Compounds useful as Raf kinase inhibitors
Inventors
Chen, Weirong • Cossrow, Jennifer • Franklin, Lloyd • Guan, Bing • Jones, John Howard • Kumaravel, Gnanasambandam • Lane, Benjamin • Littke, Adam • Lugovskoy, Alexey • Peng, Hairuo • Powell, Noel • Raimundo, Brian C. • Tanaka, Hiroko • Vessels, Jeffrey • Wynn, Thomas • Xin, Zhili
Assignees
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Publication Number
US-8293752-B2
Publication Date
2012-10-23
Expiration Date
Abstract
The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
Core Innovation
The invention relates to compounds of formula I, or pharmaceutically acceptable salts thereof, defined by optionally substituted heteroaromatic rings Cy1 and Cy2, an optionally substituted straight or branched C1-6 alkylene chain L1, and a linker L2 defined as —C(O)N(R)—. Cy1 is an optionally substituted 5-membered aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and Cy2 is an optionally substituted 6-membered aromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In formula I, each R is independently hydrogen or an optionally substituted C1-6 aliphatic group, R1 is hydrogen or an optionally substituted C1-6 aliphatic group, and each of Rx and Ry is independently selected from -halo or —N(R2)2, where each R2 is independently hydrogen or an optionally substituted C1-6 aliphatic group. The disclosed examples describe multiple specific chemical structures and exemplified compounds that share this formula I scaffold, including heteroaromatic cores, substituted anilide or aryl portions, and varying heteroaryl, amine, halo, fluorinated, chloro, CF3, hydroxyl, and cyclic amine substituents.
Claims Coverage
The claim coverage centers on one independent claim, clm-00001, defining a compound of formula I (or a pharmaceutically acceptable salt). The inventive scope is built from the Cy1/Cy2 heteroaromatic ring framework, the C1-6 alkylene linker L1, the —C(O)N(R)— group L2, and the permitted substituent options for R, R1, Rx, Ry, and R2.
Formula I compound scaffold with heteroaromatic rings
A compound of formula I (or a pharmaceutically acceptable salt thereof) wherein Cy1 is an optionally substituted 5-membered aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and Cy2 is an optionally substituted 6-membered aromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
Defined C1-6 alkylene linker and amide-like L2 group
The compound of formula I includes L1 as an optionally substituted, straight or branched C1-6 alkylene chain, and L2 as —C(O)N(R)—, where each R is independently hydrogen or an optionally substituted C1-6 aliphatic group.
Substituent options for R1, Rx, Ry, and R2
R1 is hydrogen or an optionally substituted C1-6 aliphatic group; each of Rx and Ry is independently selected from -halo or —N(R2)2; and each R2 is independently hydrogen or an optionally substituted C1-6 aliphatic group.
Selected heteroaryl options for Cy1
Cy1 is selected from an enumerated set of optionally substituted heteroaryl-ring groups, including pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, and oxadiazolyl.
Pharmaceutical composition with acceptable carrier
A pharmaceutical composition that includes a compound of claim 1 together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Combination with selected therapeutic agents
A composition combined with therapeutic agents selected from chemotherapeutic/anti-proliferative, anti-inflammatory, immunomodulatory, neurotrophic, cardiovascular, destructive bone disorder, liver disease, antiviral, blood disorder, diabetes, and immunodeficiency disorder agents.
Overall, the claims define a formula I compound scaffold with optional heteroaromatic ring substitution, a defined alkylene linker, and a C(O)N(R) linkage, while constraining the remaining positions through listed hydrogen, aliphatic, halo, and —N(R2)2 options. Dependent scope extends to specific Cy1 selections, pharmaceutical compositions, and combinations with the listed therapeutic-agent categories.
Stated Advantages
Raf-directed protein kinase inhibition in cells, including cell IC50 values reported down to about 100 nM.
Treatment of Raf-mediated disease or condition by administering an effective amount of the compounds.
Pharmaceutical compositions are described with pharmaceutically acceptable carriers and multiple routes of administration, including oral, parenteral, rectal/vaginal suppositories, and topical/transdermal.
Support for combination therapy with other anticancer agents.
Support for implantable medical device coating with kinase inhibitor compositions, including stents, microencapsule matrices, liposomes, and microemulsions.
Documented Applications
Assaying Raf inhibition in vitro, in vivo, and in biological samples, including cell line assays.
Treatment of Raf-mediated disease or condition by administering an effective amount of the compounds or pharmaceutical compositions.
Use in combination therapy with anticancer agents or other therapeutic agents listed in combination therapy categories.
Coating implantable medical devices, including stents, with kinase inhibitor compositions, including microencapsule matrices, liposomes, and microemulsions.
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