Granted Patent B2

US 12,723,023 · App. 17/985,045 · Granted Sep 1, 2026

Inventors: Kumar Rajappan (San Diego, CA); Steven Tanis (San Diego, CA); Amit Sagi (San Diego, CA); Priya Prakash Karmali (San Diego, CA); Padmanabh Chivukula (San Diego, CA)

Assignee: Arcturus Therapeutics, Inc.

C07C333/04A61K47/543A61K47/6911C07C229/04C07C229/16C07C271/20C07C275/16C07C327/06C12N15/113C12N15/88C07C2601/14C07C2602/22C07C2602/24C07C2602/28C12N2310/14

Abstract

Claims (91)

1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

R 1 and R 2 are each independently H or C 1-6 alkyl; or

R 1 and R 2 are joined to form a saturated heterocyclic ring, wherein:

R 1 is a linear C 1-4 alkylene; and

R 2 is —(CH 2 ) m (X) n —, wherein

X is O, S, or NR 9 , wherein R 9 is H or C 1-6 alkyl;

m is 1, 2, 3 or 4, and

n is 0 or 1;

L1 is a linear C 1-6 alkylene optionally substituted with one to three methyl groups;

Y is selected from the group consisting of:

wherein:

each asterisk (*) indicates the atom attached to L2 and L3; and

R 10 is H or C 1-6 alkyl;

L2 and L3 are each independently a linear C 1-8 alkylene;

L4, L5, L6, L7, L8 and L9 are each independently absent or —CH 2 —, provided that:

at least two of L4, L6 and L8 are —CH 2 —; and

at least two of L5, L7 and L9 are —CH 2 —;

R 3 and R 4 are each independently H, methyl or ethyl; and

R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of:

(a) linear C 1-20 alkyl, wherein each said linear C 1-20 alkyl is optionally substituted with one or more substituents selected from the group consisting of:

(i) C 1-6 alkyl, C 1-6 alkoxy and —F, wherein each said C 1-6 alkyl substituent is optionally substituted with one or more groups selected from the group consisting of C 1-3 alkoxy and —F;

(ii) C 3-8 monocycloalkyl, wherein each said C 3-8 monocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and —F;

(iii) C 7-12 bicycloalkyl, wherein each said C 7-12 bicycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and —F; and

(iv) C 6-10 aryl, wherein each said C 6-10 aryl is a monocyclic or bicyclic aromatic hydrocarbon optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and —F;

(b) C 3-8 monocycloalkyl, wherein each said C 3-8 monocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and —F;

(c) C 7-12 bicycloalkyl, wherein each said C 7-12 bicycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and —F; and

(d) C 6-10 aryl, wherein each said C 6-10 aryl is a monocyclic or bicyclic aromatic hydrocarbon optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and —F.

2 . The compound of claim 1 , wherein Y is selected from the group consisting of:

3 . The compound of claim 1 , wherein R 1 and R 2 are each independently C 1-6 alkyl.

4 . The compound of claim 1 , wherein R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of:

(a) linear C 1-8 alkyl, wherein each said linear C 1-8 alkyl is optionally substituted with one or more substituents selected from the group consisting of:

(i) C 1-3 alkyl, C 1-3 alkoxy and —F, wherein each said C 1-3 alkyl substituent is optionally substituted with one or more groups selected from the group consisting of C 1-3 alkoxy and —F;

(ii) saturated C 3-6 monocycloalkyl, wherein each said saturated C 3-6 monocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F;

(iii) saturated C 7-12 bicycloalkyl, wherein each said saturated C 7-12 bicycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F; and

(iv) C 6-10 aryl, wherein each said C 6-10 aryl is a monocyclic or bicyclic aromatic hydrocarbon optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F;

(b) saturated C 3-6 monocycloalkyl, wherein each said C 3-6 monocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F;

(c) saturated C 7-12 bicycloalkyl, wherein each said saturated C 7-12 bicycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F; and

(d) C 6-10 aryl, wherein each said C 6-10 aryl is a monocyclic or bicyclic aromatic hydrocarbon optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F.

5 . The compound of claim 4 , wherein R 5 , R 6 , R 7 and R 8 are each independently linear C 1-8 alkyl, wherein each said linear C 1-8 alkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy and —F, wherein each said C 1-3 alkyl substituent is optionally substituted with one or more groups selected from the group consisting of C 1-3 alkoxy and —F.

6 . The compound of claim 4 , wherein R 5 , R 6 , R 7 and R 8 are each independently linear C 1-8 alkyl optionally substituted with saturated C 3-6 monocycloalkyl, wherein each said saturated C 3-6 monocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F.

7 . The compound of claim 6 , wherein each said saturated C 3-6 monocycloalkyl is optionally substituted with one or more C 1-3 alkyl.

8 . The compound of claim 4 , wherein R 5 , R 6 , R 7 and R 8 are each independently linear C 1-8 alkyl optionally substituted with saturated C 7-12 bicycloalkyl, wherein each said saturated C 7-12 bicycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F.

9 . The compound of claim 4 , wherein R 5 , R 6 , R 7 and R 8 are each independently saturated C 3-6 monocycloalkyl, wherein each said C 3-6 monocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-3 alkoxy and —F.

10 . The compound of claim 4 , wherein R 5 , R 6 , R 7 and R 8 are each independently monocycloalkyl selected from the group consisting of:

wherein:

each asterisk (*) indicates the atom attached to the carbonyl carbon;

each R 11 is independently C 1-6 alkyl;

each R 12 is independently C 1-3 alkoxy;

each R 13 is —F;

each p is independently 0 to 11;

each q is independently 0 to 11; and

each r is independently 0 to 11;

wherein the sum of p, q and r is no greater than 11.

11 . The compound of claim 4 , wherein R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of:

wherein:

each asterisk (*) indicates the atom attached to the carbonyl carbon;

each R 14 is independently H or C 1-6 alkyl; and

each R 15 is independently H or C 1-6 alkyl.

12 . The compound of claim 1 , wherein L1 is linear unsubstituted alkylene.

13 . The compound of claim 1 , wherein L2 and L3 are each independently linear C 1-5 alkylene.

14 . The compound of claim 1 , wherein L6, L7, L8 and L9 are each —CH 2 —; and L4 and L5 are absent.

15 . The compound of claim 1 selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

16 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

17 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

18 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

19 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

20 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

21 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

22 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

23 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

24 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

25 . The compound of claim 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

26 . A lipid composition comprising a nucleic acid and a compound of claim 1 .

27 . The lipid composition of claim 26 , wherein the nucleic acid is selected from an siRNA, an mRNA, a self-replicating RNA, a DNA plasmid, and an antisense oligonucleotide, wherein the mRNA or the self-replicating RNA comprises a coding region that encodes a therapeutic protein of interest.

28 . The lipid composition of claim 27 , wherein the therapeutic protein of interest is an enzyme, and antibody, an antigen, a receptor, or a transporter.

29 . The lipid composition of claim 26 , wherein the lipid composition comprises liposomes, lipoplexes, or lipid nanoparticles.

30 . A lipid nanoparticle comprising a plurality of ligands, wherein each ligand is independently a compound of claim 1 , wherein the plurality of ligands self-assembles to form the lipid nanoparticle comprising an interior and an exterior.

31 . A pharmaceutical composition comprising the lipid nanoparticle of claim 26 and a pharmaceutically acceptable excipient.

32 . The pharmaceutical composition of claim 31 , wherein the pharmaceutical is a lyophilized composition.

Assignments (1)

Continuity (2)

References Cited (89)