1,5- disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases

• US 20030100756A1
• Filed: 08/28/2002
• Published: 05/29/2003
• Est. Priority Date: 03/02/2000
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Adams, Jerry L, Taggart, John J, Hall, Ralph F, Boehm, Jeffrey C
• Granted Patent: US 7,235,551 B2
• Time in Patent Office: Days
• US Class Current: 544/60
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Novel substituted pyrimido[4,5-d]pyrimidin-2-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.

Claims

1. A compound of the formula:

2. The compound according to claim 1 wherein the structure is of Formula (IV).

3. The compound according to claim 1 wherein R₃ is an optionally substituted aryl, arylC_1-10 alkyl, or a cycloalkyl moiety.

4. The compound according to claim 3 wherein R₁ is an optionally substituted aryl moiety.

5. The compound according to claim 3 wherein the moiety is optional substituted one or more times, independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

6. The compound according to any one of claims 1 to 5 wherein X is OR₂.

7. The compound according to any one of claims 1 to 5 wherein X is S(O)_mR₂.

8. The compound according to any one of claims 1 to 5 wherein X is (CH₂)_nNR₄R₁₄.

9. The compound according to any one of claims 1 to 5 wherein X is (CH₂)_nNR₂.

10. The compound according to any one of claims 1 to 5 wherein X is R₉.

11. The compound according to any one of claims 1 to 5 wherein Y is CR_b, or C(O).

12. The compound according to any one of claims 1 to 5 wherein Y is N(R_d), oxygen, or S(O)_m.

13. The compound according to any one of claims 1 to 5 wherein Y is a bond.

14. The compound according to any one of claims 1 to 5 wherein R₂ is an optionally substituted alkyl, heteroaryl, or hieterocyclic or heterocyclic alkyl.

15. The compound according to claim 14 wherein R₂ is an optionally substituted imidazole, tetrazole, pyrrolidine, piperidine, piperazine, or morpholine ring.

16. The compound according to claim 15 wherein the ring is substituted one or more times, independently, by halogen, C_1-10alkyl, halosubstituted C₁₁₀alkyl, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nOR₆, or (CR₁₀R₂₀)_nC(Z)OR₆.

17. The compound according to claim 1 which is

7-Methylsulfanyl-1,5-diphenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one 1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-methylsulfanyl-3,4-dihydro-1-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-methylsulfonyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-piperidin-4-ylamino)-3,4-dihydro-1 H-pyrimido[4,5-d]pyrimidin-2-one trifluoroacetate;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-1,3-dihydroxyprop-2-yl-amino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

5-(4-Fluoro-2-methylphenyl)-7-methylsulfanyl-1-((R)-1-phenylethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

5-(4-Fluoro-2-methylphenyl)-7-methylsulfanyl-1-((S)-1-phenylethyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-( 1-methylpiperazin-4-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-methylpiperazin-4-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-methyl-1H-imidazol-2-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(imidazol-1yl-)3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-7-methylsulfanyl-5-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]-pyrimidin-2-one;

1-(2,6-Difluorophenyl)-7-methylsulfanyl -5-(4-fluorophenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-([2-hydroxyethyl)-methylamino]-3,4-dihydro-1H-pyrimido[415-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-piperazin-4-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(4-hydroxypiperdin-1-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(4-carboxypiperidin-1-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(4-carboethoxypiperidin-1-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(4-hydroxymethylpiperdin-1-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-di(ethan-2-ol-)amino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-methylpiperidin-4-yl-amino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1 -(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(1-morpholin-4-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-morpholin-4-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-pyrrolidin-1-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-piperidin-1-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-pyridin-3-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-diethylamino ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-pyridin-3-yl ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-dimethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-methylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(2-methylphenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(2-methylphenyl)-7-(1-piperazin-4-yl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(2-methylphenyl)-7-(2-diethylamino ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-phenyl-7-methoxy-3,4-dihydro-1H-pyrimido[4,5-d]-pyrimidin-2-one;

1-(2-Fluorophenyl)-7-methylsulfanyl-5-(2-methyl-4-fluoro)phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2.6-Dimethylphenyl)-7-methylsulfanyl-5-(2-methyl-4-fluoro)phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1 -(2-Methylphenyl)-7-methylsulfanyl-5-(2-methyl-4-fluoro)phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-Cyclohexyl-7-methylsulfanyl-5-(2-methyl-4-fluoro)phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2-Chlorophenyl)-7-methylsulfanyl-5-(2-methyl-4-fluoro)phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-methyl-1,3-dihydroxyprop-2-ylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl-7-ethoxy-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1 -(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-((R)-2-hydroxy-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-((S)-2-hydroxy-1-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1 -(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-hydroxy-1,1-dimethyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-hydroxy-1,1-bis-hydroxy-methyl-ethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1 -(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2-hydroxyethylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1 -(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl-7-(1-methylpiperidin-4-yloxy)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1,5-Diphenyl-7-methoxy-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl-7-(2-hydroxyethoxy)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-[[bis-(2-hydroxyethyl)-amino]ethoxy]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

1-(2,6-Difluorophenyl)-5-(4-fluoro-2-methylphenyl)-7-(2,3-dihydroxypropylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one;

or

a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier or diluent.

