PAR2-modulating compounds and their use

• US 20080318960A1
• Filed: 05/16/2006
• Published: 12/25/2008
• Est. Priority Date: 05/26/2005
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Burstein, Ethan, Eeg Knapp, Anne
• Application Number:
  US11/435,817
• Publication Number:
  US 20080318960A1
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• 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: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 237/32 with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to compounds, and uses thereof, having the chemical formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound modulates the activity of PAR2 or a PAR2 subtype and thereby may be used to treat or prevent diseases involving abnormal PAR2 or PAR2 subtype activity.

Claims

1. A compound having the chemical structure:

2. The compound of claim 1, wherein R₅ is selected from the group consisting of hydrogen, methyl and cyclopropyl.

3. The compound of claim 1, wherein R₅ is substituted with 1-4 groups selected from the group consisting of hydroxy, halogen, perhaloalkyl, —

OR₁₁, —

NR₁₁ R_11a, —

CN, —

C(X)R₁₁, —

C(X)OR₁₁, —

C(X)NR₁₁R_11a, —

N(R₁₁)—

C(X)R_11a, —

N(R₁₁)—

C(X)NR₁₁R_11a and —

OC(X)R₁₁, wherein;

X is oxygen; and

,

R₁₁ and R_11a are independently selected from the group consisting of hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₇ cycloalkyl, and C₅-C₁₀ cycloalkenyl.

4. The compound of claim 1, wherein R₆ is unsubstituted or substituted phenyl wherein, if substituted, the substituent is one or more selected from the group consisting of C₁-C₄ alkyl, hydroxyl, halogen, perhaloalkyl, and OR₉, wherein:

R₉ is selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, —

CN, trifluoromethyl.

5. The compound of claim 1, wherein R₆ is unsubstituted or substituted heteroaryl wherein, if substituted, the substituent is one or more independently selected from the group consisting of halogen, C₁-C₁₀alkyl and perhaloalkyl. In an aspect of this invention the heteroaryl is pyridine or furan.

6. The compound of claim 1, wherein the substituent on R₅ is selected from the group consisting of methyl, trifluoromethyl and chloro.

7. The compound of claim 1, wherein R₆ is unsubstituted or substituted C₁-C₁₀ alkyl, wherein, if substituted, the substituent is one more independently selected from the group consisting of unsubstituted C₁-C₅ alkyl and —

C(O)OR₁₀, wherein R₁₀ is unsubstituted C₁-C₅ alkyl.

8. The compound of claim 1, wherein R₆ is substituted with 1-4 groups selected from the group consisting of hydroxy, halogen, perhaloalkyl, —

OR₁₁, —

NR₁₁ R_11a, —

CN, —

C(X)R₁₁, —

C(X)OR₁₁, —

C(X)NR₁₁R_11a, N(R₁₁)—

C(X)R_11a, —

N(R₁₁)—

C(X)NR₁₁R_11a and —

OC(X)R₁₁, wherein;

X is oxygen; and

,

R₁₁ and R_11a are independently selected from the group consisting of hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₃-C₇ cycloalkyl, and C₅-C₁₀ cycloalkenyl.

9. The compound of claim 1, wherein R₆ is selected from the group consisting of hydrogen, methyl and cyclopropyl.

10. The compound of claim 1, wherein R₆ is unsubstituted or substituted phenyl wherein, if substituted, the substituent is one or more selected from the group consisting of C₁-C₄ alkyl, hydroxyl, halogen, perhaloalkyl, and OR₉, wherein:

R₉ is selected from the group consisting of hydrogen, methyl, fluoro, chloro, bromo, —

CN, trifluoromethyl.

11. The compound of claim 1, wherein R₆ is unsubstituted or substituted heteroaryl wherein, if substituted, the substituent is one or more independently selected from the group consisting of halogen, C₁-C₁₀alkyl and perhaloalkyl.

12. The compound of claim 11, wherein the heteroaryl is pyridine or furan.

13. The compound of claim 11, wherein the substituent on R₆ is selected from the group consisting of methyl, trifluoromethyl and chloro.

14. The compound of claim 1, wherein R₆ is unsubstituted or substituted C₁-C₁₀ alkyl, wherein, if substituted, the substituent is one more independently selected from the group consisting of unsubstituted C₁-C₅alkyl and —

C(O)OR₁₀, wherein R₁₀ is unsubstituted C₁-C₅ alkyl.

15. The compound of claim 1 wherein R₁ is hydrogen.

16. The compound of claim 1, wherein R_1a is hydrogen.

17. The compound of claim 1, wherein R_1b is hydrogen.

18. The compound of claim 1, wherein, R_1c is hydrogen.

19. The compound of claim 1, wherein R₂ is hydrogen.

20. The compound of claim 1, wherein R_2a is hydrogen.

21. The compound of claim 1, wherein R₃ is benzoyl.

22. The compound of claim 1, wherein R₄ is hydrogen.

23. The compound of claim 1, wherein X is oxygen.

24. The compound of claim 1, wherein R₁, R_1a, R_1b, R_1c, R₂, R_2a and R₄ are hydrogen;

R₃ is benzoyl; and

, X is oxygen.

