Compounds and methods to treat cardiac failure and other disorders

• US 6,589,954 B1
• Filed: 05/21/1999
• Issued: 07/08/2003
• Est. Priority Date: 05/22/1998
• Status: Expired due to Term

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Scios, Inc. (Johnson & Johnson)
• Inventors: Perumattam, John J., Liu, David Y., Lewicki, John A., Schreiner, George F., Mavunkel, Babu J.
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US09/316,761
• Time in Patent Office: 1,509 Days
• Field of Search: 514/253, 544/367, 544/373
• US Class Current: 514/254.06
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 209/24 with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
• CPC Class Codes: C07D 235/06 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Indoles, benzimidazoles and benztriazoles which are substituted at the 5 or 6 position with a substituent comprising an aromatic moiety linked through a piperazine ring to said indole, benzimidazole or benztriazole are useful in treating cardiac conditions associated with heart failure and in treating conditions characterized by proinflammation.

Claims

1. A compound of the formula:

and the pharmaceutically acceptable salts thereof,

wherein each of Z¹ and Z² is independently CR⁴ or N;

where each R⁴ is independently selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S, and N and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);

or

R¹ is

 

wherein

X¹ is CO, SO, SO₂ or CHOH;

m is 1;

Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;

n is 0, 1 or 2;

Z³ is N;

X² is CH, CH₂ or an isostere thereof; and

Ar consists of one or two phenyl moieties directly coupled to X², said one or two phenyl moieties being optionally substituted by one or more substituents selected from the group consisting of halo, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, CF₃, RCO, COOR, CONR₂, NR₂, OR, SR, OOCR, NROCR; and

phenyl, itself optionally substituted by one or more of the foregoing substituents, wherein R in the foregoing optional substituents is H or alkyl (1-6C);

R² is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl or aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) with the proviso that when both Z¹ and Z² are CH, R² is other than H;

R³ is selected from the group consisting of H, halo, NO₂, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, and NROCR where R is H or alkyl (1-6C).

2. The compound of claim 1 which is of the formula

3. The compound of claim 1 wherein R² is alkyl (1-6C) or aryl, each of said alkyl or aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C).

4. The compound of claim 1 wherein X¹ is CO.

5. The compound of claim 1 wherein X² is CH₂.

6. The compound of claim 2 wherein X¹ is CO and X² is CH₂.

7. The compound of claim 1 wherein Z¹ and Z² are CR⁴.

8. The compound of claim 6 wherein Z¹ and Z² are CR⁴.

9. The compound of claim 1 wherein Z¹ is N and Z² is CH.

10. The compound of claim 6 wherein Z¹ is N and Z² is CH.

11. The compound of claim 2 which is of the formula (2).

12. The compound of claim 6 which is of the formula (2).

13. The compound of claim 2 wherein R³ is halo or OR where R is alkyl (1-6C).

14. The compound of claim 6 wherein R³ is halo or OR where R is alkyl (1-6C);

and wherein R² is alkyl (1-6C) or is aryl, each of said alkyl or aryl constituting the substituent R² optionally including one or more heteroatoms which are selected from O, S and N, and each said alkyl optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR (where R is H or 1-6C alkyl), CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C).

15. The compound of claim 1 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, OR, or NR₂ and p is 0, 1, 2 or 3.

16. The compound of claim 6 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, OR, or NR₂ and p is 0, 1, 2 or 3.

18. The compound of claim 1 wherein Z² is CH and wherein R² is alkyl (1-6C) or is aryl, each of said alkyl or aryl constituting the substituent R² optionally including one or more heteroatoms which are selected from O, S and N, and each said alkyl optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR (where R is H or 1-6C alkyl), CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C).

19. The compound of claim 1 wherein Z¹ is CR⁴ and R⁴ is other than H.

20. The compound of claim 1 wherein Z¹ is CR⁴ wherein R⁴ is other than H and Z² is CH.

21. The compound of claim 20 wherein R⁴ is alkyl optionally containing one or more heteroatoms selected from O, S and N, said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C).

22. The compound of claim 21 wherein R⁴ contains the structure

23. The compound of claim 22 which is of the formula

24. The compound of claim 23 which is of the formula (2).

25. The compound of claim 21 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, OR;

or NR₂ and p is 0, 1, 2 or 3.

26. The compound of claim 21 wherein R³ is halo or OR where R is alkyl (1-6C).

27. The compound of claim 21 wherein R² is H or alkyl (1-6C).

28. The compound of claim 21 wherein R⁴ contains NR₂.

29. The compound of claim 21 wherein R⁴ contains a saturated 5 or 6 membered ring containing 1-2 heteroatoms.

30. The compound of claim 21 wherein R⁴ contains an unsaturated 5 or 6 membered ring containing 1-2 heteroatoms.

31. The compound of claim 25 wherein R⁴ contains ═

O.

