IP Library › Granted Patent US 8,163,738

Granted Patent B2

US 8,163,738 · App. 12/064,196 · Granted Apr 24, 2012

Aminodiazepines as toll-like receptor modulators

Assignee: Array BioPharma Inc.

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Quick Facts

Patent No.: US 8,163,738
App. No.: 12/064,196
Granted: Apr 24, 2012
Kind: B2

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Abstract

Provided are compositions and methods useful for modulation signaling through the Toll-like receptor TLR8. The compositions and methods have use in the treatment of autoimmunity, inflammation allergy, asthma, graft rejection, graft versus host disease, infection, sepsis, cancer and immunodeficiency.

Claims (74)

1. A compound of the Formula

and tautomers and pharmaceutically acceptable salts thereof, wherein:

Z is H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR 6 or NR 6 R 7 , wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR 6 , NR 6 R 7 , C(═O)R 6 , C(═O)OR 6 , OC(═O)R 6 , C(═O)NR 6 R 7 , (C 1 -C 6 alkyl)amino, CH 3 OCH 2 O—, R 6 OC(═O)CH═CH 2 —, NR 6 SO 2 R 7 , SR 6 and SO 2 R 6 ;

R 1 , R 2 , R 3 and R 4 are independently selected from H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR 6 , NR 6 R 7 , C(═O)R 6 , C(═O)OR 6 , OC(═O)R 6 , C(═O)NR 6 R 7 , (C 1 -C 6 alkyl)amino, CH 3 OCH 2 O—, R 6 OC(═O)CH═CH 2 —, NR 6 SO 2 R 7 , SR 6 and SO 2 R 6 ,

or R 1 and R 2 together with the atom to which they are attached form a saturated or partially unsaturated carbocyclic ring, wherein said carbocyclic ring is optionally substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, CN, OR 6 , NR 6 R 7 , C(═O)R 6 , C(═O)OR 6 , OC(═O)R 6 , C(═O)NR 6 R 7 , (C 1 -C 6 alkyl)amino, CH 3 OCH 2 O—, R 6 OC(═O)CH═CH 2 —, NR 6 SO 2 R 7 , SR 6 and SO 2 R 6 ,

or R 3 and R 4 together are oxo;

each R 5 is independently selected from H, F, Cl, Br, I, OMe, CH 3 , CH 2 F, CHF 2 , CF 3 and CF 2 CF 3 ;

R 6 and R 7 are independently selected from H or alkyl; and

n is 0, 1, 2, 3 or 4.

2. The compound of claim 1 , wherein Z is OR 6 .

3. The compound of claim 2 , wherein R 6 is alkyl.

4. The compound of claim 3 , wherein R 6 is ethyl, propyl, isopropyl or isobutyl.

5. The compound of claim 1 , wherein Z is NR 6 R 7 .

6. The compound of claim 5 , wherein R 6 and R 7 are ethyl.

7. The compound of claim 1 , wherein n is 0 or 1.

8. The compound of claim 7 , wherein R 5 is CF 2 CF 3 .

9. The compound of claim 1 , wherein R 3 is H or alkyl and R 4 is H.

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

11. The compound of claim 1 , wherein R 1 is H or alkyl and R 2 is H.

12. The compound of claim 11 , wherein R 1 is methyl.

13. The compound of claim 1 , selected from:

(E)-ethyl 2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate;

(E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate;

(E)-ethyl 2-amino-5-methyl-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate;

(E)-isopropyl 2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate;

(E)-propyl 2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate;

(E)-isobutyl 2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate;

(E)-2-amino-N,N-diethyl-3H-benzo[e][1,4]diazepine-4(5H)-carboxamide; and

(E)-ethyl 2-amino-3-methyl-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate, and pharmaceutically acceptable salts thereof.

14. A compound of the Formula

and tautomers and pharmaceutically acceptable salts thereof, wherein:

or R 3 and R 4 together are oxo;

R 5 is H, F, Cl, Br, I, OMe, CH 3 , CH 2 F, CHF 2 , CF 3 or CF 2 CF 3 ;

R 6 and R 7 are independently selected from H or alkyl; and

n is 0, 1, 2, 3 or 4.

15. The compound of claim 14 , wherein Z is OR 6 .

16. The compound of claim 15 , wherein R 6 is alkyl.

17. The compound of claim 16 , wherein R 6 is ethyl, propyl, isopropyl, or isobutyl.

18. The compound of claim 14 , wherein Z is NR 6 R 7 .

19. The compound of claim 18 , wherein R 6 and R 7 are ethyl.

20. The compound of 14 , wherein R 5 is H or CF 2 CF 3 .

21. The compound of claim 20 , wherein R 5 is CF 2 CF 3 .

22. The compound of claim 14 , wherein R 1 is H or alkyl and R 2 is H.

23. The compound of claim 22 , wherein R 1 is methyl.

24. The compound of claim 14 , wherein R 3 is H or alkyl and R 4 is H.

25. The compound of claim 24 , wherein R 3 is methyl.

26. A pharmaceutical composition, which comprises a compound as claimed in claim 1 , together with a pharmaceutically acceptable diluent or carrier.

27. The compound of claim 14 , wherein the compound is:

(E)-ethyl 2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate, and pharmaceutically acceptable salts thereof.

28. The compound of claim 14 , wherein the compound is:

(E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate, and pharmaceutically acceptable salts thereof.

29. The compound of claim 14 , wherein the compound is:

(E)-ethyl 2-amino-5-methyl-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate, and pharmaceutically acceptable salts thereof.

30. The compound of claim 14 , wherein the compound is:

(E)-isopropyl 2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate, and pharmaceutically acceptable salts thereof.

31. The compound of claim 14 , wherein the compound is:

(E)-propyl 2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate, and pharmaceutically acceptable salts thereof.

32. The compound of claim 14 , wherein the compound is:

(E)-isobutyl 2-amino-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate, and pharmaceutically acceptable salts thereof.

33. The compound of claim 14 , wherein the compound is:

(E)-2-amino-N,N-diethyl-3H-benzo[e][1,4]diazepine-4(5H)-carboxamide, and pharmaceutically acceptable salts thereof.

34. The compound of claim 14 , wherein the compound is:

(E)-ethyl 2-amino-3-methyl-3H-benzo[e][1,4]diazepine-4(5H)-carboxylate, and pharmaceutically acceptable salts thereof.

35. A pharmaceutical composition, which comprises a compound as claimed in claim 27 , together with a pharmaceutically acceptable diluent or carrier.

36. A pharmaceutical composition, which comprises a compound as claimed in claim 28 , together with a pharmaceutically acceptable diluent or carrier.

37. A pharmaceutical composition, which comprises a compound as claimed in claim 29 , together with a pharmaceutically acceptable diluent or carrier.

38. A pharmaceutical composition, which comprises a compound as claimed in claim 30 , together with a pharmaceutically acceptable diluent or carrier.

39. A pharmaceutical composition, which comprises a compound as claimed in claim 31 , together with a pharmaceutically acceptable diluent or carrier.

40. A pharmaceutical composition, which comprises a compound as claimed in claim 32 , together with a pharmaceutically acceptable diluent or carrier.

41. A pharmaceutical composition, which comprises a compound as claimed in claim 33 , together with a pharmaceutically acceptable diluent or carrier.

42. A pharmaceutical composition, which comprises a compound as claimed in claim 34 , together with a pharmaceutically acceptable diluent or carrier.

Continuity (2)

Provisional Application 60709667 · Aug 19, 2005

Related Publication 20080306050A1 · Dec 11, 2008