25. The compound of claim 1, wherein R₅ and R₆, taken together, form a 2,3-dihydro-1H-indene ring.

32. A method of treating or preventing a disease or disorder related to PAR2 activity comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

33. The method of claim 32, wherein the disease or disorder is selected from the group consisting of:

acute or chronic pain;

acute or chronic inflammation;

diseases or disorder of the pulmonary system;

diseases or disorders of the gastrointestinal system;

diseases or disorders of the musculoskeletal system;

diseases or disorders of the central nervous system;

diseases or disorders of the cardiovascular system;

disease or disorders of the renal system;

diseases or disorders of the hepatic system;

diseases of disorders of the eye;

diseases or disorders of the skin;

diseases or disorders of the prostrate;

diseases or disorders of the pancreas;

Sjogren'"'"'s syndrome; and

,

dry mouth;

34. The method of claim 33, wherein the disease or disorder of the pulmonary system is selected from the group consisting of asthma, chronic obstructive pulmonary disease, lung cancer and pneumonitis.

35. The method of claim 33, wherein the disease or disorder of the gastrointestinal system is selected from the group consisting of gastric ulcers, colitis, inflammatory bowel syndrome, Crohn'"'"'s disease, gastric and intestinal motility, colon cancer, cancer of the stomach, and cancer of the intestine.

36. The method of claim 33, wherein the disease or disorder of the musculoskeletal system is selected from the group consisting of rheumatoid arthritis, osteoporosis and Paget'"'"'s disease.

37. The method of claim 33, wherein the disease or disorder of the central nervous system is selected from the group consisting of Alzheimer'"'"'s disease, encephalitis, meningitis, ischemia and stroke.

38. The method of claim 33, wherein the disease or disorder of the cardiovascular system is selected from the group consisting of hypertension, atherosclerosis, angina, congestive heart failure, myocarditus and cardiac ischemia.

39. The method of claim 33, wherein the disease or disorder of the renal system is selected from the group consisting of glomerular kidney disease, kidney cancer and renal failure.

40. The method of claim 33, wherein the disease or disorder of the hepatic system is selected from the group consisting hepatitis and liver cancer.

41. The method of claim 33, wherein the disease or disorder of the eye is selected from the group consisting of glaucoma, retinitis pigmentosa, cataracts, macular degeneration and dry eye.

42. The method of claim 33, wherein the disease or disorder of the skin is selected from the group consisting of dermatitis, psoriasis, pruritis, dermatitis, eczema, seborrhea, wounds, and melanoma.

43. The method of claim 33, wherein the disease or disorder of the pancreatic system is selected from the group consisting of pancreatitus, pancreatic cancer and diabetes.

44. The method of claim 33, wherein the disease or disorder is dry mouth.

45. The method of claim 33, wherein the disease or disorder is Sjogren'"'"'s syndrome.

46. The method of claim 33, wherein the disease or disorder is acute or chronic pain.

47. The method of claim 33, wherein the disease or disorder is acute or chronic inflammation.

48. The method of claim 33, wherein the disease of disorder of the prostatic system is selected from the group consisting of benign prostatic hyperplasia and prostatic cancer.

49. The method of claim 33, wherein the disease or disorder of the pancreatic system is selected from the group consisting of pancreatitis, diabetes and pancreatic cancer.

50. A method of screening for a compound that modulates the activity of PAR2 or PAR2 subtype, comprising:

contacting PAR2 or par2-subtype with a compound of claim 1; and

,

detecting changes in the activity of the PAR2 or PAR2 subtype.

51. A method of screening for a compound that modulates the activity of PAR2 or PAR2 subtype, comprising:

providing a plurality of cells that express PAR2 or PAR2 subtype;

incubating the cells or a component extracted from the cells with a compound of claim 1; and

,

detecting changes in PAR2 activity in the cell.

52. The method of claim 51, wherein the cells over-express the PAR2 or PAR2 subtype.

53. The method of claim 51, wherein the compound is selective for PAR2 or the PAR2 subtype.

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

N-[2-hydrazino-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(3-bromobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2-furylmethylene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-methoxyphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2-hydroxybenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2-bromobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(4-bromophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(2-methoxyphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(4-fluorobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide

N-[2-{(2E)-2-[1-(2-fluorophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(2-bromophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2-fluorobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-(2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-{(2E)-2-[3-(trifluoromethyl)-benzylidene]hydrazino}ethyl)benzamide,

N-{2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-[(2E)-2-(2-pyridinylmethylene)-hydrazino]ethyl}benzamide,

N-{2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-[(2E)-2-(3-pyridinylmethylene)-hydrazino]ethyl}benzamide,

N-[2-((2E)-2-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methylene}-hydrazino)-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-(2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-{(2E)-2-[1-(3-pyridinyl)-ethylidene]hydrazino}ethyl)benzamide,