19. A method of treating, including prophylaxis, of a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound of according to claim 1.

20. The method according to claim 19 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerulamephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.

69. A process for producing a compound of Formula (IV) according to claim 1, which process comprises reacting a compound of the formula

70. The process according to claim 69 wherein the compound of Formula (A) is produced by reacting a compound of the formula:

21. A compound of the formula:

22. The compound according to claim 21 wherein the structure is of Formula (I).

23. The compound according to claim 22 wherein R₁ and/or R₃ are an optionally substituted aryl.

24. The compound according to claim 23 wherein the aryl is substituted one or more times, independently, by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

25. The compound according to any one of claims 21 to 24 wherein X is R₂, OR₂, or S(O)_mR₂.

26. The compound according to any one of claims 21 to 24 wherein X is (CH₂)_nNR₄R₁₄, or (CH₂)_nNR₂R₄.

27. The compound according to claim 21, which is:

7-Methylsulfanyl-5-phenyl-1-(1-phenylethyl)-3,4-dihydro-1H-pyrimido[4,5-d]-pyrimidin-2-one;

or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 21 to 24, and a pharmaceutically acceptable carrier or diluent.

29. A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound of Formula (I) or (la) according to any one of claims 21 to 24.

30. The method according to claim 29 wherein the CSBPIRK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerularnephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.

31. A compound of the formula:

32. The compound according to claim 31 wherein the structure is of Formula (II).

33. The compound according to claim 31 wherein R₁ and/or R₃ is an optionally substituted aryl.

34. The compound according to claim 33 wherein the aryl is substituted one or more time, independently, by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

35. The compound according to claim 31 wherein X is R₂, OR₂, or S(O)_mR₂.

36. The compound according to claim 31 wherein X is or (CH₂)_nNR₄R₁₄, or (CH₂)_nNR₂R₄.

37. The compound according to any one of claims 31 to 36 wherein R₂ is an optionally substituted heteroaryl or heterocyclic.

38. A pharmaceutical composition comprising a compound according to any one of claims 31 to 36, and a pharmaceutically acceptable carrier or diluent.

39. A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound of Formula (II) or (IIa) according to any one of claims 31 to 36.

40. The method according to claim 39 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerularnephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia. eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.

41. A compound of the formula:

42. The compound according to claim 41 wherein the structure is of Formula (III).

43. The compound according to claim 41 wherein R₁ and/or R₃ is an optionally substituted aryl.

44. The compound according to claim 43 wherein the aryl is substituted one or more times, independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

45. The compound according to claim 42 wherein X is OR₂, or S(O)_mR₂.

46. The compound according to claim 42 wherein X is (CH₂)_nNR₄R₁₄, or (CH₂)_nNR₂R₄.

47. The compound according to claim 42 wherein X is R_2′

.

48. The compound according to claim 47 wherein R_2′

is an optionally substituted heteroaryl or heterocyclic ring.

49. The compound according to claim 48 wherein the ring is an optionally substituted imidazole, pyrrolidine, piperidine, piperazine, or a morpholine ring.

50. The compound according to claim 49 wherein the ring is substituted one or more times, independently, by halogen, C_1-10 alkyl, halosubstituted C_1-10 alkyl, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nOR₆, and (CR₁₀R₂₀)_nC(Z)OR₆.

51. A pharmaceutical composition comprising a compound according to any one of claims 41 to 50, and a pharmaceutically acceptable carrier or diluent.

52. A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound of Formula (III) or (IIIa) according to any one of claims 41 to 50.

53. The method according to claim 52 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter'"'"'s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, thrombosis, glomerulamephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact derrnatitis, psoriasis, sunburn, or conjunctivitis.

54. A compound of the formula:

55. The compound according to claim 54 wherein R₁ and R₃ are optionally substituted phenyl rings.

56. The compound according to claim 55 wherein the aryl is substituted one or more times, independently, by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

57. The compound according to claim 56 wherein R₃ is unsubstituted or substituted one or more times, independently with halogen.

58. The compound according to claim 55, wherein R₁ is unsubstituted or substituted one or more times, independently with halogen or alkyl.

59. The compound according to any one of claims 54 to 58 wherein X is OR₂.

60. The compound according to any one of claims 54 to 58 wherein X is S(O)_mR₂.

61. The compound according to any one of claims 54 to 58 wherein X is (CH₂)_nNR₄R₁₄.

62. The compound according to any one of claims 54 to 58 wherein X is (CH₂)_nNR₂.

63. The compound according to any one of claims 54 to 58 wherein X is R₂.

65. The compound according to claim 54 wherein R₂ is an optionally substituted alkyl, heteroaryl, or heterocyclic moiety.

66. The compound according to claim 65 wherein R₂ is an optionally substituted imidazole pyrrolidine, piperidine, piperazine, or a morpholine ring.

67. The compound according to claim 66 wherein the ring is substituted one or more times, independently, by halogen, C_1-10 alkyl, halosubstituted C_1-10 alkyl, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nOR₆, and (CR₁₀R₂₀)_nC(Z)OR₆.

68. The compound according to claim 54 wherein the structure is of Formula (V).