2,4,5-Trisubstituted pyrimidine compounds

• US 7,759,486 B2
• Filed: 08/16/2007
• Issued: 07/20/2010
• Est. Priority Date: 10/23/2000
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: GlaxoSmithKline LLC (GSK plc)
• Inventors: Hall, Ralph, Jin, Qi, Kasparec, Jiri, Boehm, Jeffrey C., Silva, Domingos J., Adams, Jerry L., Taggart, John J.
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US11/839,830
• Publication Number:
  US 20090105478A1
• Time in Patent Office: 1,069 Days
• Field of Search: 544/317
• US Class Current: 544/317
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
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• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 27/16 Otologicals
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 239/47 : One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Novel substituted 2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-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 R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

3. The compound according to claim 2 wherein the R₃ optional substituents are independently selected from C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7 cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nNR₁₀S(O)₂R₇, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₄R₁₄, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)R₆, (CR₁₀R₂₀)_nNR₁₀C(═

NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nNR₁₀C(Z)OR₇;

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, optionally substituted aryl, or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₆ is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties may be optionally substituted;

R₇ is a C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; and

wherein each of these moieties may be optionally substituted;

R₉ is hydrogen, C(Z)R₆ or optionally substituted C_1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl;

R₁₀ and R₂₀ are independently selected at each occurrence from hydrogen or C_1-4alkyl;

n is 0 or an integer having a value of 1 to 10;

m is 0 or an integer having a value of 1 or 2; and

Z is oxygen or sulfur.

4. The compound according to claim 3 wherein the R₃ optional substituents are independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

5. The compound according to claim 1 wherein R₃ is a 2,6-difluorophenyl.

6. The compound according to claim 1 wherein R₁ is an optionally substituted aryl.

7. The compound according to claim 6 wherein the R₁ aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

8. The compound according to claim 7 wherein the R₁ phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.

9. The compound according to claim 1 wherein R₁ is an optionally substituted phenyl.

10. The compound according to claim 1 wherein R₁ is a phenyl ring, substituted one or more times independently by halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

11. The compound according to claim 1 wherein R₁ is 2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.

12. The compound according to claim 11 wherein R₁ is 2-methyl-4-fluorophenyl.

13. The compound according to claim 10 wherein the halogen is fluorine, and the C_1-4 alkyl is methyl.

14. The compound according to claim 1 wherein R₁₂ is a C_1-10 alkyl.

15. The compound according to claim 1 wherein Rg is methyl.

16. The compound according to claim 1 wherein m is 0 or 2.

17. The compound according to claim 1 which is (E)-3-[4-(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid ethyl ester.

18. A compound of the formula

19. The compound according to claim 18 wherein the R₃ ring is optionally substituted one or more times independently by C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7 cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nNR₁₀S(O)₂R₇, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₄R₁₄, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)R₆, (CR₁₀R₂₀)_nNR₁₀C(═

NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nNR₁₀C(Z)OR₇; and

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, optionally substituted aryl, or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₆ is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties may be optionally substituted;

R₇ is a C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; and

wherein each of these moieties may be optionally substituted;

R₉ is hydrogen, C(Z)R₆ or optionally substituted C_1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl;

R₁₀ and R₂₀ are independently selected at each occurrence from hydrogen or C_1-4alkyl;

n is 0 or an integer having a value of 1 to 10;

m is 0 or an integer having a value of 1 or 2;

Z is oxygen or sulfur.

20. The compound according to claim 19 wherein the R₃ ring is optionally substituted independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

21. The compound according to claim 19 wherein R₃ is an optionally substituted aryl.

22. The compound according to claim 18 wherein R₃ is a phenyl ring, substituted one or more times independently by halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

23. The compound according to claim 22 wherein the phenyl is optionally substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.

