Immunomodulatory compounds
Disclosed are immunomodulatory compounds, pharmaceutical compositions containing them, and methods of making and using the compounds to treat diseases and disorders characterized by aberrant protein activity that can be targeted by cereblon.
1. A compound having a structure represented by formula (I):
wherein A represents:
wherein X is C and X 1 is N, or
X and X 1 are both C, or
X and X 1 are both N;
wherein R 1 is absent if X 1 represents N, and if X 1 represents C, R 1 represents H, or together with R 2 and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group or an optionally substituted 6-membered heterocyclic group;
R 2 represents H, halo, hydroxy, optionally substituted C1-C4 alkoxy, 1-benzyl-4-piperidinoxy, optionally substituted 5- or 6-membered carbocyclic group, optionally substituted 5- or 6-membered heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, or NR 6 R 7 , wherein each of R 6 and R 7 independently represents H or a substituent or R 2 together with R 1 and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group or an optionally substituted 6-membered heterocyclic group;
if X represents N, R 3 is absent, and if X represents C, R 3 independently represents H, halo, hydroxy, optionally substituted amine, 1-benzyl-4-piperidinoxy, optionally substituted 5- or 6-membered carbocyclic group, optionally substituted 5- or 6-membered heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, or NR 6 R 7 , or wherein R 2 and R 3 , or R 3 and R 4 , together with the atoms to which they are bound form an optionally substituted 6-membered heterocyclic group;
R 4 , and R 5 each independently represents H, halo, hydroxy, optionally substituted amine, 1-benzyl-4-piperidinoxy, optionally substituted 5- or 6-membered carbocyclic group, optionally substituted 6-membered heterocyclic group, optionally substituted aryl, or NR 6 R 7 , or wherein R 4 and R 5 , together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group or an optionally substituted 6-membered heterocyclic group;
wherein R 8 represents H, optionally substituted C1-C4 alkyl, optionally substituted amine, optionally substituted C1-C4 alkoxy, optionally substituted aryl, or an optionally substituted heteroaryl group, and R 9 represents H, halo, hydroxy, optionally substituted C1-C4 alkyl, optionally substituted amine, optionally substituted C1-C4 alkoxy, optionally substituted 5- or 6-membered carbocyclic group, or an optionally substituted 5- or 6-membered heterocyclic group;
wherein R 10 represents H, optionally substituted C1-C4 alkyl, optionally substituted amine, optionally substituted C1-C4 alkoxy, optionally substituted aryl, or an optionally substituted heteroaryl group, and R 11 , R 12 , R 13 , R 14 , and R 15 each independently represents H, halo, hydroxy, optionally substituted C1-C4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, or NR 6 R 7 , wherein each of R 6 and R 7 independently represents H or a substituent, or R 11 together with R 12 and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group or an optionally substituted 5- or 6-membered heterocyclic group, or R 12 together with R 13 and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group or an optionally substituted 5- or 6-membered heterocyclic group, or R 13 together with R 14 and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group or an optionally substituted 5- or 6-membered heterocyclic group, or R 14 together with R 15 and the other atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group or an optionally substituted 5- or 6-membered heterocyclic group;
wherein R 16 , R 17 , R 18 and R 19 independently represent H or a substituent, or wherein R 16 and R 17 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group, or wherein R 16 and R 17 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group, an optionally substituted 5- or 6-membered heterocyclic group, or wherein R 18 and R 19 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group, or an optionally substituted 5- or 6-membered heterocyclic group; or
wherein R 20 , R 21 , R 22 and R 23 independently represent H or a substituent, or wherein R 20 and R 21 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered heterocyclic group, or wherein R 21 and R 22 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group, an optionally substituted 5- or 6-membered heterocyclic group, or wherein R 22 and R 23 together with the atoms to which they are bound form an optionally substituted 5- or 6-membered carbocyclic group, or an optionally substituted 5- or 6-membered heterocyclic group;
wherein each optional substituent is independently alkyl, alkoxy, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, aralkyl, halo, hydroxyl, aryloxy, alkylthio, arylthio, cyano, carbonyl, carboxyl, amino, amido, sulfonyl, or an amino acid,
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound of claim 1 , wherein A is represented by A 1 :
3. The compound of claim 2 , wherein X is C and X 1 is N, and the compound of formula (I) is represented by formula (Ia):
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. The compound of claim 3 , wherein not all of R 2 , R 3 , R 4 , and R 5 represents H.
5. The compound of claim 3 , wherein each of R 2 , R 3 , R 4 , and R 5 represents H.
6. The compound of claim 3 , wherein one of R 2 , R 3 , R 4 , and R 5 represents C5-C6 heterocyclic substituted benzyl or 1-benzyl-4-piperidinoxy.
7. The compound of claim 2 , wherein X and X 1 are both C, and the compound of formula I is represented by formula (Ib):
or a pharmaceutically acceptable salt or stereoisomer thereof.
8. The compound of claim 2 , wherein X and X 1 are both N, and the compound of formula I is represented by formula (Ic):
or a pharmaceutically acceptable salt or stereoisomer thereof.
