Multicyclic sulfonamide compounds as inhibitors of histone deacetylase for the treatment of disease

• US 7,470,722 B2
• Filed: 06/09/2005
• Issued: 12/30/2008
• Est. Priority Date: 06/10/2004
• Status: Expired due to Fees

• Current Assignee: Kalypsys Inc
• Original Assignee: Kalypsys Inc
• Inventors: Lawrence, Charles Maxwell, Wash, Paul L., Malecha, James William, Hassig, Christian Andreus, Hoffman, Timothy Z., Noble, Stewart Alwyn, Wiley, Brandon M.
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US11/150,500
• Publication Number:
  US 20060030543A1
• Time in Patent Office: 1,300 Days
• Field of Search: 544/159, 544/339, 544/381, 546/139, 546/134, 546/246, 548/484, 548/302.7, 549/362, 549/462, 514/237.8, 514/305, 514/396, 514/452, 514/252.12, 514/315, 514/307, 514/415, 514/464, 514/299, 514/456
• US Class Current: 514/456
• CPC Class Codes: C07C 323/49 to sulfur atoms
• CPC Class Codes: C07C 327/30 having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/16 Tryptamines
• CPC Class Codes: C07D 215/36 Sulfur atoms C07D215/24 takes precedence
• CPC Class Codes: C07D 217/06 with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 221/04 Ortho- or peri-condensed ring systems
• CPC Class Codes: C07D 241/42 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 307/82 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 317/62 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
• CPC Class Codes: C07D 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 333/54 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 333/62 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07F 9/1653 : with arylalkanols

Abstract

Disclosed herein are carbonyl compounds of Formula I as described herein.

Methods and compositions are disclosed for treating disease states including, but not limited to cancers, autoimmune diseases, tissue damage, central nervous system disorders, neurodegenerative disorders, fibrosis, bone disorders, polyglutamine-repeat disorders, anemias, thalassemias, inflammatory conditions, cardiovascular conditions, and disorders in which angiogenesis play a role in pathogenesis, using the compounds of the invention. In addition, methods of modulating the activity of histone deacetylase (HDAC) are also disclosed.

Claims

1. A compound having structural formula I,

2. The compound of claim 1, wherein Q is a bond.

3. The compound of claim 2 wherein R6 and R7 are both hydrogen or are both methyl.

4. The compound of claim 3 wherein R₁, R₂, R₄, and R₅ are hydrogen.

5. The compound of claim 4 wherein G2 is selected from the group consisting of a bond, methylene, and ethylene.

6. The compound of claim 2 wherein G1 is an optionally substituted fused polycyclic aryl.

7. The compound of claim 6 wherein G1 is napththyl.

8. The compound of claim 7 wherein G1 is optionally singly or multiply substituted with substituents independently chosen from the group consisting of hydrogen, perhaloaryloxy, alkanoylalkyl, N-aryl-N-alkylamino, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamide, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, carboxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyl, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, arylsulphonyl alkanoyl, alkenoyl, aroyl, aralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarboylamido, arylamidocarboylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboamido, carboxamidoalkyl, cyanocycloalkylalkyl, cycloalkenyl, alkoxycarbonyl, aralkylthio, alkylthio, alkylsulfinyl, arylsulfinyl, dialkylamino, aminoalkyl, dialkylaminoalkyl, aminoaryl, alkylaminoaryl, acylamino, aminocarbonylalkoxy, aminocarbonylamino, aminothiocarbonylamino, and aminothiocarbonylaminoalkyl.

9. The compound of claim 8 wherein Q is a bond.

10. The compound of claim 9 wherein R₁, R₂, R₄, and R₅ are hydrogen.

11. The compound of claim 10 wherein G2 is a bond, methylene, or ethylene.

12. The compound according to claim 11 wherein the compound has a structure selected from a group consisting of:

13. The compound of claim 1 wherein G1 is an optionally substituted fused mono- or polycyclic aryl and cycloalkyl ring.

14. The compound of claim 13 wherein G1 is selected from a group consisting of:

15. The compound of claim 14 wherein G1 is optionally singly or multiply substituted with substituents independently chosen from the group consisting of hydrogen, perhaloaryloxy, alkanoylalkyl, N-aryl-N-alkylamino, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamide, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, carboxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyl, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, arylsulphonyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarboylamido, arylamidocarboylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboamido, carboxamidoalkyl, cyanocycloalkylalkyl, cycloalkenyl, alkoxycarbonyl, aralkylthio, alkylthio, alkylsulfinyl, arylsulfinyl, dialkylamino, aminoalkyl, dialkylaminoalkyl, aminoaryl, alkylaminoaryl, acylamino, aminocarbonylalkoxy, aminocarbonylamino, aminothiocarbonylamino, and aminothiocarbonylaminoalkyl.

