Diester and triester based low molecular weight, biodegradeable cationic lipids for oligonucleotide delivery

1. A cationic lipid of Formula A:

wherein:

R 1 and R 2 are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, heterocyclyl, and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three R′;

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 is optionally substituted with one to three R′;

R 3 is selected from the group consisting of (C 4 -C 20 )alkylene and (C 4 -C 20 )alkenylene, said alkylene or alkenylene is optionally substituted with one to three R′;

R 4 is selected from the group consisting of (C 1 -C 16 )alkyl and (C 2 -C 16 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;

R 5 is selected from the group consisting of (C 4 -C 8 )alkylene and (C 4 -C 8 )alkenylene, said alkylene or alkenylene is optionally substituted with one to three R′;

R 6 is (C 1 -C 2 )alkyl;

Q 1 and Q 2 are each, independently, selected from the group consisting of a bond, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —S—S—, —C(R″)═N—, —N═C(R″)—, —C(R″)═N—O—, —O—N═C(R″)—, —C(O)(NR″)—, —N(R″)C(O)—, C(S)(NR″)—, —N(R″)C(O)N(R″)—, —OC(O)O—, OSi(R″) 2 O—, —C(O)(CR″ 2 )C(O)O— and —OC(O)(CR″2)C(O)—), with the proviso that when either Q 1 or Q 2 is a bond then the other is not a bond;

X is selected from the group consisting of —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —S—S—, —C(R″)═N—, —N═C(R″)—, —C(R″)═N—O—, —O—N═C(R″)—, —C(O)(NR″)—, —N(R″)C(O)—, C(S)(NR″)—, —N(R″)C(O)N(R″)—, —OC(O)O—, OSi(R″) 2 O—, —C(O)(CR″ 2 )C(O)O— and —OC(O)(CR″ 2 )C(O)—),

each occurrence of R′ is independently selected from the group consisting of halogen, R″, OR″, SR″, CN, CO 2 R″ and CON(R″) 2 ;

each occurrence of R″ is independently selected from the group consisting of H and (C 1 -C 6 )alkyl, wherein said alkyl is optionally substituted with halogen and OH; and

n is 1, 2, 3, 4 or 5;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A cationic lipid of Formula A according to claim 1 , wherein:

R 1 and R 2 are each methyl;

n is 3;

R 3 is selected from (C 4 -C 20 )alkylene and (C 4 -C 20 )alkenylene, said alkylene or alkenylene is optionally substituted with one to three R;

R 4 is selected from (C 1 -C 16 )alkyl and (C 2 -C 16 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;

R 5 is selected from (C 4 -C 8 )alkylene and (C 4 -C 8 )alkenylene, said alkylene or alkenylene is optionally substituted with one to three R;

R 6 is (C 1 -C 2 )alkyl;

Q 1 and Q 2 are each, independently, a bond or —C(O)O—, with the proviso that when either Q 1 or Q 2 is a bond then the other is not a bond; and

X is —C(O)O—;

or a pharmaceutically acceptable salt or stereoisomer thereof.

3. A cationic lipid which is selected from:

methyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}octacos-9-enoate (Compound 1);

methyl 8-[2-(9-{[4-(dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]octanoate (Compound 2);

methyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}heptacos-9-enoate (Compound 3);

methyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}hexacos-9-enoate (Compound 4);

methyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}pentacos-9-enoate (Compound 5);

methyl (9Z)-21-{[4-(dimethylamino)butanoyl]oxy}triacont-9-enoate (Compound 6);

methyl (9Z)-21-{[4-(dimethylamino)butanoyl]oxy}nonacos-9-enoate (Compound 7);

methyl (9Z)-21-{[4-(dimethylamino)butanoyl]oxy}octacos-9-enoate (Compound 8);

methyl (9Z)-21-{[4-(dimethylamino)butanoyl]oxy}heptacos-9-enoate (Compound 9);