9. The compound of claim 3 , wherein at least one of R 2 , R 4 and R 5 represents NR 6 R 7 .
10. The compound of claim 8 , wherein NR 6 R 7 is a benzylamino group.
11. The compound of claim 2 , wherein at least one of R 2 , R 3 , R 4 and R 5 represents halo, optionally substituted amino, optionally substituted C1-C4 alkoxy or optionally substituted aryl.
12. The compound of claim 2 , wherein at least one of R 2 , R 3 , R 4 and R 5 represents methoxy, chloro, amino, benzyloxyamino, benzyloxy, benzyl, or substituted benzyloxy.
13. The compound of claim 11 , wherein at least one of R 2 , R 3 , R 4 and R 5 represents benzyloxy substituted with an alkheterocyclic group.
14. The compound of claim 13 , wherein the alkheterocyclic group is a morpholino group.
15. The compound of claim 2 , wherein R 2 represents amino, benzyloxyamino, benzyloxy, substituted benzyloxy, or methoxy.
16. The compound of claim 15 , wherein the substituent of the benzyloxy group is a —(CH 2 )—N-morpholino group.
17. The compound of claim 2 , wherein R 4 represents chloro.
18. The compound of claim 2 , wherein X 1 represents C and R 1 and R 2 together with the atoms to which they are bound form an optionally substituted 6-membered heteroaryl group.
19. The compound of claim 18 , wherein the optionally substituted 6-membered heteroaryl group is an optionally substituted pyridyl group.
20. The compound of claim 1 , wherein A is represented by A 2 :
21. The compound of claim 20 , wherein R 8 represents H or methyl and R 9 represents hydroxy, NH 2 , or Cl.
22. The compound of claim 1 , wherein A is represented by A 3 :
23. The compound of claim 22 , wherein R 10 represents H or methyl and R 11 and R 12 together with the atoms to which they are bound form an optionally substituted 5-membered heterocyclic group.
24. The compound of claim 1 , wherein A is represented by A 4 :
25. The compound of claim 24 , wherein R 16 and R 17 together with the atoms to which they are bound form an optionally substituted 6-membered aryl ring.
26. The compound of claim 25 , wherein the optionally substituted 6-membered aryl ring is an optionally substituted phenyl group.
27. The compound of claim 25 , wherein the 6-membered aryl ring is unsubstituted.
28. The compound of claim 24 , wherein R 17 and R 18 together with the atoms to which they are bound form an optionally substituted 6-membered aryl ring.
29. The compound of claim 28 , wherein the optionally substituted 6-membered aryl ring is an optionally substituted phenyl group.
30. The compound of claim 28 , wherein the 6-membered aryl ring is unsubstituted.
31. The compound of claim 24 , wherein R 18 and R 19 together with the atoms to which they are bound form an optionally substituted 6-membered aryl ring.
32. The compound of claim 31 , wherein optionally substituted 6-membered aryl ring is an optionally substituted phenyl group.
33. The compound of claim 31 , wherein the 6-membered aryl ring is unsubstituted.
34. The compound of claim 1 , wherein A is represented by A 5 :
35. The compound of claim 4 , wherein R 20 is H, methyl, phenyl, or benzyl, and R 21 , R 22 , and R 23 are each H.
36. A compound which is:
or a pharmaceutically acceptable salt or stereoisomer thereof.
37. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of claim 1 or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
38. The pharmaceutical composition of claim 37 , which is in the form of a capsule or tablet.
39. A method of treating a disease or disorder characterized or mediated by aberrant activity of a protein which is selected from the group consisting of casein kinase 1 alpha (CK1α), family with sequence similarity 83 member F (FAM83F), DTW domain containing 1 (DTWD1), zinc finger protein 91 homolog (ZFP91), ZFP62, ZFP36 ring finger protein like (ZFP36L2), ring finger protein 166 (RNF166), Ikaros family zinc finger protein 1 (IKZF1), IKZF2, IKZF3, IKZF4, IKZF5, Ras-related protein Rab-28 (RAB28), glutathione S-transferase pi 1 (GSTP1), GSPT2, mitochondrial import inner membrane translocase subunit Tim10 (TIMM10), GDNF inducible zinc finger protein 1 (GZF1), early growth response 1 (EGR1), hypermethylated in cancer 1 (HIC1), HIC2, insulinoma-associated protein 2 (INSM2), odd-skipped related transcription factor 2 (OSR2), protein polybromo-1 (PB1), PR domain zinc finger protein 15 (PRD15), spalt like transcription factor 1 (SALL1), SALL3, SALL4, WIZ, zinc finger and BTB domain-containing protein 17 (ZBT17), ZBT41, ZBT49, ZBT7A, ZBT7B, ZBTB2, ZBTB39, zinc finger protein interacting with K protein 1 (ZIK1), zinc finger protein 3 (ZNF3), ZNF217, ZNF276, ZNF316, ZNF324B, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483Or, SNF517, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF814, zinc finger and SCAN domain containing 10 (ZSC10), ZSC22, ZC827, and zinc finger with UFM1-specific peptidase domain (ZUFSP), comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.
40. The method of claim 39 , wherein the disease is multiple myeloma.
41. The compound of claim 39 , wherein the disease or disorder is characterized or mediated by aberrant activity of IKZF2.
42. The compound of claim 36 , which is
or a pharmaceutically acceptable salt or stereoisomer thereof.