Cationic lipids with various head groups for oligonucleotide delivery

1. A lipid nanoparticle comprising a cationic lipid of Formula A:

wherein:

p is 1 to 8;

R 1 and R 2 are independently selected from H, (C 1 -C 10 )alkyl, heterocyclyl, and a polyamine, wherein said heterocyclyl and polyamine are optionally substituted with one to three substituents selected from R 4 , or R 1 and R 2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle optionally substituted with one to three substituents selected from R 4 ;

R 3 is selected from H and (C 1 -C 6 )alkyl, said alkyl optionally substituted with one to three substituents selected from R 4 ;

R 4 is independently selected from halogen, OR 5 , SR 5 , CN, CO 2 R 5 and CON(R 5 ) 2 ;

R 5 is independently selected from H, (C 1 -C 10 )alkyl and aryl; and

Y is a (C 4 -C 22 )alkyl, (C 4 -C 22 )perfluoroalkyl, or a (C 4 -C 22 )alkenyl;

or any pharmaceutically acceptable salt or stereoisomer thereof.

2. The lipid nanoparticle of claim 1 , wherein:

p is 1 to 8;

is selected from:

R 3 is H; and

Y is a (C 4 -C 22 )alkyl, (C 4 -C 22 )perfluoroalkyl, or a (C 4 -C 22 )alkenyl;

or any pharmaceutically acceptable salt or stereoisomer thereof.

3. The lipid nanoparticle of claim 1 , wherein the cationic lipid is selected from:

(2S)-1-{7-[(3β)-cholest-5-en-3-yloxy]heptyloxy}-3-[(4Z)-dec-4-en-1-yloxy]-N,N-dimethylpropan-2-amine (Compound 4);

(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-[(4Z)-dec-4-en-1-yloxy]-N,N-dimethylpropan-2-amine (Compound 5);

(2R)-1-{7-[(3β)-cholest-5-en-3-yloxy]heptyloxy}-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 7);

(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 8);

(2 S)-1 -({6-[(3β)-cholest-5 -en-3 -yloxy]hexyl}oxy)-N,N-dimethyl-3-[(9Z)-octadec-9-en-1-yloxy]propan-2-amine (Compound 9);

(3β)-3-[6-{[(2S)-3-[(9Z)-octadec-9-en-1-yloxyl]-2-(pyrrolidin-1-yl)propyl]oxy}hexyloxy]cholest-5-ene (Compound 10);

(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-(octyloxy)propan-2-amine (Compound 11);

(2R)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-(pentyloxy)propan-2-amine (Compound 13);

(2R)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-3-(heptyloxy)-N,N-dimethylpropan-2-amine (Compound 14);

(2R)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(2Z)-pent-2-en-1-yloxy]propan-2-amine (Compound 15);

(2S)-1-butoxy-3-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethylpropan-2-amine (Compound 16);

(2S)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-3-[2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9-hexadecafluorononyl]oxy-N,N-dimethylpropan-2-amine(Compound 17);

2-amino-3-({9-[(3β,8ξ,9ξ,14ξ,17ξ,20ξ)-cholest-5-en-3-yloxy]nonyl}oxy)-2-{[(9Z,12Z) -octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 19); and;

2-amino-3-({6-[(3β,8ξ,14ξ,17ξ,20ξ)-cholest-5-en-3-yloxy]hexyl}oxy)-2-{[(9Z) -octadec-9-en-1-yloxy]methyl}propan-1-ol (Compound 20);

or any pharmaceutically acceptable salt or stereoisomer thereof.

4. The lipid nanoparticle of claim 1 , wherein the cationic lipid is selected from:

(2R)-1-{7-[(3β)-cholest-5-en-3-yloxy]heptyloxy}-3-[(4Z)-dec-4-en-1-yloxy]-N,N-dimethylpropan-2-amine (Compound 4a);

(2S)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-[(4Z)-dec-4-en-1-yloxy]-N,N-dimethylpropan-2-amine (Compound 5a);

(2S)-1-{7-[(3β)-cholest-5-en-3-yloxy]heptyloxy}-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 7a);

(2S)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-N,N-dimethyl- 3 -[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 8a);

(2R)-1-({6-[(3β)-cholest-5-en-3-yloxy]hexyl}oxy)-N,N-dimethyl-3-[(9Z)-octadec-9-en-1-yloxy]propan-2-amine (Compound 9a);

(3β)-3-[ 6 -{[(2R)-3-[(9Z)-octadec-9-en-1-yloxyl]-2-(pyrrolidin-1-yl)propyl]oxy}hexyloxy]cholest-5-ene (Compound 10a);

(2S)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-(octyloxy)propan-2-amine (Compound 11a);

(2S)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-(pentyloxy)propan-2-amine(Compound 13a);

(2S)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-3-(heptyloxy)-N,N-dimethylpropan-2-amine(Compound 14a);

(2R)-1-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(2Z)-pent-2-en-1-yloxy]propan-2-amine(Compound 15a); and

(2R)-1-butoxy-3-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethylpropan-2-amine(Compound 16a).

5. The lipid nanoparticle of claim 1 , wherein the cationic lipid is:

(2S)-1-({6-[(3β)-cholest-5-en-3-yloxy]hexyl}oxy)-N,N-dimethyl-3-[(9Z)-octadec-9-en-1-yloxy]propan-2-amine(Compound 9); or (2R)-1-({6-[(3β)-cholest-5-en-3-yloxy]hexyl}oxy)-N,N-dimethyl-3-[(9Z)-octadec-9-en-1-yloxy]propan-2-amine (Compound 9a)

or any pharmaceutically acceptable salt or stereoisomer thereof.

6. The lipid nanoparticle of claim 1 , wherein the nanoparticle further comprises an oligonucleotide.

7. The lipid nanoparticle of claim 6 , wherein the oligonucleotide is siRNA or miRNA.

8. The lipid nanoparticle of claim 7 , wherein the oligonucleotide is siRNA.

9. A lipid nanoparticle comprising a cationic lipid of Formula A:

wherein:

p is 1 to 8;

 is selected from:

n is 1 to 10;

R 3 is H; and

Y is a (C 4 -C 22 )alkyl, (C 4 -C 22 )perfluoroalkyl, or a (C 4 -C 22 )alkenyl;

or any pharmaceutically acceptable salt or stereoisomer thereof.

10. The lipid nanoparticle of claim 9 , wherein the nanoparticle further comprises an oligonucleotide.

11. The lipid nanoparticle of claim 10 , wherein the oligonucleotide is siRNA or miRNA.

12. The lipid nanoparticle of claim 11 , wherein the oligonucleotide is siRNA.

13. A lipid nanoparticle comprising a cationic lipid of Formula A:

wherein:

p is 1 to 8;

 is

R 3 is H; and

Y is a (C 4 -C 22 )alkyl, (C 4 -C 22 )perfluoroalkyl, or a (C 4 -C 22 )alkenyl;

or any pharmaceutically acceptable salt or stereoisomer thereof.

14. The lipid nanoparticle of claim 13 , wherein the cationic lipid is:

1-[(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-(octyloxy)propan-2-yl]guanidine (Compound 6); or

1-[(2S)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-(octyloxy)propan-2-yl]guanidine.

15. The lipid nanoparticle of claim 13 , wherein the nanoparticle further comprises an oligonucleotide.

16. The lipid nanoparticle of claim 15 , wherein the oligonucleotide is siRNA or miRNA.

17. The lipid nanoparticle of claim 16 , wherein the oligonucleotide is siRNA.