Novel compounds

• US 20060235030A1
• Filed: 03/24/2006
• Published: 10/19/2006
• Est. Priority Date: 03/25/2005
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Callahan, James F., Yan, Hongxing, Wan, Zehong
• Granted Patent: US 7,674,789 B2
• Time in Patent Office: Days
• US Class Current: 514/262.100
• 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 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 17/06 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 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 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• 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 7/02 : 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 487/04 : Ortho-condensed systems

Abstract

Novel substituted 1,5,7-trisubstituted-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-(1H)-one compounds and compositions, and their use in therapy as CSBP/RK/p38 kinase inhibitors.

Claims

1. A compound of the formula:

2. The compound according to claim 1 which is Formula (I), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

3. The compound according to claim 1 which is Formula (Ia), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

4. The compound according to claim 1 wherein R₁ is C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b or N(R_10′

)C(Z)(CR₁₀R₂₀)_vR_b.

5. The compound according to claim 4 wherein R₁ is C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b.

6. The compound according to claim 1 wherein R_b is selected from an optionally substituted alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted aryl C_1-10 alkyl, or an optionally substituted C_3-7 cycloalkyl C_1-10 alkyl.

7. The compound according to claim 6 wherein R_b is optionally substituted alkyl, optionally substituted heteroaryl, or an optionally substituted aryl.

8. The compound according to claim 7 wherein R_b is propyl, isopropyl, thiazolyl, phenyl, or 4-F phenyl.

9. The compound according to claim 6 wherein R_b is an optionally substituted aryl or aryl C_1-10alkyl moiety, and the aryl ring substituted independently at each occurrence one or more times by halogen, alkyl, cyano, OR₈, SR₅, S(O)₂R₅, C(O)R_j, C(O)OR_j, -Z′

-(CR₁₀R₂₀)s-Z′

, halosubstituted C_1-10 alkyl, or an optionally substituted aryl; and

wherein

R₈ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-4 alkyl, C_5-7 cycloalkenyl, C_5-7cycloalkenyl C_1-4 alkyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, or a heterocyclylC_1-4 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted;

R_j is independently selected at each occurrence from hydrogen, C_1-4alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-14alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted;

Z′

is independently selected at each occurrence from oxygen, or sulfur; and

s is an integer having a value of 1, 2, or 3, independently selected at each occurrence.

10. The compound according to claim 1 wherein R_b is phenyl, napthylene, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-diflurophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-chloro-4-fluorophenyl, 2-methyl phenyl, 3-methylphenyl, 4-methylphenyl, 6-methyl phenyl, 2-methyl phenyl, 3-amino phenyl, 3,4-dimethyl phenyl, 4-methyl-3-fluorophenyl, 4-trifluorophenyl, 4-ethoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 4-thiomethylphenyl, 4-acetylphenyl, 4-dimethylaminophenyl, benzyl, phenethyl, phenylpropyl, 2,3-difluoro-benzyl, 3,5-difluoro-benzyl, biphenyl, 4′

-fluorobiphenyl, 4-sulfonamindo-2-methylphenyl, 3-phenyloxyphenyl, 4-phenyloxyphenyl, 4-(1-piperidinylsulfonyl)-phenyl, or 3-(aminocarbonyl)phenyl.

11. The compound according to claim 6 wherein R_b is a C_1-10alkyl, or a C_1-10alkyl substituted one or more times, independently by halogen, cyano, alkoxy, thiol, or hydroxy.

12. The compound according to claim 11 wherein R_b is methyl, ethyl, propyl, isopropyl, t-butyl, butyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, heptyl, 2-methylpropyl, 2,2,2-trifluroethyl, 2-fluoroethyl, cyanomethyl, cyanoethyl, 2-methoxy-ethyl, 2-hydroxy propyl, serinol, or ethylthioethyl.

13. The compound according to claim 6 wherein R_b is an optionally substituted heteroaryl, heteroaryl C_1-10alkyl, heterocyclic or heterocyclic C_1-10alkyl.

14. The compound according to claim 13 wherein R_b is the moiety is a 1,3-thiazol-2-yl, 5-methyl-1,3-thiazol-2-yl, isoquinoline, 3-thiophene, indol-5yl, pyridin-3-yl, pyridine-4-yl, indazolyl, benzothiazolyl, 2-methyl-1,3-benzothiazol-5-yl, pyrazol-3-yl, 4-morpholino, 2-furanyl, 2-furanylmethyl, 2-thienyl, 2-thienylmethyl, tetrahydro-2H-pyran-4yl, tetrahydro-2H-pyran-4yl methyl, tetrahydro-2-furanyl, or tetrahydro-2-furanylmethyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1H-imidazol-4-yl or 1H-imidazol-4-yl-ethyl.

15. The compound according to claim 1 wherein R_b is an optionally substituted C_3-7 cycloalkyl or C_3-7 cycloalkyl C_1-10alkyl.

16. The compound according to claim 15 wherein R_b is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, or cyclopentylmethyl.

