Di-aliphatic substituted pegylated lipids

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R 1 and R 2 are each, independently, a C 10 to C 30 aliphatic group, wherein each aliphatic group is optionally substituted by one or more groups each independently selected from R a ;

L is -L 1 -Z 1 -(L 2 -Z 2 ) c -L 3 -;

L 1 is a bond, —(CR 5 R 5′ ) i —, or —(CR 5 R 5′ ) i —(C(R a )═C(R b )) k —(C≡C) k —(CR a R b ) j —;

Z 1 is —O—, —S—, —N(R c )—, —OC(O)—, —C(O)O—, —OC(O)O—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —N(R c )C(O)—, —C(O)N(R c )—, —N═C(R a )—, —C(R a )═N—, —O—N═C(R a )—, —O—N(R c )—; heteroaryl, or heterocyclyl;

L 2 is —(CR a R b ) p — or —(CR a R b ) j —(C(R a )═C(R b )) k —(C≡C) k —(CR a R b ) j —;

Z 2 is —O—, —S—, —N(R c )—, —OC(O)—, —C(O)O—, —OC(O)O—, —OC(O)N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)—, —C(O)N(R c )—, —N═C(R a )—, —C(R a )═N—, —O—N═C(R a )—, —O—N(R c )—, heteroaryl, or heterocyclyl;

L 3 is —(CR a R b ) i —;

each A, independently, is -L 4 -, —NH-(L 4 ) q -(CR a R b ) r —C(O)—, or —C(O)—(CR a R b ) r -(L 4 ) q -NH—; wherein each q, independently, is 0, 1, 2, 3, or 4; and each r, independently, is 0, 1, 2, 3, or 4;

each L 4 , independently, is —(CR a R b ) s O— or —O(CR a R b ) s —, wherein each s, independently, is 0, 1, 2, 3, or 4;

R 3 is H, —R c , or —OR c ;

each occurrence of R 5 and R 5′ is, independently, H, halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, or cycloalkyl;

each occurrence of R a and R b is, independently, H, halo, cyano, hydroxy, nitro, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, heteroaryl, or heterocyclyl;

each R c is, independently, H, alkyl, acyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl;

b ranges from 5 to about 500;

c is 0 or 1;

each i is, independently, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

each occurrence of j and k, independently, is 0, 1, 2, or 3; and

p is an integer from 1 to 10.

2. The compound of claim 1 , wherein R 1 and R 2 are independently C 10 to C 20 alkyl or C 10 to C 20 alkenyl.

3. The compound of claim 1 , wherein L 1 is a bond or —(CR 5 R 5 ′) i —.

4. The compound of claim 1 , wherein Z 1 is —O—, —N(H)—, —N(CH 3 )—, —OC(O)—, —C(O)O—, —OC(O)N(CH 3 )—, —N(H)C(O)O—, —N(CH 3 )C(O)O—, —N(H)C(O)N(H)—, —N(H)C(O)N(CH 3 )—, —N(CH 3 )C(O)N(CH 3 )—, —N(CH 3 )C(O)N(H)—, —N(H)C(O)—, —N(CH 3 )C(O)—, —C(O)N(H)—, —C(O)N(CH 3 )—, —O—N═C(H)—, —O—N═C(CH 3 )—, —O—N(H)—, —O—N(CH 3 )— or heteroaryl.

5. The compound of claim 1 , wherein Z 1 is —N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —N(R c )C(O)—, or —N═C(R a )—, and the leftmost nitrogen atom in Z 1 is attached to the tertiary carbon atom of formula (I), or

Z 1 is a nitrogen-containing heteroaryl or heterocyclyl, wherein the nitrogen atom of the heteroaryl or heterocyclyl is bound to L 1 or if L 1 is a bond, then to the central tertiary carbon atom.

