CATIONIC LIPIDS FOR LIPID NANOPARTICLE DELIVERY OF THERAPEUTICS TO HEPATIC STELLATE CELLS

1 . A compound of formula (I):

or a salt thereof, wherein:

R 1 is (C 5 -C 25 )alkyl, (C 5 -C 25 )alkenyl, or (C 5 -C 25 )alkynyl;

R 2 is (C 5 -C 25 )alkyl, (C 5 -C 25 )alkenyl, or (C 5 -C 25 )alkynyl;

R 3 is (C 5 -C 25 )alkyl, (C 5 -C 25 )alkenyl, or (C 5 -C 25 )alkynyl;

R 4 is (C 3 -C 15 )alkyl, (C 3 -C 15 )alkenyl, or (C 3 -C 15 )alkynyl, which (C 3 -C 15 )alkyl, (C 3 -C 15 )alkenyl, or C 3 -C 15 )alkynyl is optionally substituted with one or more groups independently selected from chloro, bromo, iodo, and —NR a R b ; and

each R a and R b is independently selected form the group consisting of H and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from halo and hydroxy; or R a and R b taken together with the nitrogen to which they are attached form a ring selected from the group consisting of aziridine, azetadine, pyrrolidine, piperidine, piperazine, morpholino, and thiomorpholino, which ring is optionally substituted with one or more groups independently selected form (C 1 -C 6 )alkyl.

2 . The compound of claim 1 , wherein R 1 is (C 5 -C 25 )alkyl.

3 . The compound of claim 1 , wherein R 1 is (C 5 -C 25 )alkenyl.

4 . The compound of claim 1 , wherein R 1 is (C 5 -C 25 )alkynyl.

5 . The compound of claim 1 , wherein R 1 is (C 5 -C 20 )alkyl.

6 . The compound of claim 1 , wherein R 1 is (C 5 -C 20 )alkenyl.

7 . The compound of claim 1 , wherein R 1 is (C 5 -C 20 )alkynyl.

8 . The compound of claim 1 , wherein R 1 is (C 10 -C 20 )alkyl.

9 . The compound of claim 1 , wherein R 1 is (C 10 -C 20 )alkenyl.

10 . The compound of claim 1 , wherein R 1 is (C 10 -C 20 )alkynyl.

11 . The compound of claim 1 , wherein R 1 is 4-decen-1-yl or 8,10-heptadecadien-1-yl.

12 . The compound of any one of claims 1-11 , wherein R 2 is (C 5 -C 25 )alkyl.

13 . The compound of any one of claims 1-11 , wherein R 2 is (C 5 -C 25 )alkenyl.

14 . The compound of any one of claims 1-11 , wherein R 2 is (C 5 -C 25 )alkynyl.

15 . The compound of any one of claims 1-11 , wherein R 2 is (C 5 -C 20 )alkyl.

16 . The compound of any one of claims 1-11 , wherein R 2 is (C 5 -C 20 )alkenyl.

17 . The compound of any one of claims 1-11 , wherein R 2 is (C 5 -C 20 )alkynyl.

18 . The compound of any one of claims 1-11 , wherein R 2 is (C 10 -C 20 )alkyl.

19 . The compound of any one of claims 1-11 , wherein R 2 is (C 10 -C 20 )alkenyl.

20 . The compound of any one of claims 1-11 , wherein R 2 is (C 10 -C 20 )alkynyl.

21 . The compound of any one of claims 1-11 , wherein R 2 is 4-decen-1-yl.

22 . The compound of any one of claims 1-21 , wherein R 3 is (C 5 -C 25 )alkyl.

23 . The compound of any one of claims 1-21 , wherein R 3 is (C 5 -C 25 )alkenyl.

24 . The compound of any one of claims 1-21 , wherein R 3 is (C 5 -C 25 )alkynyl.

25 . The compound of any one of claims 1-21 , wherein R 3 is (C 5 -C 20 )alkyl.

26 . The compound of any one of claims 1-21 , wherein R 3 is (C 5 -C 20 )alkenyl.

27 . The compound of any one of claims 1-21 , wherein R 3 is (C 5 -C 20 )alkynyl.

28 . The compound of any one of claims 1-21 , wherein R 3 is (C 10 -C 20 )alkyl.

29 . The compound of any one of claims 1-21 , wherein R 3 is (C 10 -C 20 )alkenyl.

30 . The compound of any one of claims 1-21 , wherein R 3 is (C 10 -C 20 )alkynyl.

31 . The compound of any one of claims 1-21 , wherein R 3 is 4-decen-1-yl.

32 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 15 )alkyl that is substituted with one or more groups independently selected from chloro, bromo, iodo, and —NR a R b .

33 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 15 )alkenyl that is substituted with one or more groups independently selected from chloro, bromo, iodo, and —NR a R b .

34 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 15 )alkynyl that is substituted with one or more groups independently selected from chloro, bromo, iodo, and —NR a R b .

35 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 10 )alkyl that is substituted with one or more groups independently selected from chloro, bromo, iodo, and —NR a R b .

36 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 10 )alkenyl that is substituted with one or more groups independently selected from chloro, bromo, iodo, and —NR a R b .

37 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 10 )alkynyl that is substituted with one or more groups independently selected from chloro, bromo, iodo, and —NR a R b .