17. The compound according to claim 6 wherein R_b is selected from methyl-1,3-benzothiazol-5-yl, 4′

-fluoro-3-biphenyl, 4-fluoro-phenyl, 2-fluorophenyl, 4-chlorophenyl, 3,5-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 4-fluorophenethyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 4-acetylphenyl, 4-trifluorophenyl, 4-methyl-3-fluoro-phenyl, 4-thiomethylphenyl, 4-ethyloxyphenyl, 4-methoxyphenyl, 3-phenyloxyphenyl, 3-methylphenyl, 2-methylphenyl, 5-methyl-1,3-thiazol-2-yl, 3-pyridinyl, 4-pyridinyl, 4-cyanophenyl, 3-cyanophenyl, 4-(phenylcarbonyl)phenyl, 1H-indazol-6-yl, or 3-(aminosulfonyl)phenyl.

18. The compound according to claim 1 wherein the R_1′

is independently selected from halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

19. The compound according to claim 18 wherein the substituents are independently fluorine, methyl, or CF₃.

20. The compound according to claim 18 wherein g is 1.

21. The compound according to claim 1 wherein X is S(O)_mR₂.

22. The compound according to claim 1 wherein X is (CH₂)_nNR₄R₁₄, or (CH₂)_nN(R_2′

)(R_2″

).

23. The compound according to claim 22 wherein X is (CH₂)_nNR₄R₁₄, and R₄ and R₁₄ are independently selected from hydrogen, optionally substituted C_1-10 alkyl, optionally substituted aryl, optionally substituted aryl-C_1-4 alkyl, optionally substituted heterocyclic, optionally substituted heterocylic C_1-4 alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl C_1-4 alkyl.

24. The compound according to claim 23 wherein the C_1-10 alkyl may be substituted one or more times, independently at each occurrence with NR_4′

R_14′

;

halogen, hydroxy, alkoxy, C(O)NR_4′

R_14′

;

or NR_4′

OC(O)C_1-10alkyl.

25. The compound according to claim 24 wherein R_4′

and R_14′

;

are independently selected from hydrogen or a C_1-4 alkyl.

26. The compound according to claim 25 wherein X is 3-(diethylamino)-propylamino.

27. The compound according to claim 22 wherein X is (CH₂)_nNR₄R₁₄ and one of R₄ and R₁₄ is an optionally substituted heteroaryl C_1-4 alkyl, and the heteroaryl moiety is selected from thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.

28. The compound according to claim 27 wherein the heteroaryl moiety is selected from pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.

29. The compound according to claim 22 wherein X is (CH₂)_nNR₄R₁₄ and one of R₄ and R₁₄ is a heterocyclic C_1-4 alkyl moiety selected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, diazepinyl, piperazinyl, and morpholino.

30. The compound according to claim 29 wherein the heterocyclic C_1-4 alkyl moiety is selected from pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholino.

31. The compound according to claim 22 wherein X is (CH₂)_nNR₄R₁₄ and R₄ and R₁₄ together with the nitrogen cyclize to form an optionally substituted ring selected from pyrrolidine, piperidine, piperazine, and morpholine.

32. The compound according to claim 22 wherein the R₄ and R₁₄ cyclized ring is optionally substituted one or more times independently by an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic, (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇, or NR_4′

R_14′

.

33. The compound according to claim 32 wherein the optional substituents are selected from phenyl, pyrrolidinyl, morpholino, piperazinyl, 4-methyl-1-piperazinyl, piperidinyl, 2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, 5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, diphenylmethyl, methyl, ethyl, propyl, butyl, amino, methylamino, and dimethylamino.

34. The compound according to claim 1 wherein X is R₂ and R₂ is an optionally substituted heterocyclic or heterocyclic alkyl ring substituted one or more times independently at each occurrence by an optionally substituted heterocyclic, heterocyclic C_1-10 alkyl, aryl, aryl C_1-10 alkyl, C_1-10 alkyl, (CR₁₀R₂₀)_nNR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇.

35. The compound according to claim 32 wherein R₂ is selected from 1,4′

-bipiperin-1-yl, 4-methyl-1,4′

-bipiperin-1-yl, 4-piperidinylamino, 4-amino-1-piperidinyl, 2,2,6,6-tetramethyl-4-piperidinyl)amino, 4-methyl-1-piperazinyl, (4-morpholinyl)-1-piperidinyl, (4-methyl-1-piperazinyl)-1-piperidinyl, 4-ethyl-1-piperazinyl, (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl, 5-chloro-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl, 4-(1-pyrrolidinyl)-1-piperidinyl, 4-(diphenylmethyl)-1-piperazinyl, 4-methylhexahydro-1H-1,4-diazepin-1-yl, 4-propyl-1-piperazinyl, or 4-butyl-1-piperazinyl.

36. The compound according to claim 35 wherein R₂ is 1,4′

-bipiperin-1-yl, 4-(1-pyrrolidinyl)-1-piperidinyl, and 4-methyl-1-piperazinyl.

37. The compound according to claim 1 wherein R₂ is optionally substituted one or more times, independently at each occurrence, with 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_1-10alkyl, C_5-7cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, —

C(O), cyano, nitro, aryl, aryl C_1-10 alkyl, heterocyclic, heterocyclic C_1-10 alkyl, heteroaryl, heteroaryl C_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(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)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR₄R₁₄, (CR₁₀R₂₀)_nC(═

NOR₆)NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

n is independently selected at each occurrence from 0 or an integer having a value of 1 to 10;

R₆ is independently selected at each occurrence from hydrogen, C_1-10alkyl, 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, excluding hydrogen are optionally substituted.