16. The compound of claim 15 wherein Q is a bond.

17. The compound of claim 16 wherein R₁, R₂ R₄, and R₅ are hydrogen.

18. The compound of claim 17 wherein G2 is a bond, methylene, or ethylene.

19. The compound according to claim 18 wherein the compound has the structure selected from the group consisting of:

20. The compound of claim 2 wherein G1 is an optionally substituted fused aryl and heterocycloalkyl.

21. The compound of claim 20 wherein G1 is selected from a group consisting of:

22. The compound of claim 21 wherein G1 is optionally singly or multiply substituted with substituents independently chosen from the group consisting of hydrogen, perhaloaryloxy, alkanoylalkyl, N-aryl-N-alkylamino, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamide, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, carboxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyl, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, arylsulphonyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarboylamido, arylamidocarboylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboamido, carboxamidoalkyl, cyanocycloalkylalkyl, cycloalkenyl, alkoxycarbonyl, aralkylthio, alkylthio, alkylsulfinyl, arylsulfinyl, dialkylamino, aminoalkyl, , dialkylaminoalkyl, aminoaryl, alkylaminoaryl, acylamino, aminocarbonylalkoxy, aminocarbonylamino, aminothiocarbonylamino, and aminothiocarbonylaminoalkyl.

23. The compound of claim 22 wherein Q is a bond.

24. The compound of claim 23 wherein R₁, R₂, R₄, and R₅ are hydrogen.

25. The compound according to claim 24 wherein the compound has the structure selected from a group consisting of:

26. The compound according to claim 25 wherein the compound has the structure selected from a group consisting of:

27. The compound of claim 1 wherein G1 is an optionally substituted linked biaryl.

28. The compound of claim 27 wherein G1 is

29. The compound of claim 28 wherein G1 is optionally singly or multiply substituted with substituents independently chosen from the group consisting of hydrogen, perhaloaryloxy, alkanoylalkyl, N-aryl-N-alkylamino, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido, N-cycloalkylcarboxamide, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, carboxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyl, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, arylsulphonyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarboylamido, arylamidocarboylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboamido, carboxamidoalkyl, cyanocycloalkylalkyl, cycloalkenyl, alkoxycarbonyl, aralkylthio, alkylthio, alkylsulfinyl, arylsulfinyl, dialkylamino, aminoalkyl, , dialkylaminoalkyl, aminoaryl, alkylaminoaryl, acylamino, aminocarbonylalkoxy, aminocarbonylamino, aminothiocarbonylamino, and aminothiocarbonylaminoalkyl.

30. The compound of claim 29 wherein Q is a bond.

31. The compound of claim 30 wherein R₁, R₂, R₄, and R₅ are hydrogen.

32. The compound of claim 31 wherein G2 is a bond, methylene, or ethylene.

33. The compound according to claim 32 wherein the compound has the structure selected from a group consisting of:

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

35. The compound of claim 1 wherein G1 is an optionally substituted linked aryl and heteroaryl ring.

36. The compound of claim 35 wherein G1 is selected from the group consisting of:

37. The compound of claim 36 wherein G1 is optionally singly or multiply substituted with substituents independently chosen from the group consisting of hydrogen, perhaloaryloxy, alkanoylalkyl, N-aryl-N-alkylamino, hydroxyalkoxy, carboxamidoalkoxy, alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy, aralkenoyl, N-alkylcarboxamido, N- haloalkylcarboxamido, N-cycloalkylcarboxamide, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl, cyanoalkoxy, carboxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, hydroxyl, amino, thio, nitro, alkylamino, alkylthio, arylamino, aralkylamino, arylthio, arylthioalkyl, alkylsulfonyl, arylsulphonyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyhaloalkoxy, hydroxyalkyl, aryl, aryloxy, aralkoxy, arylalkenyl, carboalkoxy, alkoxycarboxamido, alkylamidocarboylamido, arylamidocarboylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboamido, carboxamidoalkyl, cyanocycloalkylalkyl, cycloalkenyl, alkoxycarbonyl, aralkylthio, alkylthio, alkylsulfinyl, arylsulfinyl, dialkylamino, aminoalkyl, dialkylaminoalkyl, aminoaryl, alkylaminoaryl, acylamino, aminocarbonylalkoxy, aminocarbonylamino, aminothiocarbonylamino, and aminothiocarbonylaminoalkyl.

38. The compound of claim 37 wherein Q is a bond.

39. The compound of claim 38 wherein R₁, R₂, R₄, and R₅ are hydrogen.

40. The compound of claim 39 wherein G2 is a bond, methylene, or ethylene.

41. The compound according to claim 40 wherein the compound has the structure selected from the group consisting of:

42. The compound according to claim 1 wherein the compound is

43. A pharmaceutical composition comprising the compound of claim 1 in a mixture with at least one carrier, diluent or excipient.