38 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 10 )alkyl, (C 3 -C 10 )alkenyl, or (C 3 -C 10 )alkynyl, which (C 3 -C 10 )alkyl, (C 3 -C 10 )alkenyl, and C 3 -C 10 )alkynyl is substituted with one or more groups independently selected from chloro, bromo, iodo, and —NR a R b .

39 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 15 )alkyl, (C 3 -C 15 )alkenyl, or (C 3 -C 15 )alkynyl, which (C 3 -C 15 )alkyl, (C 3 -C 15 )alkenyl, and C 3 -C 15 )alkynyl is substituted with chloro, bromo, or iodo.

40 . The compound of any one of claims 1-31 , wherein R 4 is (C 3 -C 15 )alkyl, (C 3 -C 15 )alkenyl, or (C 3 -C 15 )alkynyl, which (C 3 -C 15 )alkyl, (C 3 -C 15 )alkenyl, and C 3 -C 15 )alkynyl is substituted —NR a R b .

41 . The compound of claim 40 , wherein each R a and R b is independently selected form the group consisting of (C 1 -C 6 )alkyl.

42 . The compound of claim 40 , wherein each R a and R b is methyl.

43 . The compound of any one of claims 1-31 , wherein R 4 is 5-(N,N-dimethylamino)pent-1-yl.

44 . The compound:

or

or a salt thereof, wherein:

each R a and R b is independently selected form the group consisting of H and (C 1 -C 6 )alkyl that is optionally substituted with one or more groups independently selected from halo and hydroxy; or R a and R b taken together with the nitrogen to which they are attached form a ring selected from the group consisting of aziridine, azetadine, pyrrolidine, piperidine, piperazine, morpholino, and thiomorpholino, which ring is optionally substituted with one or more groups independently selected form (C 1 -C 6 )alkyl.

45 . A compound, or a salt thereof, selected from a compound as described herein.

46 . A lipid particle comprising the compound of any one of claims 1-45 .

47 . The lipid particle of claim 46 , wherein the lipid particle further comprises a non-cationic lipid.

48 . The lipid particle of claim 46 or 47 , wherein the lipid particle further comprises a conjugated lipid that inhibits aggregation of particles.

49 . The lipid particle of any one of claims 46-48 , wherein the lipid particle further comprises a therapeutic agent.

50 . The lipid particle of claim 49 , wherein the therapeutic agent is a nucleic acid therapeutic agent.

51 . The lipid particle of claim 50 , wherein the therapeutic agent is an interfering RNA agent.

52 . The lipid particle of claim 51 , wherein the therapeutic agent is siRNA.

53 . The lipid particle of claim 50 , wherein the therapeutic agent is mRNA.

54 . The lipid particle of any one of claims 50-53 , wherein the nucleic acid therapeutic agent comprises at least one modified nucleotide.

55 . The lipid particle of claim 54 , which comprises at least one 2′—O—methyl (2′OMe) nucleotide.

56 . The lipid particle of any one of claims 46-55 , wherein, the non-cationic lipid is cholesterol or a derivative thereof.

57 . The lipid particle of any one of claims 46-55 , wherein the non-cationic lipid is cholesterol.

58 . The lipid particle of any one of claims 46-55 , wherein the non-cationic lipid comprises a phospholipid.

59 . The lipid particle of any one of claims 46-55 , wherein the non-cationic lipid comprises a mixture of a phospholipid and cholesterol.

60 . The lipid particle of any one of claims 58-59 , wherein the phospholipid is distearoylphosphatidylcholine (DSPC).

61 . The lipid particle of any one of claims 47-60 , wherein the conjugated lipid is a polyethyleneglycol (PEG)-lipid conjugate.

62 . The lipid particle of claim 61 , wherein the PEG-lipid conjugate is a PEG-dimyristyloxypropyl (PEG-DMA) conjugate.

63 . A composition comprising a compound of any one of claims 1-45 .

64 . A pharmaceutical composition comprising a lipid particle of any one of claims 46-62 , and a pharmaceutically acceptable carrier.

65 . A method for the in vivo delivery of a therapeutic agent, the method comprising: administering to a mammalian subject a lipid particle of any one of claims 49-62 .

66 . A lipid particle of any one of claims 49-62 for use in the in vivo delivery of a therapeutic agent to a mammal.

67 . The use of a lipid particle of any one of claims 49-62 to prepare a medicament for the in vivo delivery of a therapeutic agent to a mammal.

68 . A method for treating a disease or disorder in a mammalian subject in need thereof, the method comprising:

administering to the mammalian subject a therapeutically effective amount of a lipid particle of any one of claims 49-62 .

69 . The method of claim 68 , wherein the disease or disorder is liver fibrosis.

70 . The method of claim 68 , wherein the disease or disorder is non-alcoholic steatohepatitis (NASH).

71 . The method of claim 68 , wherein the disease or disorder is alcoholic steatohepatitis (ASH).

72 . The method of claim 68 , wherein the disease or disorder is liver fibrosis associated non-alcoholic steatohepatitis (NASH) or alcoholic steatohepatitis (ASH).

73 . A method of delivering a therapeutic agent to a hepatic stellate cell (HSC), in vivo or in vitro, comprising contacting the HSC with the lipid particle of any one of claims 49-62 .