38. The compound according to claim 36 wherein R₂ is an optionally substituted alkyl.

39. The compound according to claim 38 wherein the C_1-10alkyl is optionally substituted by (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nOR₆, or (CR₁₀R₂₀)_nNR₄R₁₄.

40. The compound according to claim 1 wherein R₂ is (CR₁₀R₂₀)_q′

X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or (CR₁₀R₂₀)_q′

C(A₁)(A₂)(A₃).

41. The compound according to claim 40 wherein X₁ is oxygen or N(R_10′

).

42. The compound according to claim 41 wherein at least one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)_nOR₆.

43. The compound according to claim 42 wherein q is 1 or 2, and q′

is 0.

44. The compound according to claim 22 wherein X is (CH₂)_nN(R_2′

)(R_2″

), and R_2′

is an optionally substituted C_1-10 alkyl, cycloalkyl, heterocyclic, heterocyclyl C_1-10 alkyl, heteroarylalkyl.

45. The compound according to claim 44 wherein the R_2′

moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently, at each occurrence, 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_1-10alkyl, C_5-7cycloalkenyl, C_5-7 cycloalkenylC_1-10 alkyl, halogen, —

C(O), cyano, nitro, aryl, aryl C_1-10 alkyl, aryl, aryl C_1-10 alkyl, heterocyclic, heterocyclic C_1-10 alkyl, heteroaryl, heteroaryl C_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR_eR_e′

, (CR₁₀R₂₀)_nNR_eR_e′

C_1-4alkylNR_eR_e′

, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR_eR_e′

, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR_eR_e′

, (CR₁₀R₂₀)_nC(═

NOR₆)NR_eR_e′

, (CR₁₀R₂₀)_nOC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

R₆ is independently selected at each occurrence from 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, excluding hydrogen are optionally substituted;

R₇ is independently selected at each occurrence from C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl moiety, and wherein each of these moieties may be optionally substituted;

R_e are R_e′

are each independently selected at each occurrence from hydrogen, C_1-4 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, aryl, aryl-C_1-14 alkyl, heterocyclic, heterocyclic C_1-4 alkyl, heteroaryl or a heteroaryl C_1-4 alkyl moiety;

or R_e and R_e′

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 nitrogen; and

wherein each of these moieties, excluding hydrogen, may be substituted 1 to 4 times, independently at each occurrence by halogen;

hydroxy;

hydroxy substituted C_1-10alkyl;

C_1-10alkoxy;

halosubstituted C_1-10 alkoxy;

amino, mono &

di-substituted C_1-4 alkyl amino, S(O)_mR_f;

C(O)R_j;

C(O)ORj;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_dR_d′

;

C(O)NR_4′

R_14′

;

NR_4′

C(O)C_1-10alkyl;

NR_4′

C(O)aryl;

cyano;

nitro;

C_1-10 alkyl;

C_3-7cycloalkyl;

C_3-7cycloalkyl C_1-10 alkyl;

halosubstituted C_1-10 alkyl;

aryl, aryl C_1-4 alkyl, heterocyclic, heterocyclicC_1-4 alkyl, heteroaryl, or heteroC_1-4alkyl, and wherein these aryl, heterocyclic, and heteroaryl containing moieties may be optionally substituted one to two times independently at each occurrence by halogen, C_1-4 alkyl, hydroxy, hydroxy substituted C_1-4 alkyl, C_1-10 alkoxy, S(O)_malkyl, amino, mono &

di-substituted C_1-4 alkyl amino, C_1-4 alkyl, or CF₃;

R_f is independently selected at each occurrence from C_1-10alkyl, aryl, aryl C_1-10alkyl, heteroaryl, heteroaryl C_1-10alkyl, heterocyclic, or a heterocyclic C_1-10alkyl moiety, and wherein these moieties may all be optionally substituted;

R_4′

and R_14′

are each independently selected at each occurrence from hydrogen or C_1-4 alkyl, or R_4′

and R_14′

can cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR_9′

;

R_j is independently selected at each occurrence from hydrogen, C_1-4alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; and

n is 0 or an integer having a value of 1 to 10, and is independently selected at each occurrence.

46. The compound according to claim 45 wherein R_2′

is a heterocyclic ring or heterocyclic alkyl substituted one or more times, independently by C_1-10 alkyl, aryl, arylalkyl, (CR₁₀R₂₀)_nNR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇.

47. The compound according to claim 22 wherein the (CH₂)_nN(R_2′

)(R_2″

) moiety is 1-(phenylmethyl)-4-piperidinamine, 2-[4-(phenylmethyl)-1-piperazinyl]ethylamine, 2-(1-piperidinyl)ethylamine, 2-(1-methyl-2-pyrrolidinyl)ethylamine, 1-[(phenylmethyl)-3-pyrrolidinyl]amine, 3-[(1-pyrrolidinyl)propyl]amine, 3-[(hexahydro-1H-azepin-1-yl)propyl]amine, (1-methyl-4-piperidinyl)amine, 3-[(4-morpholinyl)propyl]amine, 3-[(2-oxo-1-pyrrolidinyl)propyl]amine, 2-[(4-morpholinyl)ethyl]amine, 2-[(1-pyrrolidinyl)ethyl]amine, or [(1-ethyl-2-pyrrolidinyl)methyl]amine.

