Tetrasubstituted pyrimidine compounds as chemical intermediates

• US 7,629,462 B2
• Filed: 12/20/2006
• Issued: 12/08/2009
• Est. Priority Date: 03/02/2000
• Status: Expired due to Fees

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Smithkline Beecham Corporation (GlaxoSmithKline PLC)
• Inventors: Boehm, Jeffrey C., Adams, Jerry L., Taggart, John J., Hall, Ralph F.
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US11/613,598
• Publication Number:
  US 20070167467A1
• Time in Patent Office: 1,084 Days
• Field of Search: 544/317, 514/274
• US Class Current: 544/317
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• 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: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Novel substituted pyrimido[4,5-d]pyrimidin-2-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 X₁ is methyl.

3. The compound according to claim 1 wherein R₁ and R₃ are each an optionally substituted aryl ring.

4. The compound according to claim 3 wherein R₁ and R₃ are each an optionally substituted phenyl ring.

5. The compound according to any claim 1 wherein the R₃ moiety is optionally substituted one or more times independently with C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10 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, wherein

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

wherein each of these moieties may be optionally substituted;

R₄ and R₁₄ are each independently selected from hydrogen, optionally substituted C_1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C_1-4 alkyl, or R₄ and R₁₄ together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR₉, and which ring is optionally substituted;

Z is oxygen or sulfur;

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; and

wherein each of these moieties, excluding hydrogen, may be optionally substituted;

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

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

R₁₀ and R₂₀ are each independently selected from hydrogen or C_1-4 alkyl.

6. The compound according to claim 5 wherein R₃ is an optionally substituted phenyl ring.

7. The compound according to claim 6 wherein R₃ is substituted one or more times, independently with halogen.

8. The compound according to claim 1 wherein R₃ is phenyl, cyclohexyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or 2,6-difluorophenyl.

9. The compound according to claim 1 wherein R₁ is an aryl optionally substituted one to four times, independently, halogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, cyano, nitro, (CR₁₀R₂₀)_vNR₄R₁₄, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄, (CR₁₀R₂₀)_vC(Z)OR₈, (CR₁₀R₂₀)_vCORa, (CR₁₀R₂₀)_vC(O)H, S(O)mR₅, (CR₁₀R₂₀)_vOR₈, ZC(Z)R₁₁, NR₁₀C(Z)R₁₁, or NR₁₀S(O)₂R₇, and wherein

Ra is C_1-4alkyl, halo-substituted C_1-4alkyl, C_2-4alkenyl, C_2-4 alkynyl, C_3-7cycloalkyl, C_5-7 cycloalkenyl, aryl, aryl C_1-4 alkyl, heteroaryl, heteroaryl C_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_vOR₇, (CR₁₀R₂₀)_vS(O)mR₇, (CR₁₀R₂₀)_vNHS(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄, and wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl moieties are optionally substituted;

R₅ is hydrogen, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl or NR₄R₁₄, excluding the moieties SR₅ (wherein m is

     0) being SNR₄R₁₄, S(O)₂R₅ being SO₂H (wherein m is

     2) and S(O)R₅ being SOH, (wherein m is

     1);

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

wherein each of these moieties may be optionally substituted;

R₈ is hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4alkenyl, 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 alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, and heteroaryl alkyl moieties, may be optionally substituted;

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

R₁₁ is C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4alkynyl, 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 alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaryl alkyl moieties may be optionally substituted;

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

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

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

11. The compound according to claim 10 wherein X₁ is methyl.

12. The compound according to claim 11 wherein R₃ is an optionally substituted phenyl ring.

13. The compound according to claim 4 wherein X₁ is methyl.

14. The compound according to claim 1 wherein R₁ is a phenyl ring substituted by halogen or alkyl.

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

16. The compound according to claim 1 which is:

(5-Aminomethyl-2-methylsulfanyl-6-phenyl-pyrimidin-4-yl)-phenylamine;

or

5-Aminomethyl-6-(4-fluoro-2-methylphenyl)-2-methylsulfanylpyrimidin-4-yl-(2,6-difluorophenyl)amine.