897373-62-5

Scaffold hopping is a common strategy for generating kinase inhibitors that bind to the DFG-out inactive conformation. Small structural differences in inhibitor scaffolds can have significant effects on potency and selectivity across the kinome, however, these effects are often not studied in detail. Herein, we outline a design strategy to generate an array of DFG-out conformation inhibitors with three different hinge-binders and two DFG-pocket groups. We studied inhibitor selectivity across a large segment of the kinome and elucidated binding preferences that can be used in scaffold hopping campaigns. Using these analyses, we identified two selective inhibitors that display low nanomolar potency against Axl or wild-type and clinically relevant mutants of Abl.

The current invention provides urea derivatives, in particular compounds having the core structure heteroaryl-NH-CO-NH-aryl-O- heteroaryl, for use in treating, ameliorating, delaying, curing and/ or preventing a disease or condition associated with muscle cells and/or satellite cells, such as Duchenne muscular dystrophy, Becker muscular dystrophy, cachexia or sarcopenia.

Described herein are methods of treating various disorders in patients in need thereof, comprising administering to the patient the compound of Formula (I) or a pharmaceutically acceptable salt thereof. Exemplary disorders that can be treated by the methods described herein include gynecologic carcinosarcomas, endometrial adenocarcinomas, mesotheliomas, ovarian cancers, pancreatic ductal adenocarcinomas, and lung cancers.

The receptor tyrosine kinase inhibitor, Tie2, has significant roles in endothelial signaling and angiogenesis and is relevant in the pathophysiology of several diseases. However, there are relatively few small molecule probes available to study Tie2, maki

Compounds of the present invention find utility in the treatment of hyperproliferative diseases, mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary tumor sites secondary sites, myeloproliferative diseases, chronic myelogenous leukemia, acute lymphocytic leukemia, papillary thyroid carcinoma, non small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, thyroid cancer, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, i.e. diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, human inflammation, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic obstructive pulmonary disease, bone resorptive diseases, graft-versus-host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof, a disease caused by c-ABL kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, c-KIT kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, VEGFR kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, PDGFR kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, FLT-3 kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, TIE-2 kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, TRK kinases, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, c-MET kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by a HER kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of Raf kinases and disease polymorphs thereof. Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.

The present invention is concerned with novel compounds useful in the treatment of hyperproliferative diseases and mammalian cancers, especially human cancers. The invention also pertains to methods of modulating kinase activities, pharmaceutical compositions, and methods of treating individuals, incorporating or using the compounds. The preferred compounds are active small molecules set forth in formulae Ia-Iww.

Novel compounds and methods of using those compounds for the treatment of inflammatory conditions, hyperproliferative diseases, cancer, and diseases characterized by hypervascularization are provided. In a preferred embodiment, modulation of the activation state of p38 kinase protein ab1 kinase protein, bcr-ab1 kinase protein, braf kinase protein, VEGFR kinase protein, or PDGFR kinase protein comprises the step of contacting said kinase protein with the novel compounds.