48. The compound according to claim 45 wherein R_2′

is a C_1-10 alkyl substituted by (CR₁₀R₂₀)_nNR_eR_e′

or (CR₁₀R₂₀)_nNR_eR_e′

C_1-4alkylNR_eR_e′

.

49. The compound according to claim 48 wherein R_e and R_e′

are independently selected from methyl, ethyl, isopropyl, n-butyl, or t-butyl, and n=0.

50. The compound according to claim 22 wherein (CH₂)_nN(R_2′

)(R_2″

) is 3-(dimethylamino)propyl(methyl)amine, 3-(diethylamino)propylamine, propylamine, (2,2-dimethylpropyl)amine, (2-hydroxypropyl)amino, 2-(dimethylamino)ethylamine, 2-(dimethylamino)ethyl(methyl)amine, 3-(dimethylamino)propylamine, 2-(dimethylamino)ethyl(methyl)amine, 3-(diethylamino)propylamine, 2-(methylamino)ethylamine, [(1-methylethyl)amino]ethylamine, 3-(diethylamino)propylamine, 3-(dibutylamino)propylamine, 3-[(1-methylethyl)amino]propylamine, 3-(1,1-dimethylethyl)aminopropylamine, 3-(dimethylamino)-2,2-dimethylpropylamine, 4-(diethylamino)-1-methylbutylamine, or 3-[[3-(dimethylamino)propyl]-(methyl)amino]propyl(methyl)amine.

51. 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.

52. The compound according to claim 51 wherein R₃ is optionally substituted one or more times, independently at each occurrence, with halogen, nitro, 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_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR₁₆R₂₆, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₁₆R₂₆, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR₁₆R₂₆, (CR₁₀R₂₀)_nOC(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR₁₆R₂₆, or (CR₁₀R₂₀)_nN(R₁₀)C(Z)OR₇; and

wherein

R₆ is independently selected at each occurrence from 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, excluding hydrogen are optionally substituted;

R₇ is independently selected at each occurrence from C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; and

n is 0 or an integer having a value of 1 to 10, and is independently selected at each occurrence.

53. The compound according to claim 52 wherein the R₃ is an optionally substituted aryl.

54. The compound according to claim 53 wherein the aryl is a phenyl substituted one or more times independently at each occurrence by halogen, (CR₁₀R₂₀)_nOR₆, C_1-10 alkyl, (CR₁₀R₂₀)_nNR₁₆R₂₆, or halosubstituted alkyl.

55. The compound according claim 54 wherein the phenyl is substituted one or more times independently by halogen, hydroxy, alkoxy, amino, alkyl, or CF₃.

56. The compound according to claim 55 wherein the phenyl is disubstituted independently at each occurrence by halogen or methyl.

57. The compound according to claim 56 wherein R₃ is 2,6-difluorophenyl.

58. The compound according to claim 1 wherein R₃ is a 2,6-difluoro phenyl, R_1′

is independently selected at each occurrence from hydrogen, fluorine, or methyl;

g is 1 or 2;

R₁ is C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b, R_b is C_1-10 alkyl or an optionally substituted aryl;

X is (CH₂)_nN(R_2′

)(R_2″

), n is 0, and R_2′

is an alkyl substituted by (CR₁₀R₂₀)_nNR_eR_e′

.

59. The compound according to claim 58 wherein the compound is of Formula (Ic), R_e and R_e′

are independently selected from methyl, ethyl, isopropyl, n-butyl, or t-butyl, R_b is C_1-10 alkyl, g is 1;

C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b, and Z is oxygen, R₁₀, is hydrogen, and v=0.

60. The compound according to claim 1, which is:

1,1-Dimethylethyl {1-[4-{5-[(cyclobutylamino)carbonyl]-2-methylphenyl}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}carbamate;

3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-cyclobutyl-4-methylbenzamide;

1,1-Dimethylethyl {1-[4-(5-{[(cyclopropylmethyl)amino]carbonyl}-2-methylphenyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]-4-piperidinyl}carbamate;

3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide;

3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-[2-(4-fluorophenyl)ethyl]-4-methylbenzamide;

1,1-Dimethylethyl(1-{8-(2,6-difluorophenyl)-4-[5-({[2-(4-fluorophenyl)ethyl]amino}carbonyl)-2-methylphenyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl}-4-piperidinyl)carbamate;

3-[2-[(2-Aminoethyl)(methyl)amino]-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(cyclopropylmethyl)-4-methylbenzamide;

N-(Cyclopropylmethyl)-3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzamide;

N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-]pyrimidin-4-yl]-4-methylbenzamide;

1,1-Dimethylethyl 4-{[4-(5-{[(cyclopropylmethyl)amino]carbonyl}-2-methylphenyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate;

N-(3-{8-(2,6-Difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-thiophenecarboxamide;

3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide;

3-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)-propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

N-{3-[8-(2,6-difluorophenyl)-2-(dimethylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

