1,5-DISUBSTITUTED-3,4-DIHYDRO-1H-PYRIMIDO[4,5-D]PYRIMIDIN-2-ONE COMPOUNDS AND THEIR USE IN TREATING CSBP/P38 KINASE MEDIATED DISEASES

• US 20070167467A1
• Filed: 12/20/2006
• Published: 07/19/2007
• Est. Priority Date: 03/02/2000
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GlaxoSmithKline PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Adams, Jerry, Boehm, Jeffrey, Hall, Ralph, Taggart, John
• Granted Patent: US 7,629,462 B2
• Time in Patent Office: Days
• US Class Current: 514/262.100
• 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

1-70. -70. (canceled)

71. A compound of the formula:

72. The process according to claim 71 wherein X₁ is methyl.

73. The process according to claim 71 wherein R₁ and R₃ are each an optionally substituted aryl ring.

74. The compound according to claim 73 wherein R₁ and R₃ are each an optionally substituted phenyl ring.

75. The compound according to any claim 71 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)_nNR₁₀OC(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.

76. The compound according to claim 75 wherein R₃ is an optionally substituted phenyl ring.

77. The compound according to claim 76 wherein R₃ is an unsubstituted or substituted one or more times, independently with halogen.

78. The compound according to claim 71 wherein R₃ is phenyl, cyclohexyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or 2,6-difluorophenyl.

79. The compound according to claim 71 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),CORa, (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_2-4 alkenyl, 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, (CR₁OR₂₀)_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.

80. The compound according to claim 79 wherein R₁ is an optionally substituted phenyl ring.

81. The compound according to claim 80 wherein X₁ is methyl.

82. The compound according to claim 81 wherein R₃ is an optionally substituted phenyl ring.

83. The compound which is

84. The compound according to claim 83 wherein X₁ is methyl.

85. The compound according to claim 84 wherein R₁ and R₃ are each an optionally substituted aryl.

86. The compound according to any claim 85 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)_n S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₄R₁₄, (CR₁₀R₂₀)_nNR₁₀C(Z)R₆, (CR_10R20)_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.

87. The compound according to claim 86 wherein R₃ is an optionally substituted phenyl ring.

88. The compound according to claim 87 wherein R₃ is an unsubstituted or substituted one or more times, independently with halogen.

89. The compound according to claim 83 wherein R₃ is phenyl, cyclohexyl, 2-chlorophenyl, 2,6-dimethylphenyl, 2-fluorophenyl, 2-methylphenyl, or 2,6-difluorophenyl.

90. The compound according to claim 83 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_2-4 alkenyl, 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.

91. The compound according to claim 90 wherein R₁ is an optionally substituted phenyl ring.

92. The compound according to claim 91 wherein X₁ is methyl, R₃ is an optionally substituted phenyl ring.

93. The process according to claim 87 wherein R₁ is an optionally substituted phenyl ring.