methyl (11Z)-19-{[4-(dimethylamino)butanoyl]oxy}octacos-11-enoate (Compound 10);

methyl (7Z)-19-{[4-(dimethylamino)butanoyl]oxy}octacos-7-enoate (Compound 11);

methyl 8-[2-(9-{[4-(dimethylamino)butanoyl]oxy}heptadecyl)cyclopropyl]octanoate (Compound 12);

methyl 8-[2-(9-{[4-(dimethylamino)butanoyl]oxy}hexadecyl)cyclopropyl]octanoate (Compound 13);

methyl 8-[2-(9-{[4-(dimethylamino)butanoyl]oxy}pentadecyl)cyclopropyl]octanoate (Compound 14);

methyl 8-[2-(11-{[4-(dimethylamino)butanoyl]oxy}icosyl)cyclopropyl]octanoate (Compound 15);

methyl 8-[2-(11-{[4-(dimethylamino)butanoyl]oxy}nonadecyl)cyclopropyl]octanoate (Compound 16);

methyl 8-{2-[11-(dimethylamino)octadecyl]cyclopropyl}octanoate (Compound 17);

methyl 8-[2-(11-{[4-(dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]octanoate (Compound 18);

methyl 10-[2-(7-{[4-(dimethylamino)butanoyl]oxy}hexadecyl)cyclopropyl]decanoate (Compound 19);

methyl 6-[2-(11-{[4-(dimethylamino)butanoyl]oxy}icosyl)cyclopropyl]hexanoate (Compound 20);

ethyl (7Z)-17-{[4-(dimethylamino)butanoyl]oxy}hexacos-7-enoate (Compound 21);

ethyl 6-[2-(9-{[4-(dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]hexanoate (Compound 22);

(2Z)-non-2-en-1-yl 10-{[4-(dimethylamino)butanoyl]oxy}nonadecanoate (Compound 23); (2-hexylcyclopropyl)methyl 10-{[4-(dimethylamino)butanoyl]oxy}nonadecanoate (Compound 24);

(2Z)-undec-2-en-1-yl 8-{[4-(dimethylamino)butanoyl]oxy}heptadecanoate (Compound 25);

(2Z)-hept-2-en-1-yl 12-{[4-(dimethylamino)butanoyl]oxy}henicosanoate (Compound 26);

(2-octylcyclopropyl)methyl 8-{[4-(dimethylamino)butanoyl]oxy}heptadecanoate (Compound 27);

(2-butylcyclopropyl)methyl 12-{[4-(dimethylamino)butanoyl]oxy}henicosanoate (Compound 28);

methyl (19Z,22Z)-9-{[4-(dimethylamino)butanoyl]oxy}octacosa-19,22-dienoate (Compound 29);

ethyl (18Z,21Z)-8-{[4-(dimethylamino)butanoyl]oxy}heptacosa-18,21-dienoate (Compound 30);

methyl 9-{[4-(dimethylamino)butanoyl]oxy}-16-(2-octylcyclopropyl)hexadecanoate (Compound 31);

ethyl 8-{[4-(dimethylamino)butanoyl]oxy}-15-(2-octylcyclopropyl)pentadecanoate (Compound 32);

dimethyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}heptacos-9-enedioate (Compound 33); and

1-methyl 18-[(2Z)-non-2-en-1-yl] 9-{[4-(dimethylamino)butanoyl]oxy}octadecanedioate (Compound 34);

or a pharmaceutically acceptable salt or stereoisomer thereof.

4. An LNP composition which comprises a cationic lipid of Formula A according to claim 1 , cholesterol, DSPC and PEG-DMG.

5. A lipid nanoparticle comprising a cationic lipid according to claim 1 .

6. The lipid nanoparticle according to claim 5 , wherein the nanoparticle comprises an oligonucleotide.

7. The lipid nanoparticle according to claim 6 wherein the oligonucleotide is siRNA.