N-{3-[8-(2,6-difluorophenyl)-2-(ethyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

3-[2-(4-Amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide;

3-{8-(2,6-Difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide;

3-{8-(2,6-Difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide;

3-(8-(2,6-Difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide;

3-(8-(2,6-Difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(phenylmethyl)benzamide;

1,1-Dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate;

3-[8-(2,6-Difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide;

3-[8-(2,6-Difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide;

1,1-Dimethylethyl 4-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(phenylmethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}-1-piperidinecarboxylate;

3-{8-(2,6-Difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(phenylmethyl)benzamide;

N-(3-{8-(2,6-difluorophenyl)-7-oxo-2-[(2,2,6,6-tetramethyl-4-piperidinyl)amino]-5,6,7,8-tetrahydropyrimido[4,5-]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide;

N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;

N-{3-[8-(2,6-difluorophenyl)-2-(ethyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;

N-(3-{8-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide;

N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;

1,1-dimethylethyl 4-{[8-(2,6-difluorophenyl)-4-(5-{[(3-fluoro-4-methylphenyl)carbonyl]amino}-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-]pyrimidin-2-yl]amino}-1-piperidinecarboxylate;

N-{3-[8-(2,6-difluorophenyl)-2-(dimethylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;

3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide; and

a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

61. The compound according to claim 1 which is:

N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide;

N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide;

N-{3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide;

3-[8-(2,6-Difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide; and

a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

62. A compound according to claim 1 which is

N-{3-[2-(4-amino-1-piperidinyl)-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

N-{3-[8-(2,6-difluorophenyl)-2-(ethyloxy)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

N-(3-{8-(2,6-difluorophenyl)-2-[(1-methylethyl)oxy]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylphenyl)-3-fluoro-4-methylbenzamide

N-{3-[8-(2,6-difluorophenyl)-7-oxo-2-(4-piperidinylamino)-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

N-{3-[8-(2,6-difluorophenyl)-2-(dimethylamino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide

3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide

3-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide

3-{8-(2,6-difluorophenyl)-2-[[2-(dimethylamino)ethyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

3-{8-(2,6-difluorophenyl)-2-[4-(methylamino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

3-{8-(2,6-difluorophenyl)-2-[[3-(dimethylamino)propyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

3-[8-(2,6-difluorophenyl)-2-({2-[(1-methylethyl)amino]ethyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

3-{8-(2,6-difluorophenyl)-2-[[2-(dimethylamino)ethyl](methyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methyl-N-(1-methylethyl)benzamide

3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide

3-(8-(2,6-difluorophenyl)-2-{[2-(methylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide

3-{8-(2,6-difluorophenyl)-2-[(1-methyl-4-piperidinyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

3-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methyl-N-(1-methylethyl)benzamide

3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

3-(8-(2,6-difluorophenyl)-2-{[3-(dimethylamino)propyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-4-methylbenzamide

3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

3-{8-(2,6-difluorophenyl)-2-[(1H-imidazol-2-ylmethyl)amino]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-N-(4-fluorophenyl)-4-methylbenzamide

3-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

3-[8-(2,6-difluorophenyl)-2-({3-[(1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

3-[8-(2,6-difluorophenyl)-2-({3-[(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide

3-[2-{[3-(dibutylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

3-[8-(2,6-difluorophenyl)-2-({3-[(1-methylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide

3-[8-(2,6-difluorophenyl)-2-({3-[(1,1-dimethylethyl)amino]propyl}amino)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide;

and

a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

63. A compound of general formula (I) or (Ia) according to claim 1, as described in any of Examples 1 to 230 herein, or a tautomer, diastereomer, enantiomer, or salt thereof.

65. A pharmaceutical composition comprising an effective amount of a compound, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof according to claim 1 and a pharmaceutically acceptable carrier or diluent.

66. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt, solvate or physiologically functional derivative according to claim 1, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients, for administration by intravenous, intramuscular, subcutaneous, intranasal, oral inhalation, intrarectal, intravaginal or intraperitoneal means.

67. A method of treating an inflammatory component of a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, according to claim 1.

68. The method according to claim 67 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 (COPD), 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, atheroschlerosis, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, atheroschlerosis, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.

69. A method of treating the inflammation associated with the common cold or a 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, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof according to claim 1.

70. The method according to claim 69 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.

71. A method of treating inflammation in a mammal in need thereof comprising adminisering to said mammal an effective amount of a compound according to claim 1.

72. A method of treating traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 1.

73. A method of treating, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, or chronic obstructive pulmonary disease (COPD) in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 1.

74. A method of treating atherosclerosis, inflammatory bowel disease, Crohn'"'"'s disease, or ulcerative colitis in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 1.

81. A compound of the formula:

82. The compound according to claim 81 wherein R₃ is a 2,6-difluorophenyl, and Rg is methyl.

83. The compound according to claim 81 which is

3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid;

N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide;

N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide;

3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide;

3-[8-(2,6-Difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;

N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide;

3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide;

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N,N,4-trimethylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide;

3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide;

or

3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido-[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid.