6. The compound of claim 1 , wherein c is 1 and L 2 is —(CR a R b ) p .

7. The compound of claim 1 , wherein c is 1 and Z 2 is —O—, —C(O)O—, —C(O)N(R c )—, or heteroaryl.

8. The compound of claim 1 , wherein each A is, independently, L 4 and each L 4 is, independently —OCH 2 CH 2 —, —CH 2 CH 2 O—, —OCH 2 CH 2 CH 2 —, —OCH(CH 3 )CH 2 CH 2 —, —OCH 2 CH 2 —CH(CH 3 )—, —OCH(CH 3 )CH 2 — or —OCH 2 CH(CH 3 )—.

9. The compound of claim 1 , wherein R 3 is alkoxy.

10. The compound of claim 9 , wherein R 3 is methoxy.

11. The compound of claim 1 , wherein b is from about 30 to about 60.

12. The compound of claim 1 , wherein c is 0.

13. The compound of claim 1 , wherein c is 1.

14. The compound of claim 1 , wherein

R 1 and R 2 are each, independently C 12 to C 20 alkyl or C 12 to C 20 alkenyl;

L is -L 1 -Z 1 -L 3 - or -L 1 -Z 1 -(L 2 -Z 2 )-L 3 -;

L 1 is a bond or —(CR 5 R 5′ ) i —;

Z 1 is —O—, —N(R c )—, —OC(O)—, —C(O)O—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —N(R c )C(O)—, —C(O)N(R c )—, —O—N═C(R a )—, —O—N(R c )—, heteroaryl, or heterocyclyl;

L 2 is —(CR a R b ) p ;

Z 2 is —O—, —C(O)O—, —C(O)N(R c )—, or heteroaryl;

L 3 is —(CR a R b ) i —;

each A is, independently, -L 4 -;

each L 4 is, independently, —OCH 2 CH 2 —, —CH 2 CH 2 O—, —OCH(CH 3 )CH 2 or —OCH 2 CH(CH 3 )—;

R 3 is —OR c ;

each occurrence of R a is, independently, H or alkyl;

each occurrence of R b is, independently, H or alkyl; and

R c is H or alkyl.

15. The compound of claim 1 , wherein

R 1 and R 2 are each, independently C 12 to C 20 alkyl or C 12 to C 20 alkenyl; and

Z 1 is —N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —N(R c )C(O)—, or —N═C(R a )—, wherein the leftmost nitrogen atom in Z 1 is bound to L 1 or if L 1 is a bond, then to the central tertiary carbon atom of formula (I)), or

Z 1 is a nitrogen-containing heteroaryl or heterocyclyl, wherein the nitrogen atom of the heteroaryl or heterocyclyl is bound to L 1 or if L 1 is a bond, then to the central tertiary carbon atom of formula (I).

16. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein

R 1 and R 2 are each, independently C 10 to C 30 aliphatic group;

L is -L 1 -Z 1 -L 3 -;

L 1 is a bond or —(CR 5 R 5′ ) i —;

Z 1 is —N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —N(R c )C(O)—, or —N═C(R a )—, wherein the leftmost nitrogen atom in Z 1 is bound to L 1 or if L 1 is a bond, then to the central tertiary carbon atom of formula (II)), or

Z 1 is a nitrogen-containing heteroaryl or heterocyclyl, wherein the nitrogen atom of the heteroaryl or heterocyclyl is bound to L 1 or if L 1 is a bond, then to the central tertiary carbon atom of formula (II));

L 3 is —(CR a R b ) i —;

each A is, independently, -L 4 -;

b ranges from about 5 to about 500;

each L 4 , independently, is —OCH 2 CH 2 —, —CH 2 CH 2 O—, —OCH(CH 3 )CH 2 — or —OCH 2 CH(CH 3 )—;

R 3 is —OR c ;

each occurrence of R a , R c , R 5 and R 5′ is, independently, H or alkyl; and

i is 2, 3, 4 or 5.

