Compounds for regulating trained immunity, and their methods of use

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is —H or —C(O)—R X ;

R 2 and R 3 are each independently selected from the group consisting of —H, alkyl, aryl, alkylene-aryl, —C(O)-alkyl, and —C(O)-aryl;

R 4 , R 5 , and R 5′ are each alkyl;

R 6 and R 11 are each independently —H or alkyl;

R 7 is —Y-triazolyl-L;

Y is alkylene;

L is selected from the group consisting of a fatty acid chain, -alkylene-C(O)—W, -alkylene-O—C(O)—W, -alkylene-N-(alkylene-C(O)—NR 11 -alkylene-NR 11 —C(O)—W) 2 , and -alkylene-N-(alkylene-C(O)—W) 2 ;

W is a fatty acid chain, —O-alkylene-C(H)(OR 8 )-alkylene-OR 9 , a phospholipid, or a sterol;

R 8 and R 9 are each independently R X or —C(O)—R X ;

R 22 , R 33 , R 33′ , R 44 , R 44′ , R 55 , and R 55′ are each independently H or R A ;

R X is a fatty acid chain;

wherein each aforementioned alkyl, alkylene, alkylene-aryl, aryl, and triazolyl is optionally substituted with one or more R A , wherein R A is independently selected for each occurrence from the group consisting of hydrogen, halo, alkoxy, haloalkoxy, cyano, hydroxyl, —N(R C )(R D ), —C(O)N(R C )(R D ), —N(R C )C(O)R B , —OC(O)NR C R D , —NR C C(O)OR B , —OC(O)R B , —C(O)OR B , —C(O)R B , —CO 2 H, —NO 2 , —SH, S(O) X R B , aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and R B ; wherein X is 0, 1, or 2,

R C and R D are independently selected for each occurrence from the group consisting of hydrogen, alkyl, haloalkyl —C(O)R B , and —C(O)OR B ; or R C and R D are taken together with the nitrogen to which they are attached to form a heterocyclic ring optionally substituted with R A ; and

R B is alkyl, alkenyl, or alkynyl optionally substituted with one or more fluoro.

2. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 2 is —H or benzyl.

4. The compound of claim 1 , wherein R 2 is —H.

5. The compound of claim 1 , wherein R 22 , R 33 , R 33′ , R 44 , R 44′ , R 55 , and R 55′ are each —H.

6. The compound of claim 1 , wherein R 4 is alkyl.

7. The compound of claim 4 , wherein R 4 is methyl.

8. The compound of claim 1 , wherein R 3 and R 6 are both —H.

9. The compound of claim 1 , wherein Y is —CH 2 —.

10. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

X 1 is —N— and X 2 is —C—; or X 1 is —C— and X 2 is —N—.

11. The compound of claim 10 , wherein the compound of formula (II) is a compound of formula (IIA):

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10 , wherein Y is C 1-6 alkylene.

13. The compound of claim 10 , wherein R A is —H.

14. The compound of claim 1 , wherein L is —CH 2 —C(O)—W.

15. The compound of claim 1 , wherein W is a —C 8-30 alkyl.

16. The compound of claim 1 , wherein W is:

wherein R X and R X′ are each independently a —C 8-30 fatty acid chain.

17. The compound of claim 16 , wherein R X and R X′ are each independently a —C 8-30 alkyl.

18. The compound of claim 17 , wherein R X and R X′ are both —(CH 2 CH 2 ) 8 —CH 3 .

19. The compound of claim 1 , wherein W is cholesterol:

20. The compound of claim 1 , wherein W is a phospholipid.

21. The compound of claim 20 , wherein W is a phospholipid having the structure:

wherein

Y Q1 , Y Q2 , and Y Q3 are each independently alkylene and R X and R X′ are each independently a fatty acid chain having at least 15 carbons.

22. The compound of claim 21 , wherein R X and R X′ are each independently a —C 15-20 alkyl or a —C 15-20 alkenyl.

23. The compound of claim 20 , wherein W is a phospholipid having the structure:

or a pharmaceutically acceptable salt thereof;

wherein R X and R X′ are each independently a C 8-30 fatty acid chain.

24. The compound of claim 23 , wherein R X and R X′ are each independently a C 12-18 fatty acid chain.

25. The compound of claim 23 , wherein the fatty acid chain is saturated.

26. The compound of claim 23 , wherein R X and R X′ are both —(CH 2 CH 2 ) 8 —CH 3 .

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

and a pharmaceutically acceptable salt thereof, wherein Bn is a benzyl group.

28. A nanobiologic composition, comprising a high-density lipoprotein (HDL)-derived nanoparticle wherein the nanoparticle comprises one or more phospholipids, and a compound of claim 1 .

29. The nanobiologic composition of claim 28 , wherein the phospholipid is independently selected from the group consisting of a phosphatidylcholine, a phosphatidylethanolamine, a phosphatidylinositol, a phosphatidylserine, a sphingomyelin or other ceramide, a phospholipid-containing oil, a phosphatidylglycerol, a phosphatidic acid, a lysophosphatidylcholine, and combinations thereof.

30. The nanobiologic composition of claim 28 , wherein the phospholipid is selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and further comprising a lysolipid selected from the group consisting of l-myristoyl-2-hydroxy-sn-glycero-phosphocholine (MH PC), and 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (PH PC).

31. The nanobiologic composition of claim 28 , wherein the HDL-derived nanoparticle further comprises apoA-I or a peptide mimetic of apoA-I.

32. The nanobiologic composition of claim 28 , wherein the HDL-derived nanoparticle further comprises cholesterol.

33. The nanobiologic composition of claim 32 , wherein the HDL-derived nanoparticle comprises one or more phospholipids and cholesterol in a molar ratio in the range of about 1:0.05 to about 1:0.25.

34. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. A method for activating a NOD2 receptor in a subject in need thereof, comprising administering to the subject an effective amount of the nanobiologic composition of claim 28 .

36. The compound of claim 10 , wherein the compound of formula (II) is a compound of formula (II-1):

or a pharmaceutically acceptable salt thereof.

37. The compound of claim 27 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

38. The compound of claim 27 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

39. The compound of claim 27 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

40. The compound of claim 27 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.