Method of treating diseases associated with altered kinase activity with bicyclo-pyrazoles

Bicyclo-pyrazole compds. of formula [I; R = an optionally further substituted group selected from the group consisting of COR', CO2R', CONHR', CONR'R'', NHC(:NH)NHR', C(:NH)NHR', SO2R', SO2NHR', and SO2NR'R''; R1 = H or an optionally further substituted group selected from the group consisting of R', COR', CO2R', CONHR', CONR'R'', NHC(:NH)NHR', C(:NH)NHR', SO2R', SO2NHR', and SO2NR'R''; R', R'' = independently H, straight or branched C1-6 alkyl, aryl, C3-6 cycloalkyl, or aryl-C1-6 alkyl or R' and R'' taken together form a C4-6 alkylene chain; Ra, Rb, Rc, Rd = independently H, optionally further substituted straight or branched C1-6 alkyl, aryl, aryl-C1-6 alkyl or CH2OR' (wherein R' is as above defined), or Ra and Rb and/or Rc and Rd, taken together with the carbon atom to which they are bonded, form an optionally substituted C3-6 cycloalkyl; m and n, each independently, represents 0 or an integer from 1 to 2, provided that m + n≤2] or pharmaceutically acceptable salts thereof were prepd. by the solid phase synthesis. These compds. are useful for treating diseases caused by and/or assocd. with disregulated protein kinases, i.e. altered protein kinase activity (no data). Said disease caused by and/or assocd. with an altered protein kinase activity is selected from the group consisting of cancer and cell proliferative disorders wherein the cancer is selected from the group consisting of leukemia, ovary cancer, colon cancer, breast cancer, lung cancer, and pancrea cancer. Thus, a soln. of 3-amino-5-(tert-butoxycarbonyl)-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole (10.7 mmol, 2.4 g) in 20 mL anhyd. CH2Cl2 was added under nitrogen atm. to Me isocyanate polystyrene resin (200-400 mesh, 2% DVB, loading 1.49 mmol/g, 10 g) previously swelled in 200 mL anhyd. CH2CH2 and gently stirred at 22° for 18 h, followed by filtration, washing with CH2Cl2, and vacuum drying, to give N-[3-amino-5-(carbo-tert-butoxy)-4,6-dihydropyrrolo[3,4-c]pyrazol-1-yl]-N'-methylpolystyrene urea (II). II (3.01 mmol, 3.5 g) previously swelled in 90 mL anhyd. CH2Cl2 and 16.5 mL DIEA (96.32 mmol) was treated dropwise with a soln. of phenylacetyl chloride (24.08 mmol, 3.18 mL) in 10 mL anhyd. CH2Cl2 and gently stirred at 22° for 18 h, followed by filtration, washing with CH2Cl2 and MeOH, and vacuum drying, to give N-[3-(2-phenylacetamido)-5-(tert-butoxycarbonyl)-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-1-yl]-N'-methylpolystyrene urea (III). III (3.01 mmol) was treated with a soln. of 50% CF3CO2H in anhyd. CH2Cl2 and gently stirred at 22° for 2 h, followed by filtration, washing with 10% CF3CO2H in anhyd. CH2Cl2, CH2Cl2, and MeOH, and vacuum drying, to give N-(3-(2-phenylacetamido)-4,6-dihydropyrrolo[3,4-c]pyrazol-1-yl)-N'-methylpolystyrene urea (IV). Phenylacetic acid (0.43 mmol, 58.5 mg), NMM (0.43 mmol), and PyBop (0.43 mmol, 223.8 mg) were added to IV (0.086 mmol, 100 mg) previously swelled in 4 mL anhyd. DMF and the resulting suspension was gently stirred at 22° for 24 h to give, after filtration, washing with DMF, CH2Cl2, MeOH, and vacuum drying, N-(3-(2-phenylacetamido)-5-phenylacetyl-4,6-dihydropyrrolo[3,4-c]pyrazol-1-yl)-N'-methylpolystyrene urea (V). Aq. 35% NaOH (1.72 mmol, 143 μL) was added to V (0.086 mmol) previously swelled in 4 mL MeOH and the resulting suspension was gently stirred at 40° for 72 h. The resin was then filtered and the filtrate neutralized with 25% HCl and evapd. to dryness. The residue was partitioned between 4 mL CHCl3 and satd. NaHCO3 (200 μL). The org. layer was dried over Na2SO4 and evapd. to give 65% N-(5-phenylacetyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl)phenylacetamide (VI) as a yellow solid (21.0 mg).