32. The compound of claim 31 wherein R⁴ contains the structure:

64. A method to treat a condition characterized by a pro-inflammation response which method comprises administering to a subject in need of such treatment an amount of a compound of any of claims 1, 17, 33, 49 or 57 or a pharmaceutical composition thereof effective to treat said condition.

65. The method of claim 64 wherein said condition characterized by inflammation is acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, uveitis, IBD, acute renal failure, head trauma, or ischemic/reperfusion injury.

66. A method to treat a heart condition associated with cardiac failure, which method comprises administering to a subject in need of such treatment an amount of a compound of any of claims 1, 17, 33, 49 or 57 or a pharmaceutical composition thereof effective to treat said heart condition.

67. The method of claim 66 wherein said chronic heart condition is congestive heart failure, cardiomyopathy or myocarditis.

17. A compound which is selected from the group consisting of:

4-(2,6-difluorobenzyl)-piperazinyl-benzymidazole-5-carboxamide;

4-(2,3-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(3,5-difluorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(3-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-carboxymethyl benzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-methoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-trifluoxomethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-methylbenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(2,4-dichlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(3,4-dichlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;

4-[trans-3-(trifluoromethyl)-cinnamoyl]-piperazinyl-benzimidazole-5-carboxamide;

4-(4-chlorobenzoyl)-piperazinyl-benzimidazole-5-carboxamide;

4-benzoylpiperazine-benzimidazole-5-carboxamide;

4-(2-trifluoromethylbenzoyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-methoxybenzoyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(3,4-dichlorophenyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-chlorobenzhydryl)-piperazinyl-benzimidazole-5-carboxamide;

4-trans-1-cinnamyl piperazinyl-benzimidazole-5-carboxamide;

4-[bis(4-fluorophenyl)-methyl]-piperazinyl-benzimidazole-5-carboxamide;

4-(4-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(2-chlorobenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-benzylpiperazinyl-benzimidazole-5-carboxamide;

4-(4-methylthiobenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(3,4,5-trimethoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-diethylaminobenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(biphenylmethyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-Phenoxybenzyl)-piperazinyl-benzimidazole-5-carboxamide;

4-(4-chlorobenzyl)-piperazinyl-1-(2-propyl)-indole-5-carboxamide;

4-(3-chlorobenzyl)-piperazinyl-N-benzyl-benzimidazole-5-carboxamide;

4-(3-chlorobenzyl)-piperazinyl-N-benzyl-benzimidazole-6-carboxamide;

4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-5-carboxamide;

4-(3-chlorobenzyl)-piperazinyl-N-(2-propyl)-benzimidazole-6-carboxamide;

4-(3-chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-5-carboxamide;

4-(3-chlorobenzyl)-piperazinyl-N-ethyl-benzimidazole-6-carboxamide;

4-(3-chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-5-carboxamide; and

4-(3-chlorobenzyl)-piperazinyl-N-methyl-benzimidazole-6-carboxamide.

33. A compound of the formula:

and the pharmaceutically acceptable salts thereof,

wherein each of Z¹ and Z² is independently CR⁴ or N;

where each R⁴ is independently selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S, and N and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);

or

R¹ is

 

wherein

X¹ is CO or an isostere thereof,

m is 1;

Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;

n is 0, 1 or 2;

Z³ is N;

X² is CH, CH₂ or an isostere thereof; and

Ar is a phenyl moiety optionally substituted by a substituent selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, CF₃, RCO, COOR, CONR₂, NR₂, OR, SR, OOCR, NROCR, and phenyl, itself optionally substituted by the foregoing substituents, wherein R in the foregoing optional substituents is H or alkyl (1-6C);

R² is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) with the proviso that if both Z¹ and Z² are CH, R² is other than H;

R³ is selected from the group consisting of H, halo, NO₂, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, and NROCR where R is H or alkyl (1-6C).

34. The compound of claim 33 wherein Z¹ is CR⁴ wherein CR⁴ is other than H.

35. The compound of claim 33 wherein Z² is CH and wherein R² is alkyl (1-6C) or is aryl, each of said alkyl or aryl constituting the substituent R² optionally including one or more heteroatoms which are selected from O, S and N, and said alkyl optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR (where R is H or 1-6C alkyl), CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C).

36. The compound of claim 33 wherein Z¹ and Z² are both CR⁴.

37. The compound of claim 33 wherein Z¹ is CR⁴ wherein CR⁴ is other than H and Z² is CH.

38. The compound of claim 37 which is of the formula

39. The compound of claim 38 which is of the formula (2).

40. The compound of claim 39 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, — OR, or NR₂ and p is 0, 1, 2 or 3.

41. The compound of claim 39 wherein R³ is halo or OR where R is alkyl (1-6C).

42. The compound of claim 39 wherein R² is H or alkyl (1-6C).

43. The compound of claim 37 wherein R⁴ is alkyl optionally containing one or more heteroatoms selected from O, S and N and said alkyl is optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C).

