N-[4-(1H-Pyrazolo[3,4-B]pyrazin-6yl)-phenyl]-sulonamides and Their Use As Pharmaceuticals

摘要

The kinase superfamily remains an active area of interest to the pharmaceutical industry, as these enzymes are key players in a wide range of cellular functions. They regulate numerous cell functions, including, but not limited to, signal transduction, transcriptional regulation, cell motility, cell division, and apoptosis. The serumand glucocorticoid regulated kinases (SGKs) are a family of serine/threonine kinases that consists of three members, SGK-1, SGK-2, and SGK-3. SGK-1 has been implicated in the progression of osteoarthritis, one of the most common forms of degenerative joint disease. The pathological course of this disease includes destruction of articular cartilage, leaving the underlying bone tissue exposed. In advanced cases, joint replacement surgery may be required. Pathological changes in the associated ligaments and synovial membranes are also hallmarks of this condition. Recent studies have also demonstrated that changes in SGK-1 expression levels are associated with osteoarthritis. Specifically, comparative gene expression studies have established that this enzyme is expressed in degenerated/degenerating cartilage but not in healthy cartilage. Additional studies inmouse embryos have demonstrated that the presence of SGK-1 is directly associated with hypertrophy and degradation of cartilage tissue, suggesting that it causes or promotes the pathological progression of osteoarthritis. As such, inhibitors of SGK-1 may be useful for the treatment and prevention of osteoarthritis. The present patent application describes a series of phenylpyrazolopyrazine capable of inhibiting SGK-1 and their method of use for the treatment of degenerative joint disorders, degenerative cartilage changes, diabetes, cardiovascular diseases, fibrosis, inflammatory processes, pain, tumors, and cerebral infarctions.