24. The compound according to claim 18 wherein R₃ is a 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.

25. The compound according to claim 18 wherein R₃ is a 2,6-difluorophenyl.

26. The compound according to claim 18 wherein R₁ is an aryl which is optionally substituted one or more times, independently, by halogen, C_1-4 alkyl, halo-substituted-C_1-4 alkyl, cyano, nitro, (CR₁₀R₂₀)_vNR₄R₁₄, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄, (CR₁₀R₂₀)_vC(Z)OR₈, (CR₁₀R₂₀)_vCOR_a′

, (CR₁₀R₂₀)_vC(O)H, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_vOR₈, ZC(Z)R₁₁, NR₁₀C(Z)R₁₁, or NR₁₀S(O)₂R₇; and

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, optionally substituted aryl, or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₅ is hydrogen, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl or NR₄R₁₄, excluding the moieties SR₅ being SNR₄R₁₄, S(O)₂R₅ being SO₂H and S(O)R₅ being SOH;

R₆ is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties may be optionally substituted;

R₇ is a C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; and

wherein each of these moieties may be optionally substituted;

R₈ is hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_tOR₇, (CR₁₀R₂₀)_tS(O)_mR₇, (CR₁₀R₂₀)_tNHS(O)₂R₇, or (CR₁₀R₂₀)_tNR₄R₁₄; and

wherein the cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties may be optionally substituted;

R₉ is hydrogen, C(Z)R₆ or optionally substituted C_1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl;

R₁₀ and R₂₀ are independently selected at each occurrence from hydrogen or C_1-4alkyl;

R₁₁ is C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_tOR₇, (CR₁₀R₂₀)_tS(O)_mR₇, (CR₁₀R₂₀)_tNHS(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄; and

wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and heterocyclylalkyl moieties may be optionally substituted;

v is 0 or an integer having a value of 1 or 2;

t is an integer having a value of 1 to 3;

wherein

R_a′

is C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4alkyl, heterocyclyl, heterocyclyl C_1-4 alkyl, (CR₁₀R₂₀)OR₇, (CR₁₀R₂₀)_vS(O)_mR₇, (CR₁₀R₂₀)NHS(O)₂R₇, or (CR₁₀R₂₀)NR₄R₁₄, and wherein the aryl, arylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionally substituted; and

Z is oxygen or sulfur.

27. The compound according to claim 18 wherein R₁ is a phenyl ring substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

28. The compound according to claim 26 wherein R₁ is an optionally substituted aryl.

29. The compound according to claim 28 wherein R₁ is an optionally substituted phenyl.

30. The compound according to claim 18 wherein R₁ is a phenyl ring, substituted one or more times independently by halogen, C_1-4 alkyl, or halo-Substituted-C_1-4 alkyl.

31. The compound according to claim 30 wherein R₁ is substituted in the 2,4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position.

32. The compound according to claim 31 wherein R₁ is 2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.

33. The compound according to claim 18 wherein R₁ is 2-methyl-4-fluorophenyl.

34. The compound according to claim 18 wherein Rg is methyl.

35. The compound according to claim 18 wherein m is 0 or 2.

36. A compound of the formula

37. The compound according to claim 36 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

38. The compound according to claim 37 wherein the R₃ optional substituents are independently selected from C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7 cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nNR₁₀S(O)₂R₇, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₄R₁₄, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)R₆, (CR₁₀R₂₀)_nNR₁₀C(═

NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z) NR₄R₁₄, or (CR₁₀R₂₀)_nNR₁₀C(Z)OR₇; and

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, optionally substituted aryl, or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₆ is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties may be optionally substituted;

R₇ is a C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; and

wherein each of these moieties may be optionally substituted;

R₉ is hydrogen, C(Z)R₆ or optionally substituted C_1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl;

R₁₀ and R₂₀ are independently selected at each occurrence from hydrogen or C_1-4alkyl;

n is 0 or an integer having a value of 1 to 10;

m is 0 or an integer having a value of 1 or 2;

Z is oxygen or sulfur.

