Novel compounds

• US 20040209901A1
• Filed: 04/06/2004
• Published: 10/21/2004
• Est. Priority Date: 10/23/2000
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Hall, Ralph, Jin, Qi, Kasparec, Jiri, Boehm, Jeffrey C., Silva, Domingos J., Adams, Jerry L., Taggart, John J.
• Granted Patent: US 7,314,881 B2
• Time in Patent Office: Days
• US Class Current: 514/264.1
• 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
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 which is Formula (I).

3. The compound according to claim 1 which is Formula (Ia).

4. The compound according to claim 1 wherein R₁ is an optionally substituted phenyl or napthyl.

5. The compound according to claim 4 wherein the phenyl is substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

6. The compound according to claim 5 wherein the substituents are independently fluorine, C_1-4 alkyl, or CF₃.

7. The compound according to claim 5 wherein the phenyl ring 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.

14. The compound according to claim 1 wherein R₂ is X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃).

15. The compound according to claim 14 wherein X₁ is oxygen or N(R₁₀).

16. The compound according to claim 14 wherein at least one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)_nOR₆.

17. The compound according to claim 16 wherein q is 1 or 2.

18. 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.

19. The compound according to claim 18 wherein R₃ is optionally substituted one or more times independently with C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10alkynyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7cycloalkenyl, C_5-7cycloalkenylC_1-10alkyl, halogen, cyano, nitro, (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)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nNR₁₀C(Z)OR₇.

20. The compound according to claim 19 wherein the optional substitutent is halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

22. The compound according to claim 1 which is:

2-(2-Diethylamino-ethylamino)-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one;

8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

4,8-Bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

4-(2-Fluoro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

4-(2-Chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

4-(2-Fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one;

8-Cyclopropyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

4-(4-Fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

8-Cyclopropylmethyl-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

8-sec-Butyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

4,8-Bis-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

8-(2,6-Difluoro-phenyl)-4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

8-Cyclopropylmethyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;

4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one;

4,8-Bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one

23. The compound according to claim 1 which is:

8-(2,6-Dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido [2,3-d]pyrimidin-7-one;

4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-ortho-tolyl-8H-pyrido [2,3-d]pyrimidin-7-one;

4-(4Fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one;

8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[2-(tert-butoxycarbonylamino)ethoxy]-8H-pyrido[2,3-d]pyrimidin-7-one

2-(1-hydroxymethyl-1-methyl-2-hydroxyethylamino)-4-(4-fluoro-2-methylphenyl)-8-(2-fluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

2-(1-hydroxymethyl-1-methyl-2-hydroxyethylamino)-4-(4-fluoro-2-methylphenyl)-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one;

8-(2,6-Difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-trihydroxy-methylaminomethyl]-8H-pyrido[2,3-d]pyrimidin-7-one;

8-(2-Fluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-[N-([2,2-dimethyl-2-hydroxy]ethylamino)]-8H-pyrido[2,3-d]pyrimidin-7-one;

8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-[N-2,2-dimethylethanolamino]-8H-pyrido[2,3-d]pyrimidin-7-one;

8-Cyclohexyl-4-(4-fluoro-2-methylphenyl)-2-[-N-dihydroxymethylmethylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;

4-(4-Fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-1-methyl-ethylamino)-8-o-tolyl-8H-pyrido[2,3-d]pyrimidin-7-one;

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

25. 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 according to claim 1.

26. The method according to claim 25 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.

27. A method of treating the common cold or respiratory viral infection caused by human rhinovirus (HRV), other enteroviruses, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, or adenovirus in a human in need thereof which method comprises administering to said human an effective amount of a compound according to claim 1.

28. The method according to claim 27 wherein the respiratory viral infection exacerbates asthma, exacerbates chronic bronchitis, exacerbates chronic obstructive pulmonary disease, exacerbates otitis media, exacerbates sinusitis, or wherein the respiratory viral infection is associated with a secondary bacterial infection, otitis media, sinusitis, or pneumonia.

31. The compound according to claim 25 wherein R₁ is an optionally substituted aryl ring.

32. The compound according to claim 31 wherein the aryl is a phenyl substituted one or more times independently with halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

33. The compound according to claim 32 wherein the 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.

34. The compound according to claim 31 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

35. The compound according to claim 34 wherein the R₃ moiety is optional 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.