86. The compound according to claim 81 which is Formula (Id), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

95. The compound according to claim 81 wherein X is (CH₂)_nNR₄R₁₄, or (CH₂)_nN(R_2′

)(R_2″

).

96. The compound according to claim 95 wherein X is (CH₂)_nNR₄R₁₄, and R₄ and R₁₄ are independently selected from hydrogen, optionally substituted C_1-10 alkyl, optionally substituted aryl, optionally substituted aryl-C_1-4 alkyl, optionally substituted heterocyclic, optionally substituted heterocylic C_1-4 alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl C_1-4 alkyl.

98. The compound according to claim 95 wherein X is (CH₂)_nNR₄R₁₄ and one of R₄ and R₁₄ is an optionally substituted heteroaryl C_1-4 alkyl, and the heteroaryl moiety is selected from thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.

99. The compound according to claim 95 wherein X is (CH₂)_nNR₄R₁₄ and one of R₄ and R₁₄ is a heterocyclic C_1-4 alkyl moiety selected from tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, diazepinyl, piperazinyl, and morpholino.

100. The compound according to claim 95 wherein X is (CH₂)_nNR₄R₄ and R₄ and R₁₄ together with the nitrogen cyclize to form an optionally substituted ring selected from pyrrolidine, piperidine, piperazine, and morpholine.

64. A compound as defined in any one of Examples 1 to 230 or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

75. A compound of the formula:

76. A compound according to claim 75 wherein:

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-1,3-thiazol-2-ylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(1-methylethyl)benzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-propylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-phenylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)benzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N-dimethylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-methylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-(1-methylethyl)benzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzoic acid

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-propylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methyl-N-phenylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N-(4-fluorophenyl)-3-methylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,N,3-trimethylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-N,3-dimethylbenzamide

4-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-3-methylbenzamide;

or

a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

77. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof according to claim 75, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

78. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt, solvate or physiologically functional derivative according to claim 75 in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients, for administration by intravenous, intramuscular, subcutaneous, intranasal, oral inhalation, intrarectal, intravaginal or intraperitoneal means.

79. A method of treating an inflammatory component of a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, according to claim 75.

80. A compound of the formula:

84. A compound of the formula:

85. The compound according to claim 84 which is Formula (Ic), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

87. The compound according to claim 84 wherein R₁ is C(Z)N(R_11′

)(CR₁₀R₂₀)_vR_b.

88. The compound according to claim 84 wherein R_b is an optionally substituted heteroaryl, heteroarylalkyl, heterocyclic, or heterocyclicalkyl.

89. The compound according to claim 88 wherein R_b is an optionally substituted heteroaryl, or heteroarylalkyl.

90. The compound according to claim 84 wherein R_b is a 1,3-thiazol-2-yl, 5-methyl-1,3-thiazol-2-yl, isoquinoline, 3-thiophene, indol-5-yl, pyridin-3-yl, pyridine-4-yl, indazolyl, benzothiazolyl, 2-methyl-1,3-benzothiazol-5-yl, pyrazol-3-yl, 4-morpholino, 2-furanyl, 2-furanylmethyl, 2-thienyl, 2-thienylmethyl, tetrahydro-2H-pyran-4yl, tetrahydro-2H-pyran-4-yl methyl, tetrahydro-2-furanyl, or tetrahydro-2-furanylmethyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1H-imidazol-4-yl or 1H-imidazol-4-yl-ethyl.

91. The compound according to claim 84 wherein R_b is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, or cyclopentylmethyl.

92. The compound according to claim 84 wherein the R_1′

is independently selected from halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

93. The compound according to claim 92 wherein the substituents are independently fluorine, methyl, or CF₃.

94. The compound according to claim 84 wherein g is 1.

97. The compound according to claim 93 wherein the C_1-10 alkyl may be substituted one or more times, independently at each occurrence with NR_4′

R_14′

;

halogen, hydroxy, alkoxy, C(O)NR_4′

R_14′

;

or NR_4′

C(O)C_1-10alkyl.

101. The compound according to claim 92 wherein the R₄ and R₁₄ cyclized ring is optionally substituted one or more times independently by an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic, (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇, or NR_4′

R_14′

,

102. The compound according to claim 101 wherein the optional substituents are selected from phenyl, pyrrolidinyl, morpholino, piperazinyl, 4-methyl-1-piperazinyl, piperidinyl, 2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, 5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, diphenylmethyl, methyl, ethyl, propyl, butyl, amino, methylamino, and dimethylamino.

103. The compound according to claim 84 wherein X is R₂ and R₂ is an optionally substituted heterocyclic or heterocyclic alkyl ring substituted one or more times independently at each occurrence by an optionally substituted heterocyclic, heterocyclic C_1-10 alkyl, aryl, aryl C_1-10 alkyl, C_1-10 alkyl, (CR₁₀R₂₀)_nNR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇.