44. The compound of claim 43 wherein R⁴ contains NR₂.

45. The compound of claim 43 wherein R⁴ contains a saturated 5- or 6-membered ring containing 1-2 heteroatoms.

46. The compound of claim 43 wherein R⁴ contains an unsaturated 5- or 6-membered ring containing 1-2 heteroatoms.

47. The compound of claim 43 wherein R⁴ contains ═

O.

48. The compound of claim 47 wherein R⁴ contains the structure.

49. A compound of the formula:

and the pharmaceutically acceptable salts thereof,

wherein Z¹ is CR^4′

and Z² is CH;

where R^4′

is selected from the group consisting of alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S, and N and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);

or

R¹ is

 

wherein

X¹ is CO or an isostere thereof;

m is 1;

Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;

n is 0, 1 or 2;

Z³ is N;

X² is CH, CH₂ or an isostere thereof; and

Ar is one or two phenyl moieties, optionally substituted by one or more substituents selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, CF₃, RCO, COOR, CONR₂, NR₂, OR, SR, OOCR, NROCR, and phenyl itself optionally substituted by the foregoing substituents, wherein R in the foregoing optional substituents is H or alkyl (1-6C);

R² is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl or aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);

R³ is selected from the group consisting of H, halo, NO₂, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, and NROCR where R is H or alkyl (1-6C).

50. The compound of claim 49 where R^4′

is alkyl optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N where R in the preceding substituents is H or 1-6C alkyl.

51. The compound of claim 50 wherein R^4′

contains ═

O.

52. The compound of claim 51 wherein R^4′

contains;

53. The compound of claim 52 where R² is selected from the group consisting of alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S and N, and each of and alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C).

54. The compound of claim 49 where R^4′

is aryl optionally substituted by at least one substituent selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, or NROCR, CN, and a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N where R in the preceding substituents is H or 1-6C alkyl.

55. The compound of claim 54 wherein R⁴′

comprises 4 pyridyl, 2-pyridyl, 3-pyridyl, 2-piperidyl, 3-piperidyl, or 4-piperidyl.

56. The compound of claim 52 wherein Ar is

wherein each X³ is independently alkyl (1-6C), halo, — OR, or NR₂ and p is 0, 1, 2 or 3.

57. A compound of the formula:

and the pharmaceutically acceptable salts thereof,

wherein Z¹ and Z² are each independently N or CR⁴;

where R⁴ is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S, and N and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);

or

R¹ is

 

wherein

X¹ is CO or an isostere thereof;

m is 1;

Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;

n is 1 or 2;

Z³ is N;

X² is CH, CH₂ or an isostere thereof; and

Ar is one or two phenyl moieties, optionally substituted by one or more substituents selected from halo, nitro, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, CF₃, RCO, COOR, CONR₂, NR₂, OR, SR, OOCR, NROCR, and phenyl, itself optionally substituted by the foregoing substituents, wherein R in the foregoing optional substituents is H or alkyl (1-6C);

R² is selected from the group consisting of H, alkyl (1-6C) and aryl, each of said alkyl or aryl optionally including one or more heteroatoms which are selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C);

R³ is selected from the group consisting of H, halo, NO₂, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, and NROCR where R is H or alkyl (1-6C).

58. The compound of claim 57 where R⁴ is alkyl optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, and saturate or unsaturated 5- or 6-membered rings optionally containing 1-2 heteroatoms where R in the preceding substituents is H or 1-6C alkyl.

59. The compound of claim 57 wherein R⁴ contains ═

O.

60. The compound of claim 59 wherein R⁴ contains:

61. The compound of claim 60 wherein R² is selected from the group consisting of alkyl (1-6C) and aryl, each of said alkyl and aryl optionally including one or more heteroatoms selected from O, S and N, and each of said alkyl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, ═

O, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C) and each of said aryl being optionally substituted by one or more substituents selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N, where R in the foregoing optional substituents is H or alkyl (1-6C).

62. The compound of claim 57 wherein R⁴ is aryl optionally substituted by at least one substituent selected from the group consisting of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, or NROCR, CN, a five- or six-membered saturated carbocyclic ring or heterocyclic ring containing 1-2 N, and a six-membered aromatic ring optionally containing 1-2 N where R in the preceding substituents is H or 1-6C alkyl.

63. The compound of claim 62 wherein R⁴ comprises 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-piperidyl, 3-piperidyl, or 4-piperidyl.