36. The compound according to claim 35 wherein the optional substituents are independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

84. The compound according to claim 1 wherein X₁ is oxygen or N(R₁₀).

85. The compound according to claim 1 wherein at least one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)_nOR₆.

86. The compound according to claim 85 wherein q is 1 or 2.

8-13. -13. (Cancelled)

21. (cancelled)

29. A compound of the formula

30. The compound according to claim 29 wherein R₁ is an optionally substituted heteroaryl ring.

37. The compound according to claim 29 which is:

2-Methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde;

4-(2-Chlorophenyl)-6-(1-ethylpropylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(2-Chlorophenyl)-6-(2-chlorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(2-Fluorophenyl)-6-(2-chlorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

or

4-(2-Fluoro-phenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde.

38. The compound according to claim 29 which is

4-Amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde.

4-Cyclopropylamino-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(Cyclopropylmethylamino)-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(2,6-Difluorophenylamino)-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(2-Fluorophenyl)-6-(2-fluorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-sec-Butylamino-6-(2-fluorophenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(4-Fluoro-2-methylphenyl)-6-isopropylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(Cyclopropylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(Cyclopropylmethylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(4-Fluoro-2-methyl-phenyl)-6-(2-fluorophenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-sec-Butylamino-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(2,6-Difluorophenylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

4-(1-Ethylpropylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde;

2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylamino-pyrimidine-5-carbaldehyde;

or

2-Methylsulfanyl-4-(2-methyl-4-fluorophenyl)-6-cyclohexylamino-pyrimidine-5-carbaldehyde.

39. A compound of the formula

40. The compound according to claim 39 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

41. The compound according to claim 40 wherein the 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, (CR₁₀R_20)nOR, (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.

42. The compound according to claim 41 wherein the optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

43. The compound according to claim 40 wherein R₁ is an optionally substituted aryl.

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

45. The compound according to claim 44 wherein the 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.

46. The compound according to claim 40 wherein R₁₂ is a C_1-10 alkyl.

47. The compound according to claim 40 which is

(E)-3-[4-(2,6-Difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid ethyl ester.

48. A process for producing a compound according to Formula (Ia)

49. The process according to claim 48 wherein the base is pyridine, diisopropyl ethylamine, or pyrrolidine.

50. The process according to claim 48 wherein the acetylating agent is acetic anhydride, acetyl chloride, or ketene.

51. The process according to claim 48 wherein R₃ is an optionally substituted aryl.

52. The process according to claim 48 wherein R₁ is a halogen or an optionally substituted aryl.

53. The process according to claim 52 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

54. The compound according to claim 53 wherein the 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.

55. The process according to claim 48 wherein X is (CH₂)_nNR₄R₁₄, or (CH₂)_nN(R₂)₂.

56. The process according to claim 48 wherein R₂ is the moiety X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃).

57. The process according to claim 56 wherein X₁ is oxygen or N(R₁₀).

58. The process according to claim 57 wherein at least one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)_nOR₆.

74. The compound according to claim 56 wherein R₁ is a phenyl ring substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

75. The compound according to claim 74 wherein the 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.

59. A process of making a compound of the Formula:

60. The process according to claim 59 wherein the organic solvent is an organic hydrocarbon, cresol, dioxane, DMF, pyridine, or xylene.

61. The process according to claim 59 wherein the base is diisopropyl ethylamine, pyridine, DBU, lithium bis(trimethylsilyl)amide, or LDA.

62. The process according to claim 59 wherein R₃ is an optionally substituted aryl.

63. The process according to claim 59 wherein X is (CH₂)_nNR₄R₁₄, or (CH₂)_nN(R₂)₂.

64. The process according to claim 59 wherein R₂ is the moiety X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃).

65. The process according to claim 64 wherein X₁ is oxygen or N(R₁₀).

66. The process according to claim 65 wherein at least one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)_nR₆.

67. The process according to claims 64 to wherein R₁ is an optionally substituted aryl.

68. The process according to claim 67 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

69. The compound according to claim 68 wherein the 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.

70. A compound of the formula

71. The compound according to claim 70 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)_nOR, (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.

72. The compound according to claim 71 wherein the optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

73. The compound according to claim 70 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.

76. A compound of the formula

77. The compound according to claim 76 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

78. The compound according to claim 77 wherein the 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, (CR₁₀OR₂₀)_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.

79. The compound according to claim 78 wherein the optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

80. The compound according to claim 76 wherein R₁ is an optionally substituted aryl.

81. The compound according to claim 80 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

82. The compound according to claim 81 wherein the 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.

83. The compound according to claim 76 wherein R₁₂ is a C_1-10 alkyl.

87. The compound 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one or a pharmaceutically acceptable salt thereof.

88. A pharmaceutical composition comprising an effective amount of 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

89. 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 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.

90. The method according to claim 89 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.

91. A method of treating a inflammation in a mammal in need thereof, which method comprises administering to said mammal an effective amount of 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.