104. The compound according to claim 103 wherein R₂ is selected from 1,4′

-bipiperin-1-yl, 4-methyl-1,4′

-bipiperin-1-yl, 4-piperidinylamino, 4-amino-1-piperidinyl, 2,2,6,6-tetramethyl-4-piperidinyl)amino, 4-methyl-1-piperazinyl, (4-morpholinyl)-1-piperidinyl, (4-methyl-1-piperazinyl)-1-piperidinyl, 4-ethyl-1-piperazinyl, (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl, 5-chloro-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl, 4-(1-pyrrolidinyl)-1-piperidinyl, 4-(diphenylmethyl)-1-piperazinyl, 4-methylhexahydro-1H-1,4-diazepin-1-yl, 4-propyl-1-piperazinyl, or 4-butyl-1-piperazinyl.

105. The compound according to claim 84 wherein R₂ is optionally substituted one or more times, independently at each occurrence, with 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_1-10alkyl, C_5-7cycloalkenyl, C_5-7 cycloalkenyl C_1-10 alkyl, halogen, —

C(O), cyano, nitro, aryl, aryl C_1-10 alkyl, heterocyclic, heterocyclic C_1-10 alkyl, heteroaryl, heteroaryl C_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR₄R₁₄, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₄R₄, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR₄R₁₄, (CR₁₀R₂₀)_nC(═

NOR₆)NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇.

106. The compound according to claim 105 wherein R₂ is an optionally substituted alkyl.

107. The compound according to claim 106 wherein the C_1-10 alkyl is optionally substituted by (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nOR₆, or (CR₁₀R₂₀)_nNR₄R₁₄.

108. The compound according to claim 84 wherein R₂ is (CR₁₀R₂₀)_q′

X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or (CR₁₀R₂₀)_q′

C(A₁)(A₂)(A₃).

109. The compound according to claim 108 wherein X₁ is oxygen or N(R_10′

).

110. The compound according to claim 109 wherein at least one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)_nOR₆, q is 1 or 2, and q′

is 0.

111. The compound according to claim 84 wherein X is (CH₂)_nN(R_2′

)(R_2″

), and R_2′

is an optionally substituted C_1-10 alkyl, cycloalkyl, heterocyclic, heterocyclyl C_1-10 alkyl, heteroarylalkyl.

112. The compound according to claim 111 wherein the R₂, moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently, at each occurrence, 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_1-10alkyl, C_5-7cycloalkenyl, C_5-7 cycloalkenylC_1-10 alkyl, halogen, —

C(O), cyano, nitro, aryl, aryl C_1-10 alkyl, aryl, aryl C_1-10 alkyl, heterocyclic, heterocyclic C_1-10 alkyl, heteroaryl, heteroaryl C_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR_eR_e′

, (CR₁₀R₂₀)_nNR_eR_e′

C_1-4alkylNR_eR_e′

, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR_eR_e′

, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R₁₀)C(═

N(R_10′

))NR_eR_e′

, (CR₁₀R₂₀)_nC(═

NOR₆)NR_eR_e′

, (CR₁₀R₂₀)_nOC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

R₆ is independently selected at each occurrence from hydrogen, C_1-10alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties, excluding hydrogen are optionally substituted;

R₇ is independently selected at each occurrence from C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl moiety, and wherein each of these moieties may be optionally substituted;

R_e are R_e′

are each independently selected at each occurrence from hydrogen, C_1-4 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, aryl, aryl-C_1-14 alkyl, heterocyclic, heterocyclic C_1-4 alkyl, heteroaryl or a heteroaryl C_1-4 alkyl moiety;

or R_e and R_e′

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 nitrogen; and

wherein each of these moieties, excluding hydrogen, may be substituted 1 to 4 times, independently at each occurrence by halogen;

hydroxy;

hydroxy substituted C_1-10alkyl;

C_1-10alkoxy;

halosubstituted C_1-10 alkoxy;

amino, mono &

di-substituted C_1-4 alkyl amino, S(O)mR_f;

C(O)R_j;

C(O)ORj;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_dR_d′

;

C(O)NR_4′

R_14′

;

NR_4′

C(O)C_1-10alkyl;

NR_4′

C(O)aryl;

cyano;

nitro;

C_1-10 alkyl;

C_3-7cycloalkyl;

C_3-7cycloalkyl C_1-10 alkyl;

halosubstituted C_1-10 alkyl;

aryl, aryl C_1-4 alkyl, heterocyclic, heterocyclicC_1-4 alkyl, heteroaryl, or heteroC_1-4alkyl, and wherein these aryl, heterocyclic, and heteroaryl containing moieties may be optionally substituted one to two times independently at each occurrence by halogen, C_1-4 alkyl, hydroxy, hydroxy substituted C_1-4 alkyl, C_1-10 alkoxy, S(O)_malkyl, amino, mono &

di-substituted C_1-4 alkyl amino, C_1-4 alkyl, or CF₃;

R_f is independently selected at each occurrence from C_1-10alkyl, aryl, aryl C_1-10alkyl, heteroaryl, heteroaryl C_1-10alkyl, heterocyclic, or a heterocyclic C_1-10alkyl moiety, and wherein these moieties may all be optionally substituted;

R_4′

and R_14′

are each independently selected at each occurrence from hydrogen or C_1-4 alkyl, or R_4′

and R_14′

can cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR_9′

;

R_j is independently selected at each occurrence from hydrogen, C_1-4alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; and

n is 0 or an integer having a value of 1 to 10, and is independently selected at each occurrence.

