Small-Molecule Inhibitors of Ikb Kinase and Ikb Kinase-Related Kinases

Small-molecule inhibitors of IkB kinase and IkB kinase-related kinases

Sabin Llona-Minguez,*1 Jessica Baiget,2 Simon P Mackay2

1 Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, S-171 21, Sweden

2 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 165 Cathedral Street, Glasgow, G4 0RE, UK

Supporting information

Table 1. Patented chemical matter (or relevant pubchem) on small-molecule inhibitors of IKK and IKK-related kinases from 2000 to 2012 (IKKβ selective or IKKβ- IKKα non-selective inhibition is assumed unless otherwise stated).

Applicant / Chemotype / Reference
Asahi Kasei / Isoquinoline / WO2010038465
Astellas / Thieno-pyridine carboxamide / WO2005123745
Hydroxyaryl-pyrimidine / WO2005100341
Astra Zeneca / Thiophene carboxamide / WO2001058890
WO2003010158
WO2003010163
WO2004063185
WO2004063186
WO2005016909
7-Azabenzimidazole / Bioorg. Med. Chem. Lett., 2012, 22 (5), 2063-2069 (IKKε- TBK1)
Bayer / Hydroxyaryl-pyridine / WO2002024679
WO200244153
(-)-7-[2-(Cyclopropylmethoxy)-6-hydroxyphenyl]-5-[(3S)-3-piperidinyl]-1,4-dihydro-2H-pyrido [2,3-d][1,3]oxazin-2-one / WO2003076447
Boehringer Ingelheim / Thieno-pyridine carboxamide / WO2003103661
WO2005056562
US20070293533
Benzothiophene carboxamide / WO2005012283
Pyrido-thieno-pyrimidine / WO2005035537
Pyrazolyl-pyrazinamine / WO2009089042
Bristol-Myers Squibb / Imidazoquinoxaline, benzopyrazoloquinazoline, benzoimidazoquinoxaline and benzoimidazoquinoline / WO2002028860
WO2002060386
Triazolo-purine / WO2005011609
Pyrazolo-purine / WO2004075846
Imidazo-thieno-pyrazine / WO2003084959
Imidazo-oxazolo[4,5-b]pyridine and imidazo-thiazolo[4,5-b]pyridine / WO2004106293
US20060106051
Imidazo-thiazolo-pyridine / WO2006053166
Imidazo-thieno-pyridine / US20060178393
Dihydroimidazo-pyrrolopyridine / WO2006122137
Celltech / Anilino-pyrimidine / Bioorg. Med. Chem. Lett., 2004, 14 (2), 409.
Chroma Therapeutics / Thiophene carboxamide / WO2008053182
WO2008053185
WO2009130434
WO2009130475
WO2010122294
Daiichi Sankyo / Imidazo-pyridazine / WO2008072682
Domainex / 2-Aminopyrimidine benzonitrile / WO2012010826 (IKKε - TBK1)
Elli Lilly / Pyrimidinyl benzothiophene / WO2007092095
Gencross / (RS)-2-(Cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one / US20060173011
Genomics Institute of the Novartis Research Foundation / Pyrrolo-pyrimidine / WO2005107760 (TBK1)
GlaxoSmithKline / Thiophene carboxamide / WO200230353
WO2003028731
WO2003029241
WO2003029242
WO2003104218
WO2004053087
Imidazole carboxamide / WO200230423
Indole carboxamide / WO2005067923
Benzimidazole / WO2005075465 (IKKε)
Benzothiophene carboxamide / WO2003104219
4H-indeno[1,2-b]thiophene carboxamide / WO2003086309
Indole carboxamide / WO2006034317
WO2007076286
WO2007062318
WO2007005534
WO2008118724
5-(2-Isopropylisoindolin-5-yl)-3-(1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)-1H-indole-7-carboxamide / WO2010102968
Indazole carboxamide / WO2006002434
WO2007102883
Amino- and hydroxy-benzamide / WO2007025575
7-Azaindole -benzenesulfonamide / WO2008034860
WO2009112473
WO2009112475
7-Azaindole / WO2008110508 (IKKα)
5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-indazol-3-amine
5-(1H-Pyrazolo[3,4-b]pyridin-4-yl)-1H-indazol-3-amine / WO2008132121 (IKKα)
