7 , wherein the compound comprises a hairpin or stem loop oligonucleotide further comprising a blunt end.

9. A viral vector encoding a compound according to claim 6 .

10. An oligonucleotide capable of inducing interferon production, wherein the oligonucleotide comprises 5′-GCUCAUUUACCAGCGUAAAUGAGC-3′ (SEQ ID NO: 841), and wherein the oligonucleotide further comprises a self complementary base pairing region of less than 12 base pairs which are capable of forming a double-stranded section of the oligonucleotide.

11. The oligonucleotide of claim 10 , which forms a hairpin structure comprising the double-stranded section and a loop.

12. The oligonucleotide of claim 10 , which comprises a blunt end.

13. The oligonucleotide of claim 10 , which comprises a 5′-OH, a 5′-triphosphate, or a 5′-diphosphate.

14. The oligonucleotide of claim 10 , wherein at least one nucleotide comprises a sugar group modified at its 2′ position, wherein the 2′ modification is selected from the group consisting of: 2′-OH, 2′-methyl, 2′-OCF 3 , 2′-OCH 2 C≡CH, NH 2 , 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyl-oxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA).

15. A pharmaceutical composition comprising an oligonucleotide of claim 10 , wherein the oligonucleotide comprises at least one phosphorothioate group.

16. The oligonucleotide of claim 10 , wherein the molecule comprises at least one modified nucleobase.

17. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein: any X is independently selected from O and S, any Y is independently selected from OH and SH, any V is independently selected from O and S, and any K is independently selected from H and

18. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein: any R 1 is selected from the group consisting of H, halogen, —OH, —OMe, Me, —OCF 3 , O(CH 2 ) 2 OCH 3 , NH 2 , and —OCH 2 C≡CH; any R 2 is independently selected from the group consisting of H, halogen, —OH, —OMe, Me, and —OCF 3 ; and Rx is hydrogen.

19. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein: any X is independently selected from O and S; any Y is independently selected from OH and SH; any V is independently selected from O and S; K is H; any W and Z within a single nine membered bicycle is independently selected from W═N and Z ═—CH—, W═—CH— and Z═N and W═—CH— and Z is CH; any R 1 is selected from the group consisting of H, halogen, —OH, —OMe, Me, —OCF 3 , —O(CH 2 ) 2 OCH 3 , —NH 2 , and —OCH 2 C≡CH; any R 2 is independently selected from the group consisting of H, halogen, —OH, —OMe, -Me, and —OCF 3 ; R x is hydrogen; R s is NH 2 ; and any R 3 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, and —C≡CH.