Granted Patent B2

US 12,595,226 · App. 17/761,984 · Granted Apr 7, 2026

Inventors: Kerry E. Benenato (Cambridge, MA); Souvik Biswas (Cambridge, MA); Mark Cornebise (Cambridge, MA); Edward Hennessy (Cambridge, MA); Ellalahewage S. Kumarasinghe (Cambridge, MA)

Assignee: ModernaTX, Inc.

C07C217/08A61K9/1272C07C2601/04

Abstract

Claims (66)

1 . A compound of Formula (A):

or its N-oxide, or a salt thereof, wherein

m is selected from 5, 6, 7, 8, and 9;

R 2 and R 3 are each independently selected from the group consisting of H, C 1-14 alkyl, and C 2-14 alkenyl;

R 4 is selected from —(CH 2 ) n OH, wherein n is selected from 1, 2, 3, 4, and 5, and

wherein n2 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and R 10 is —N(R) 2 , wherein each R is independently selected from the group consisting of C 1-6 alkyl, C 2-3 alkenyl, and H;

M and M′ are each independently selected from —OC(O)O— and —C(O)O—;

wherein at least one of M and M′ is —OC(O)O—;

R′ a is C 1-18 alkyl or C 2-18 alkenyl; and

R″ is a C 3 -C 13 alkyl, optionally substituted with OH.

2 . The compound of claim 1 , wherein R″ is selected from

wherein

denotes a point of attachment with N, and

denotes a point of attachment with M.

3 . The compound of claim 1 , wherein the compound has one of the following structures:

4 . The compound of claim 1 , wherein R′ a is:

wherein

denotes a point of attachment;

R aα , R aβ , and R aγ are each independently selected from the group consisting of H, C 1-12 alkyl, and C 2-12 alkenyl, wherein at least one of R aα , R aβ , and R aγ is selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl; and

R′ is a C 1-12 alkyl or C 2-12 alkenyl.

5 . The compound of claim 4 , wherein:

R aβ and R aγ are each H and R aα is C 1-6 alkyl;

R aα and R aγ are each H and R aβ is C 1-6 alkyl; and/or

R aα and R aβ are each H and R aγ is C 1-6 alkyl.

6 . The compound of claim 5 , wherein R aβ is C 2 alkyl.

7 . The compound of claim 5 , wherein R aγ is a C 5 or a C 6 alkyl.

8 . The compound of claim 4 , wherein R′ is a C 5 or a C 6 alkyl.

9 . The compound of claim 1 , wherein the compound has the following structure:

10 . The compound of claim 1 , wherein R 4 is —(CH 2 ) n OH.

11 . The compound of claim 1 , wherein R 4 is —(CH 2 ) 2 OH.

12 . The compound of claim 1 , wherein R 4 is

13 . The compound of claim 1 , wherein R 4 is

14 . The compound of claim 1 , wherein n2 is 2 or 4.

15 . A compound selected from:

and N-oxides and salts thereof.

16 . An empty lipid nanoparticle (empty LNP) comprising a compound of claim 1 , a phospholipid, a structural lipid, and a PEG lipid.

17 . The empty LNP of claim 16 , comprising about 40 mol % to about 60 mol % said compound, about 0 mol % to about 20 mol % phospholipid, about 30 mol % to about 50 mol % structural lipid, and about 0 mol % to about 5 mol % PEG lipid;

wherein the phospholipid is selected from the group consisting of:

1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC),

1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),

1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC),

1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC),

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC),

1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC),

1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC),

1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC),

1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine,

1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE),

1,2-distearoyl-sn-glycero-3-phosphoethanolamine,

1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine,

1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine,

1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine,

1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine,

1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and

mixtures thereof;

wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, and mixtures thereof; and/or

wherein the PEG lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof.

18 . The empty LNP of claim 16 , wherein the PEG lipid is selected from PEG 2k -DMG and PEG-1:

and mixtures thereof.

19 . A loaded lipid nanoparticle (loaded LNP), which comprises the empty LNP of claim 16 , and one or more therapeutic and/or prophylactic agents.

20 . The loaded LNP of claim 19 , wherein the one or more therapeutic and/or prophylactic agents is a nucleic acid; wherein the nucleic acid is an RNA, and wherein the RNA is selected from the group consisting of a short interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a RNA interference RNAi) molecule, a microRNA (miRNA), an antagomir, an antisense RNA, a ribozyme, a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and mixtures thereof.

21 . The loaded LNP of claim 20 , wherein the RNA is an mRNA.

22 . A pharmaceutical composition comprising the loaded LNP of claim 19 , and a pharmaceutically acceptable carrier.

23 . A method of delivering a therapeutic and/or prophylactic agent to a cell within a subject, and/or to the organ of a subject, the method comprising administering to the subject the loaded LNP of claim 19 .

24 . A method of producing a polypeptide of interest in a cell within a subject, the method comprising administering to the subject the loaded LNP of claim 19 .

25 . A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the loaded LNP of claim 19 .

Assignments (2)

Continuity (2)

References Cited (400)