Isoquinoline / J. Med. Chem., 2009, 52 (9), 3098–3102
Hoffman-La Roche / Imidazo-quinoline semicarbazone
(with Tularik) / WO2002041843
Imididazo-pyrimidine pyrimidinecarboxaldehyde thiosemicarbazone / WO2003040131
Imidazo-quinoline and quinazoline
(with Tularik) / WO2003048152
Thieno-pyridazine carboxamide / WO2005105808
Thieno-pyridine carboxamide / WO2005105809
Hutchison MediPharma / 2-(5-Chloro-2-(((1S,2R)-2-hydroxycyclopentyl)amino)pyrimidin-4-yl)-N-cyclopropyl-1H-indole-4-carboxamide
2-(5-Chloro-2-(((1S,2S)-2-hydroxycyclopentyl)amino)pyrimidin-4-yl)-N-cyclopropyl-1H-indole-4-carboxamide / WO2011134140
Institute of Medical Molecular Design / N-phenyl benzamide / WO2003103654
Je Il / Thieno-pyrimidine / WO2007102679
Kyorin / Thieno-pyrimidine carboxamide / WO2008020622
Dihydrothieno[2,3-e]indazole carboxamide / WO2011077502
Korea Institute of Science and Technology / Aminopyrimidine / KR2012021370
Thiazolidinone / KR2012035684
Leo / 4-Pyridyl-cyanoguanidine / WO2002094265
WO2006066584
Medical Research Council / 2,4-Diamino-pyrimidine / WO2009122180 (IKKε -TBK1)
Pyrrolo-pyrimidine / WO2010100431 (IKKε - TBK1)
Merck / γ-Carboline / WO2007061764
7-Azaindole / WO2012104007 (IKKε - TBK1)
Triazolo-pyrrolo-pyrimidine / WO2012095142 (IKKε - TBK1)
2-Aminopyridine and 2-aminopyrazine / WO2012161877 (IKKε - TBK1)
Thiazole carboxamide / WO2012161879 (IKKε - TBK1)
Millenium (Takeda) / β-Carboline / WO2003039545
WO2004092167
WO2007097981
(S)-N-(6-chloro-9H-pyrido[3,4-b]indol-8-yl)-4-(2-((2S,6R)-2,6-dimethylmorpholino)-2-oxoethyl)-6,6-dimethylmorpholine-3-carboxamide / WO2009054970
Myrexis / 2-Aminopyrimidine benzonitrile / WO2011046970 (IKKε - TBK1)
WO2012142329 (IKKε - TBK1)
Novartis / Anilinopyrimidine / WO2004089913
Pharmacia (Pfizer) / Thiophene carboxamide / WO2003037886
WO2005105777
Dihydronaphtho[2,1-b]thiophene carboxamide / WO2004009582
Pyrazole carboxamide / WO2005037797
Fused pyrazole carboxamide / WO2003024935
WO2003024936
WO2003027075
WO2003035625
WO2003070706
WO2003095430
Hydroxyaryl-pyrazinone / WO2005035527
Hydroxyaryl-pyrimidine / WO2005040133
Ribapharm / Thieno-pyridine carboxamide / WO2005058315
Sanofi-Aventis / Anilino-pyrimidine / WO2007006926
WO2008099072
WO2008099073
WO2008099074
WO2008099075
WO2009056693
β-Carboline / WO200168648
Pyridyl-benzimidazole / WO200100610
WO200130774
Pyrimidyl-benzimidazole / WO2004022057
WO2004022553
WO2005113544
(S)-2-(2-(2-(methylamino)pyrimidin-4-yl)-1H-indole-5-carboxamido)-3-(phenyl(pyridin-2-yl)amino)propanoic acid / WO2006076318
Santen / Indole carboxamide / WO2008087933
WO2010007972
Signal (Celgene) / Anilinopyrimidine / WO2002046171
Pyrazolyl-pyrazinamine / WO2009089042
Takeda / 6-Azaindole / WO2005097129
Thieno-pyridine carboxamide / JP2005194198
Benzothieno[3,2-b]furan carboxamide / WO2006036031
Tularik / Thieno-pyridine carboxamide and thieno-pyrazole carboxamide / US20040097485
University of Michigan / 2-Amino-7-isopropyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid / US20120208836 (IKKε - TBK1)
University of Nagoya City / Adenine / JP2007099702 (IKKα)
University of Nebraska / Quinoxaline / WO2012071414
University of Hong Kong Baptist / (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one / US20120053235
Wyeth (Pfizer) / Anilino-pyrimidine / US20060079543
US20070244140
US20080275073