Patent RU-2652638-C2 (RU)
Inventor: KAZUSHELLI Franchesko
IPC: A61K31/519
Filed: 2011-12-16
Granted: 2018-04-28
Abstract: FIELD: biochemistry. 
     SUBSTANCE: present invention relates to novel pyrazolo [4,3-h]quinazoline compounds selected from the group indicated below and corresponding to general formula (I). Cell proliferative disorders is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis. Inflammatory and autoimmune diseases are selected from multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases (IBD), Crohn's disease, irritable bowel syndrome, pancreatitis, ulcerative colitis, diverticulosis, myasthenia gravis, vasculitis, psoriasis, scleroderma, asthma, allergy, systemic sclerosis, vitiligo, arthritis such as osteoarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis. Formula (I)  
     
       
     
     where radicals A, R1-R3, R5 correspond to the values, said compounds, which are selected from 1-(2-hydroxyethyl)-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-hydroxyethyl)-8-methoxy-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-tert-butyl-N-methyl-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-tert-butyl-N-[2-(dimethylamino)etliyl]-8-(metliylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-tert-butyl-N-(2-hydroxyethyl)-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-tert-butyl-N-(1-methylpiperidin-4-yl)-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-tert-butyl-N-[2-(1H-imidazol-5-yl)ethyl]-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-[2-(dimethylamino)ethyl]-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 6-amino-1-[2-(dimethylamino)ethyl]-8-(metliylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 2-[2-(dimethylamino)ethyl]-8-(methylsulfanyl)-2H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-aminoethyl)-8-(methylsulfanyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 2-(2-aminoethyl)-8-(methylsulfanyl)-2H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(methylsulfanyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(methylsulfanyl)-2-(piperidin-4-ylmethyl)-2H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-[4-(piperazin-1-yl)phenoxy]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-phenoxy-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(3-aminophenoxy)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(4-aminophenoxy)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-(pyridin-4-yloxy)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(2-fluoroethoxy)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-[4-(4-methylpiperazin-1-yl)phenoxy]-4,5H-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-[4-(4-methylpiperazin-1-yl)phenoxy]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-[4-(piperazin-1-yl)phenoxy]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[2-bromo-4-(4-methylpiperazin-1-yl)phenoxy]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[2-bromo-4-(4-methylpiperazin-1-yl)phenoxy]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-[3-(piperazin-1-yl)phenoxy]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-[3-(piperazin-1-yl)phenoxy]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[3-(dimethylamino)phenoxy]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(2-chlorophenoxy)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(2-fluorophenoxy)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[2-fluoro-4-(4-methylpiperazin-1-yl)phenoxy]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[2-fluoro-4-(4-methylpiperazin-1-yl)phenoxy]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[2-acetyl-4-(4-methylpiperazin-1-yl)phenoxy]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[2-acetyl-4-(piperazin-1-yl)phenoxy]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[2-cyano-4-(4-methylpiperazin-1-yl)phenoxy]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-hydroxyethyl)-8-phenoxy-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-hydroxyethyl)-8-[4-(4-methylpiperazin-1-yl)phenoxy]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-hydroxyethyl)-8-[3-(4-methylpiperazin-1-yl)phenoxy]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-hydroxyethyl)-8-(3-nitrophenoxy)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-(3-nitrophenoxy)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-[3-(4-methylpiperazin-1-yl)phenoxy]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-tert-butyl-8-[4-(4-methylpiperazin-1-yl)phenoxy]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-methoxy-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-ethoxy-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-methoxy-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(3-formylphenoxy)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-{3-[(4-methylpiperazin-1-yl)methyl]phenoxy}-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-[3-(hydroxymethyl)phenoxy]-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-{3-[(dimethylamino)methyl]phenoxy}-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-methyl-8-[3-(morpholin-4-ylmethyl)phenoxy]-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(3-aminophenoxy)-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(3-aminophenoxy)-1-(2-hydroxyethyl)-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-fluoroethyl)-8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-chloroethyl)-8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-hydroxyethyl)-8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(2-methoxyethyl)-8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-[3-(dimethylamino)propyl]-8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, 1-(1-amino-2-methyl-1-oxopropan-2-yl)-8-(methylsulfanyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, and other compounds specified in claim 1. 
     EFFECT: compounds have dysregulated protein kinase PIM-1, PIM-2, PIM-3 activity and can be used for treating diseases caused by and/or associated with said disorder, such as cancer, cell proliferative disorders and diseases and immune cell-associated diseases and disorders. 
     15 cl, 2 dwg, 53 ex, 2 tbl