NOVEL COMPOUNDS

• US 20080033170A1
• Filed: 08/16/2007
• Published: 02/07/2008
• Est. Priority Date: 10/23/2000
• Status: Abandoned Application

• Current Assignee: Smithkline Beecham Corporation (GSK plc)
• Original Assignee: Smithkline Beecham Corporation (GSK plc)
• Inventors: Taggart, John, Silva, Domingos, Adams, Jerry, Boehm, Jeffrey, Hall, Ralph, Jin, Qi, Kasparec, Jiri
• Application Number:
  US11/839,833
• Publication Number:
  US 20080033170A1
• Time in Patent Office: Days
• US Class Current: 544/58.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 239/47 : One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Novel substituted 2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.

Claims

24. The process according to claim 24 wherein the R₁ in Formula (VIa) is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

25. The process according to claim 24 wherein the R₁ phenyl in Formula (VIa) 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.

41-1. The process according to claim 1 wherein R₁ is 2-methyl-4-fluorophenyl.

43. A process of making a compound of the formula:

wherein

R₁ is an optionally substituted aryl or an optionally substituted heteroaryl ring;

R₂ is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, aryl, arylC_1-10 alkyl, heteroaryl, heteroarylC_1-10 alkyl, heterocyclic, or a heterocyclylC_1-10 alkyl moiety, which moieties are all optionally substituted, or R₂ is the moiety X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃);

A₁ is an optionally substituted C_1-10 alkyl;

A₂ is an optionally substituted C_1-10 alkyl;

A₃ is hydrogen or is an optionally substituted C_1-10 alkyl;

R₃ is an C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, aryl, arylC_1-10 alkyl, heteroaryl, heteroarylC_1-10 alkyl, heterocyclic, or a heterocyclylC_1-10 alkyl moiety, which moieties are optionally substituted;

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;

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 from hydrogen or C_1-4alkyl;

X is R₂, OR₂, S(O)_mR₂, (CH₂)_nN(R₁₀)S(O)_mR₂, (CH₂)_nN(R₁₀)C(O)R₂, (CH₂)_nN₄R₁₄, or (CH₂)_nN(R₂)₂;

X₁ is N(R₁₀), O, S(O)_m, or CR₁₀R₂₀;

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;

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

Z is oxygen or sulfur;

or a pharmaceutically acceptable salt thereof,

which process comprises reacting a compound of the formula;

wherein

R₁ is an aryl or heteroaryl ring, which ring is optionally substituted,

R₃ is an C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, aryl, arylC_1-10 alkyl, heteroaryl, heteroarylC_1-10 alkyl, heterocyclic, or a heterocyclylC_1-10 alkyl moiety, which moieties are optionally substituted; and

R₁₂ is a C_1-10 alkyl, aryl, heteroaryl, or arylalkyl;

m is 0 or an integer having a value of 1 or 2; and

Rg is a C_1-4 alkyl;

with heating in a suitable organic solvent, and optionally with a base.

2. The process according to claim 1 wherein the base is pyridine, diisopropyl ethylamine, or pyrrolidine.

4. The process according to claim 2 wherein the acetylating agent is acetic anhydride, acetyl chloride, or ketene.

44. The process according to claim 43 wherein the organic solvent is an organic hydrocarbon, cresol, dioxane, DMF, pyridine, or xylene.

45. The process according to claim 44 wherein the base is diisopropyl ethylamine, pyridine, DBU, lithium bis(trimethylsilyl)amide, or LDA.