113. The compound according to claim 112 wherein R_2′

is a heterocyclic ring or heterocyclic alkyl substituted one or more times, independently by C_1-10 alkyl, aryl, arylalkyl, (CR₁₀R₂₀)_nNR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇.

114. The compound according to claim 84 wherein the (CH₂)_nN(R_2′

)(R_2″

) moiety is 1-(phenylmethyl)-4-piperidinamine, 2-[4-(phenylmethyl)-1-piperazinyl]ethylamine, 2-(1-piperidinyl)ethylamine, 2-(1-methyl-2-pyrrolidinyl)ethylamine, 1-[(phenylmethyl)-3-pyrrolidinyl]amine, 3-[(1-pyrrolidinyl)propyl]amine, 3-[(hexahydro-1H-azepin-1-yl)propyl]amine, (1-methyl-4-piperidinyl)amine, 3-[(4-morpholinyl)propyl]amine, 3-[(2-oxo-1-pyrrolidinyl)propyl]amine, 2-[(4-morpholinyl)ethyl]amine, 2-[(1-pyrrolidinyl)ethyl]amine, or [(1-ethyl-2-pyrrolidinyl)methyl]amine.

115. The compound according to claim 113 wherein R_2′

is an optionally substituted C_1-10 alkyl substituted by (CR₁₀R₂₀)_nNR_eR_e′

or (CR₁₀R₂₀)_nNR_eR_e′

C_1-14alkylNR_eR_e.

116. The compound according to claim 115 wherein R_e and R_e′

are independently selected from methyl, ethyl, isopropyl, n-butyl, or t-butyl.

117. The compound according to claim 84 wherein (CH₂)_nN(R_2′

)(R_2″

) is 3-(dimethylamino)propyl(methyl)amine, 3-(diethylamino)propylamine, propylamine, (2,2-dimethylpropyl)amine, (2-hydroxypropyl)amino, 2-(dimethylamino)ethylamine, 2-(dimethylamino)ethyl(methyl)amine, 3-(dimethylamino)propylamine, 2-(dimethylamino)ethyl(methyl)amine, 3-(diethylamino)propylamine, 2-(methylamino)ethylamine, [(1-methylethyl)amino]ethylamine, 3-(diethylamino)propylamine, 3-(dibutylamino)propylamine, 3-[(1-methylethyl)amino]propylamine, 3-(1,1-dimethylethyl)aminopropylamine, 3-(dimethylamino)-2,2-dimethylpropylamine, 4-(diethylamino)-1-methylbutylamine, or 3-[[3-(dimethylamino)propyl]-(methyl)amino]propyl(methyl)amine.

118. The compound according to claim 84 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

119. The compound according to claim 118 wherein R₃ is optionally substituted one or more times, independently at each occurrence, with C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10alkynyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-10alkyl, C_5-7cycloalkenyl, C_5-7cycloalkenylC_1-10 alkyl, halogen, cyano, nitro, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(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)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R₁₀)C(═

N(R₁₀))NR₄R₁₄, (CR₁₀R₂₀)_nOC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nN(R_10′

)C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

R₆ is independently selected at each occurrence from 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, excluding hydrogen are optionally substituted;

R₇ is independently selected at each occurrence from C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl moiety, and wherein each of these moieties may be optionally substituted; and

n is 0 or an integer having a value of 1 to 10, and is independently selected at each occurrence.

120. The compound according to claim 119 wherein the R₃ is an optionally substituted aryl.

121. The compound according to claim 120 wherein the aryl is a phenyl substituted one or more times independently at each occurrence by halogen, (CR₁₀R₂₀)_nOR₆, C_1-10 alkyl, (CR₁₀R₂₀)_nNR₁₆R₂₆, or halosubstituted alkyl.

122. The compound according to claim 121 wherein the phenyl is substituted one or more times independently by halogen, hydroxy, alkoxy, amino, alkyl, or CF₃.

123. The compound according to claim 122 wherein the phenyl is disubstituted independently at each occurrence by halogen or methyl.

124. The compound according claim 123 wherein the phenyl ring is substituted one or more times independently by halogen.

125. The compound according to claim 124 wherein R₃ is a 2,6-difluorophenyl.

126. A pharmaceutical composition comprising an effective amount of a compound, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof according to claim 84 and a pharmaceutically acceptable carrier or diluent.

127. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt, solvate or physiologically functional derivative according to claim 84, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients, for administration by intravenous, intramuscular, subcutaneous, intranasal, oral inhalation, intrarectal, intravaginal or intraperitoneal means.

128. A method of treating an inflammatory component of a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a compound, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, according to claim 84.

129. The method according to claim 128 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 (COPD), 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, atheroschlerosis, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, neurodegenrative disease, muscle degeneration, atheroschlerosis, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, influenza induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis.

130. A method of treating inflammation in a mammal in need thereof comprising adminisering to said mammal an effective amount of a compound according to claim 84.

131. A method of treating, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 84.

132. A method of treating, asthma, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, or chronic obstructive pulmonary disease (COPD) in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 84.

133. A method of treating atherosclerosis, inflammatory bowel disease, Crohn'"'"'s disease, or ulcerative colitis, in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 84.