N-(2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-{(2E)-2-[1-(2-pyridinyl)ethylidene]hydrazino}ethyl)benzamide,

N-[2-[(2E)-2-(1,3-dimethylbutylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[2-(3-methoxyphenyl)-1-methylethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)propylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-fluorophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-((2E)-2-{1-[3-(trifluoromethyl)phenyl]ethylidene}hydrazino)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-chlorophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-cyanophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-((2E)-2-[1-(3-hydroxyphenyl)ethylidene]hydrazino)-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-methylphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(4-methyl-2-pyridinyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-((2E)-2-[1-(3-bromophenyl)-2,2-dimethylpropylidene]-hydrazino)-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)-2-methylpropylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[(3-bromophenyl)(cyclopropyl)methylene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)butylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2,2-dimethyl-1-phenylpropylidene)hydrazino]-2-oxo-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3,5-dimethoxyphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-((2E)-2-{1-[3,5-bis(trifluoromethyl)phenyl]ethylidene}-hydrazino)-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3,5-difluorophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(3,5-dibromobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3,5-dibromophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide, and,

N-[2-{(2E)-2-[1-(3,5-dimethylphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide.

26. A method of screening for a compound that modulates the activity of PAR2 or a PAR2 subtype, comprising:

providing a recombinant cell comprising a nucleic acid that expresses PAR2 or a PAR2 subtype;

contacting the recombinant cell with a test compound; and

,

detecting changes in the activity of the PAR2 or the PAR2 subtype in the cell.

27. The method of claim 26, further comprising comparing the effect of the compound on the recombinant cell with its effect on a cell that does not contain a nucleic acid that expresses PAR2 or PAR2 subtype.

28. The method of claim 26, wherein the nucleic acid expressing PAR2 or PAR2 subtype comprises at least 20 contiguous nucleotides which hybridizes under stringent hybridization conditions to at least 20 contiguous nucleotides of a complement of nucleic acid SEQ ID NO:

1 or of a nucleic acid that encodes a polypeptide having SEQ ID NO;

2.

29. The method of claim 26, wherein the nucleic acid expressing PAR2 or PAR2 subtype comprises at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides of a nucleic acid that encodes SEQ ID NO:

2.

30. The method of claim 26, wherein the nucleic acid expressing PAR2 or PAR2 subtype comprises at least 50, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, at least 1500, at least 1600, at least 1700, at least 1800, at least 1900, at least 2000, at least 2100, at least 2200, at least 2300, at least 2400, or at least 2500, contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of the same number of contiguous nucleotides of a nucleic acid that encodes the amino acid sequence of SEQ ID NO:

2.

31. The method of claim 26, wherein the nucleic acid encodes the polypeptide sequence of SEQ ID NO:

2

55. A method for treating or preventing a disease or disorder related to PAR2 activity comprising administering a therapeutically effective amount to a patient in need thereof of a compound selected from the group consisting of:

N-[2-hydrazino-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(3-bromobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2-furylmethylene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-methoxyphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2-hydroxybenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2-bromobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(4-bromophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(2-methoxyphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(4-fluorobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(2-fluorophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(2-bromophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2-fluorobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-(2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-{(2E)-2-[3-(trifluoromethyl)-benzylidene]hydrazino}ethyl)benzamide,

N-{2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-[(2E)-2-(2-pyridinylmethylene)-hydrazino]ethyl}benzamide,

N-{2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-[(2E)-2-(3-pyridinylmethylene)-hydrazino]ethyl}benzamide,

N-[2-((2E)-2-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methylene}-hydrazino)-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-(2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-{(2E)-2-[1-(3-pyridinyl)-ethylidene]hydrazino}ethyl)benzamide,

N-(2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-{(2E)-2-[1-(2-pyridinyl)ethylidene]hydrazino}ethyl)benzamide,

N-[2-[(2E)-2-(1,3-dimethylbutylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[2-(3-methoxyphenyl)-1-methylethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)propylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-fluorophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)-2-((2E)-2-{(1-[3-(trifluoromethyl)phenyl]ethylidene}hydrazino)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-chlorophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-cyanophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-hydroxyphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-methylphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(4-methyl-2-pyridinyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)-2,2-dimethylpropylidene]-hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)-2-methylpropylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[(3-bromophenyl)(cyclopropyl)methylene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3-bromophenyl)butylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(2,2-dimethyl-1-phenylpropylidene)hydrazino]-2-oxo-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3,5-dimethoxyphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-((2E)-2-{1-[3,5-bis(trifluoromethyl)phenyl]ethylidene}-hydrazino)-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3,5-difluorophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-[(2E)-2-(3,5-dibromobenzylidene)hydrazino]-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide,

N-[2-{(2E)-2-[1-(3,5-dibromophenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide; and

,

N-[2-{(2E)-2-[1-(3,5-dimethylphenyl)ethylidene]hydrazino}-2-oxo-1-(4-oxo-3,4-dihydro-1-phthalazinyl)ethyl]benzamide.