INDAZOLINONE COMPOSITIONS USEFUL AS KINASE INHIBITORS

• US 20090048250A1
• Filed: 08/20/2007
• Published: 02/19/2009
• Est. Priority Date: 10/25/2002
• Status: Active Grant

• Current Assignee: Alex Aronov, David J. Lauffer, Huan Qiu Li, Pan Li, Ronald Charles Tomlinson
• Original Assignee: Alex Aronov, David J. Lauffer, Huan Qiu Li, Pan Li, Ronald Charles Tomlinson
• Inventors: Li, Pan, Lauffer, David J., Aronov, Alex, Li, Huan Qiu, Tomlinson, Ronald Charles
• Granted Patent: US 7,842,712 B2
• Time in Patent Office: Days
• US Class Current: 514/234.500
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides compounds of formula I:

These compounds, and pharmaceutically acceptable compositions thereof, are useful generally as kinase inhibitors, particularly as inhibitors of PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, and Aurora-2. Accordingly, compounds and compositions of the invention are useful for treating or lessening the severity of a variety of disorders, including, but not limited to, heart disease, diabetes, Alzheimer'"'"'s disease, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases.

Claims

1. A compound of formula I:

64. The compound of claim 1, wherein either of R³ or R⁴ is -Q¹-A-Q²-Y, wherein A is an optionally substituted C_2-4alkylidene unit (represented by A¹-A²-A³-A⁴) and compounds have the general formula IVa or IVb:

65. The compound of claim 64, wherein one of A¹, A², A³ or A⁴ is absent, and the remaining three are each independently selected from an optionally substituted methylene unit, wherein each methylene unit is optionally replaced by —

O—

or —

CO—

, wherein the one or more of the methylene units is unsubstituted or is substituted with an aryl, aralkyl or C_1-6aliphatic group, or wherein two substituents on the same methylene unit, or two substituents on two adjacent methylene units taken together form a 3-6-membered carbocyclic or heterocyclic ring.

66. The compound of claim 64, wherein Y is an optionally substituted heteroaryl moiety.

67. The compound of claim 64, wherein Y is selected from one of the following heteroaryl moieties a-y:

68. The compound of claim 67, wherein Y is one of the following heteroaryl moieties:

69. The compound of claim 67, wherein Y is a pyrazole moiety, h.

70. The compound of claim 67, wherein each R¹⁰ is independently hydrogen, C_1-4aliphatic, alkoxycarbonyl, optionally substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, or (N-heterocycle)carbonyl.

71. The compound of claim 67, wherein each occurrence of R¹⁰ is independently methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═

CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇), CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, or CO(piperidin-1-yl).

72. The compound of claim 67, wherein, Y is a pyrazole moiety, h′

, wherein the pyrazole is substituted with R^10a and R^10b

73. The compound of claim 72, wherein R^10a and R^10b taken together may represent a substituted or unsubstituted cycloaliphatic, cycloheteroaliphatic, aryl or heteroaryl moiety and comprises one of the following groups:

74. The compound of claim 64, wherein when R³ is -Q¹-A-Q²-Y, R⁴ is hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl.

75. The compound of claim 74, wherein R⁴ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂.

76. The compound of claim 64, wherein when R⁴ is -Q¹-A-Q²-Y, R³ is preferably hydrogen, C_1-3aliphatic, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, mono- or di-alkylamino, mono- or di-alkylaminoalkyl, or optionally substituted phenyl.

77. The compound of claim 76, wherein R³ is hydrogen, methyl, ethyl, cyclopropyl, hydroxy, phenyl or —

CH₂NH₂.

78. The compound of claim 64, wherein R⁵ is hydrogen, halogen, —

NO₂, —

CN, hydroxy, optionally substituted C_1-3alkyl, optionally substituted alkoxy, —

SO₂NH₂, or —

C(O)alkyl.

79. The compound of claim 78 wherein R⁵ is C₁, CF₃, OCF₃, CH₃, —

CN, —

SO₂NH₂ or —

C(O)Me.

85. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

86. The composition according to claim 85, further comprising an additional therapeutic agent.

87. A method of inhibiting a PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, or Aurora-2 family kinase activity in a biological sample comprising the step of contacting said biological sample with:

a) a composition according to claim 85;

or

b) a compound of claim 1

or a pharmaceutically acceptable derivative thereof.

88. A method of treating or lessening the severity of a PRAK, GSK3, ERK2, CDK2, MK2, SRC, SYK, or Aurora-2-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to claim 85.

89. A method of treating or lessening the severity of a disease or condition selected from cardiovascular diseases, diabetes, neurological disorders, immunodeficiency disorders, inflammatory diseases, allergic diseases, autoimmune diseases, destructive bone disorders such as osteoporosis, proliferative disorders, infectious diseases and viral diseases comprising the step of administering to said patient a composition according to claim 85.

90. The method according to claim 89, comprising the additional step of administering to said patient an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an anti-infective agent, an antiviral agent, or an agent for treating cardiovascular disease, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

2-63. -63. (canceled)

80-83. -83. (canceled)