39. The compound according to claim 38 wherein the R₃ optional substituents are independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

40. The compound according to claim 38 wherein R₃ is an optionally substituted C_1-10 alkyl or aryl.

41. The compound according to claim 40 wherein R₃ is a phenyl ring, substituted one or more times independently by halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

42. The compound according to claim 41 wherein the R₃ phenyl ring is optionally substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.

43. The compound according to claim 36 wherein R₃ is a 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.

44. The compound according to claim 43 wherein R₃ is a 2,6-difluorophenyl.

45. The compound according to claim 36 wherein R₁ is an optionally substituted aryl.

46. The compound according to claim 45 wherein R₁ is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

47. The compound according to claim 46 wherein the R₁ phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2, 4, 6-position.

48. The compound according to claim 47 wherein R₁ is 2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.

49. The compound according to claim 36 wherein R₁ is 2-methyl-4-fluorophenyl.

50. The compound according to claim 36 wherein R₁ is optionally substituted one or more times, independently, by halogen, C_1-4 alkyl, halo-substituted-C_1-4 alkyl, cyano, nitro, (CR₁₀R₂₀)_vNR₄R₁₄, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄, (CR₁₀R₂₀)_vC(Z)OR₈, (CR₁₀R₂₀)_vCOR_a′

, (CR₁₀R₂₀)_vC(O)H, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_vOR₈, ZC(Z)R₁₁, NR₁₀C(Z)R₁₁, or NR₁₀S(O)₂R₇; and

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, optionally substituted aryl, or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₅ is hydrogen, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl or NR₄R₁₄, excluding the moieties SR₅ being SNR₄R₁₄, S(O)₂R₅ being SO₂H and S(O)R₅ being SOH;

R₆ is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties may be optionally substituted;

R₇ is a C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; and

wherein each of these moieties may be optionally substituted;

R₈ is hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_tOR₇, (CR₁₀R₂₀)_tS(O)_mR₇, (CR₁₀R₂₀)_tNHS(O)₂R₇, or (CR₁₀R₂₀)_tNR₄R₁₄; and

wherein the cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties may be optionally substituted;

R₉ is hydrogen, C(Z)R₆ or optionally substituted C_1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl;

R₁₀ and R₂₀ are independently selected at each occurrence from hydrogen or C_1-4alkyl;

R₁₁ is C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_tOR₇, (CR₁₀R₂₀)_tS(O)_mR₇, (CR₁₀R₂₀)_tNHS(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄; and

wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and heterocyclylalkyl moieties may be optionally substituted;

v is 0 or an integer having a value of 1 or 2;

t is an integer having a value of 1 to 3;

wherein

R_a′

is C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_5-7 cycloalkenyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4alkyl, heterocyclyl, heterocyclyl C_1-4 alkyl, (CR₁₀R₂₀)_vOR₇, (CR₁₀R₂₀)_vS(O)_mR₇, (CR₁₀R₂₀)_vNHS(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄, and wherein the aryl, arylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionally substituted; and

Z is oxygen or sulfur.

51. The compound according to claim 50 wherein R₁ is an optionally substituted phenyl.

52. The compound according to claim 36 wherein R₁₂ is a C_1-10 alkyl.

53. The compound according to claim 36 wherein Rg is methyl.

54. The compound according to claim 36 wherein m is 0 or 2.

55. The compound according to claim 38 wherein the R₃ is an aryl ring optionally substituted one or more times independently by C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7 cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_n NR₁₀S(O)₂R₇, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₄R₁₄, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)R₆, (CR₁₀R₁₀)_nNR₁₀C(═

NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nNR₁₀C(Z)OR₇; and

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, optionally substituted aryl, or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉;

R₆ is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties may be optionally substituted;

R₇ is a C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; and

wherein each of these moieties may be optionally substituted;

R₉ is hydrogen, C(Z)R₆ or optionally substituted C_1-10 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl;

R₁₀ and R₂₀ are independently selected at each occurrence from hydrogen or C_1-4alkyl;

n is 0 or an integer having a value of 1 to 10;

m is 0 or an integer having a value of 1 or 2;

Z is oxygen or sulfur.