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

47. The process according to claim 43 wherein in the compound of Formula (Va) m is 0.

51. The process according to claim 43 wherein in the compound of Formula (Ia):

R₁ is an optionally substituted aryl or an optionally substituted heteroaryl ring;

R₂ is the moiety X₁(CR₁₀R₂₀)_qC(A1)(A2)(A₃);

A₁ is an optionally substituted C_1-10 alkyl;

A₂ is an optionally substituted C_1-10 alkyl;

A₃ is hydrogen or is an optionally substituted C_1-10 alkyl; and

wherein A₁, A₂, and A₃,excluding hydrogen, are optionally substituted 1 to 4 times by (CR₁₀R₂₀)_nOR₆;

R₃ is an C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, aryl, arylC_1-10 alkyl, heteroaryl, heteroarylC_1-10 alkyl, heterocyclic, or a heterocyclylC_1-10 alkyl moiety, which moieties are optionally substituted;

R₆ is hydrogen, or C_1-10 alkyl;

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

X is R₂;

XI is N(R₁₀), O, S(O)_m, or CR₁₀R₂₀;

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; and

q is 0 or an integer having a value of 1 to 10.

52. The process according to claim 43 wherein X is (CH₂)_nNR₄R₁₄, or (CH₂)_nN(R₂)₂.

53. The compound according to claim 51 wherein R₃ is an optionally substituted C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylalkyl, or aryl.

54. The compound according to claim 53 wherein R₃ is optionally substituted one or more times independently with C_1-10 alkyl, halo-substituted C_1-10 alkyl, C_2-10 alkenyl, C_2-10alkynyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7cycloalkenyl, C_5-7cycloalkenylC_1-10 alkyl, halogen, cyano, nitro, (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 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;

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;

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

Z is oxygen or sulfur.

55. The process according to claim 54 wherein the R₃ optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

56. The process according to claim 55 wherein R₃ is an optionally substituted aryl.

58. The process according to claim 51 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.

59. The process according to claim 58 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.

62. The process according to claim 51 wherein R₃ in Formula (Va) is a 2,6-difluorophenyl.

63. The process according to claim 51 wherein the R₁ in Formula (Va) is an optionally substituted aryl.

64. The process according to claim 63 wherein the R₁ in Formula (Va) is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

65. The process according to claim 64 wherein the R₁ phenyl in Formula (Va) 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.

66. The process according to claim 51 wherein R₂ is the moiety X₁ (CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃).

67. The process according to claim 66 wherein X₁ is oxygen or N(R₁₀).

68. The process according to claim 67 wherein at least one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)_nOR₆.

69. The process according to claim 68 wherein q is 0, n is 0, and R₆ is hydrogen.

70. The process according to claim 51 wherein q is 0.

71. The process according to claim 70 wherein X₁ is N(R₁₀), and R₁₀ is hydrogen, and A₁ and A₂ are independently CH₂OH.

72. The process according to claim 71 wherein A₃ is hydrogen.

73. The process according to claim 69 wherein X₁ is N(R₁₀), and R₁₀ is hydrogen.

74. The process according to claim 51 wherein the aryl ring of 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;

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;

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;

Z is oxygen or sulfur;

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_1-4 alkyl, heterocyclyl, heterocyclylC_1-4 alkyl, (CR₁₀R₂₀)_vOR₇, (CR₁₀R₂₀)_vS(O)_mR₇, (CR₁₀R₂₀)_vNHS(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄, wherein the aryl, arylalkyl, heteroaryl, and heteroaryl alkyl may be optionally substituted.

75. The process according to claim 43 wherein R₁ is an optionally substituted phenyl.

76. The process according to claim 51 wherein R₁ is an optionally substituted phenyl.

77. The process according to claim 75 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

78. The process according to claim 76 wherein the aryl is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl.

79. The process according to claim 78 wherein the R₁ 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.

80. The process according to claim 79 wherein R₁ is 2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl.

81. The process according to claim 80 wherein R₁ is 2-methyl-4-fluorophenyl.

82. The process according to claim 43 wherein R₁ is 2-methyl-4-fluorophenyl.

83. The process according to claim 43 wherein the compound of Formula (I) is 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.

45-2. The process according to claim 43 wherein the base is diisopropyl ethylamine, pyridine, DBU, lithium bis(trimethylsilyl)amide, or LDA.