17. A compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein

R 1 and R 2 are each, independently C 12 to C 20 alkyl or C 12 to C 20 alkenyl;

L is -L 1 -Z 1 -L 2 -Z 2 -L 3 -;

L 1 is a bond or —(CR 5 R 5′ ) i —;

Z 1 is —N(R c )—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —N(R c )C(O)—, or —N═C(R a )—, wherein the leftmost nitrogen atom in Z 1 is bound to L 1 or if L 1 is a bond, then to the central tertiary carbon atom of formula (II)), or

Z 1 is a nitrogen-containing heteroaryl or heterocyclyl, wherein the nitrogen atom of the heteroaryl or heterocyclyl is bound to L 1 or if L 1 is a bond, then to the central tertiary carbon atom of formula (II);

L 2 is —(CR a R b ) p ;

Z 2 is —O—, —C(O)O—, —C(O)N(R c )—, or heteroaryl;

L 3 is —(CR a R b ) i —;

each A is, independently, -L 4 -;

b ranges from about 5 to about 500;

each L 4 , independently, is —OCH 2 CH 2 —, —CH 2 CH 2 O—, —OCH(CH 3 )CH 2 — or —OCH 2 CH(CH 3 )—;

R 3 is —OR c ;

each occurrence of R a , R b , R c , R 5 and R 5′ is, independently, H or alkyl;

i is 2, 3, 4 or 5; and

p is 1 to 10.

18. The compound selected from:

or a pharmaceutically acceptable salt thereof, wherein

n is an integer from 1 to 1,000; and

m is 0, 1, 2, 3, 4, 5, or 6.

19. The compound of claim 18 , wherein n is from about 30 to about 60.

20. A lipid particle comprising a compound of formula (I) claim 1 , a cationic lipid, a neutral lipid, and a sterol.

21. The lipid particle of claim 20 , wherein the cationic lipid is present in a mole percentage of about 20% and about 60%; the neutral lipid is present in a mole percentage of about 5% to about 25%; the sterol is present in a mole percentage of about 25% to about 55%; and the compound according to formula (I) is present in a mole percentage of about 0.5% to about 15%.

22. The lipid particle of claim 20 , further comprising an active agent selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

23. A pharmaceutical composition comprising a lipid particle of claim 20 and a pharmaceutically acceptable carrier.

24. A method of modulating the expression of a target gene in a cell comprising providing a lipid particle of claim 22 to the cell.

25. The compound of claim 1 , wherein b ranges from about 10 to about 500.

26. The compound of claim 1 , wherein b ranges from about 10 to about 250.

27. The compound of claim 1 , wherein b ranges from about 25 to about 100.

28. The compound of claim 1 , wherein b ranges from about 40 to about 50.

29. The compound of claim 16 , wherein b ranges from about 10 to about 500.

30. The compound of claim 16 , wherein b ranges from about 10 to about 250.

31. The compound of claim 16 , wherein b ranges from about 25 to about 100.

32. The compound of claim 16 , wherein b ranges from about 30 to about 60.

33. The compound of claim 16 , wherein b ranges from about 40 to about 50.

34. The compound of claim 17 , wherein b ranges from about 10 to about 500.

35. The compound of claim 17 , wherein b ranges from about 10 to about 250.

36. The compound of claim 17 , wherein b ranges from about 25 to about 100.

37. The compound of claim 17 , wherein b ranges from about 30 to about 60.

38. The compound of claim 17 , wherein b ranges from about 40 to about 50.

39. The compound of claim 1 , wherein R 3 is —R c , or —OR c , and R c is alkyl, acyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl.

40. The compound of claim 1 , wherein Z 1 is —S—, —N(R c )—, —OC(O)—, —C(O)O—, —OC(O)O—, —N(R c )C(O)O—, —N(R c )C(O)N(R c )—, —N(R c )C(O)—, —C(O)N(R c )—, —N═C(R a )—, —C(R a )═N—, —O—N═C(R a )—, —O—N(R c )—; heteroaryl, or heterocyclyl.