4-amino substituted-6-aryl/heteroaryl substituted-2-methylsulfanyl-pyrimidine-5-carbaldehyde intermediates

• US 7,314,934 B2
• Filed: 08/19/2003
• Issued: 01/01/2008
• Est. Priority Date: 10/23/2000
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: Smithkline Beecham Corporation (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:
  US10/470,629
• Publication Number:
  US 20050203109A1
• Time in Patent Office: 1,596 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
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• 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 R₁ is a phenyl substituted one or more times independently with halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

3. The compound according to claim 2 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.

4. 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.

5. The compound according to claim 4 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)_nNHS(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

wherein

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.

6. The compound according to claim 5 wherein the R₃ moiety is optionally substituted one or more times, independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

7. The compound according to claim 1 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.

8. The compound according to claim 1 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;

or

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

10. The compound according to claim 2 wherein the phenyl is substituted one or more times independently with fluoro or methyl.

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

wherein

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,

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

Z is oxygen or sulfur.

14. The compound according to claim 11 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7cycloalkyl, C_3-7cycloalkylalkyl, or aryl.

15. The compound according to claim 14 wherein R₃ is an optionally substituted C_1-10 alkyl, or aryl.

16. The compound according to claim 15 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.

17. The compound according to claim 16 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.

18. The compound according to claim 17 wherein R₃ is a 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.

19. The compound according to claim 16 wherein R₃ is a 2,6-difluorophenyl.

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

21. The compound according to claim 19 wherein Rg is methyl.

22. The compound according to claim 1 wherein m is 0.

23. The compound according to claim 21 wherein m is 0.

37. The compound according to claim 13 wherein R₁ is an optionally substituted phenyl.

38. The compound according to claim 13 wherein R₁ is a phenyl ring, optionally substituted one or more times independently by halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

39. The compound according to claim 13 wherein R₁ is a phenyl ring substituted in the 2, 4, or 6-position, or di-substituted in the 2,4-position.

9. The compound which is 4-(2,6-Difluorophenylamino)-6-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde.

24. A compound of the formula

25. The compound according to claim 24 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

26. The compound according to claim 25 wherein the R₃ moiety 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)_nNHS(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

wherein

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.

27. The compound according to claim 26 wherein the R₃ moiety is optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

28. The compound according to claim 24 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.

29. The compound according to claim 28 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.

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

31. The compound according to claim 28 wherein R₃ is a 2,6-difluorophenyl.

32. The compound according to claim 24 wherein Rg is methyl.

33. The compound according to claim 31 wherein Rg is methyl.

34. The compound according to claim 24 wherein m is 0.

35. The compound according to claim 33 wherein mis 0.

36. The compound according to claim 24 wherein R₁ is 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, NR₁₀OC(Z)R₁₁, or NR₁₀S(O)₂R₇; and

wherein

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_1-4alyl, 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,

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

Z is oxygen or sulfur.

40. The compound according to claim 24 wherein Rg is methyl, m is 0.

41. The compound according to claim 40 wherein R₃ is an optionally substituted aryl.