PI3K PROTEIN KINASE INHIBITORS, PARTICULARLY DELTA AND/OR GAMMA INHIBITORS

摘要

The present disclosure provides novel compounds useful as PI3K protein kinase modulators, in particular as PI3K delta (δ) and/or gamma (γ) protein kinase modulators. The present disclosure also provides methods for preparing PI3K protein kinase modulators, pharmaceutical compositions containing them, and methods of treatment, prevention and/or amelioration of PI3K kinase mediated diseases or disorders with them.

主权项

1. A compound of formula (I)or a tautomer thereof, N-oxide thereof, pharmaceutically acceptable ester thereof, prodrug thereof, or pharmaceutically acceptable salt thereof, wherein
each occurrence of R1 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or halogen; X is CH or N; each occurrence of R is independently H, substituted or unsubstituted alkyl or halogen; Ra and Rb are independently selected from H and substituted or unsubstituted alkyl; Rc is H, substituted or unsubstituted alkyl, —NH2 or halogen; each occurrence of n is independently selected from 0, 1, 2, 3 or 4 and Cy is selected from wherein R2 and R3 are independently selected from H, halogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, CN, —NH—SO2—R′, —NO2, —NH2, —NH—C(O)—R′, —C(O)—NH—R′, —SO2—R′ or —SO2NR′R′; R′ is selected from H, hydroxy, halogen, carboxyl, cyano, nitro, oxo(═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl; R4 is H or substituted or unsubstituted alkyl;with the proviso that the compound is not:
1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-phenyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-fluoro-2-(2-fluorophenyl) Benzamide, 3-[4-[[1,2-dihydro-8-methyl-2-(2-methylphenyl)-1-oxo-3-isoquinolinyl]methyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl] 3-[4-amino-1-[[1,2-dihydro-8-methyl-2-(2-methylphenyl)-1-oxo-3-isoquinolinyl]methyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N-methyl-Benzamide 1(2H)-Isoquinolinone, 3-[[4-amino-3-[4-(aminomethyl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-chlorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-ethylphenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-[2-(1-methylethyl)phenyl] 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-fluoro-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-fluoro-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-chloro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1 (2H)-Isoquinolinone, 3-[[4-amino-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-chloro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-chloro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-chloro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-chloro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-chloro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-chloro-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-2-(2-fluorophenyl)-8-methyl 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl) 1(2H)-Isoquinolinone, 3-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-8-methyl-2-(2-methylphenyl); and Benzenesulfonamide, 3-[4-amino-1-[[3,4-dihydro-5-methyl-3-(2-methylphenyl)-4-oxo-2-quinazolinyl]methyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl] Benzonitrile, 3-[4-amino-1-[[3,4-dihydro-5-methyl-3-(2-methylphenyl)-4-oxo-2-quinazolinyl]methyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl] 4(3H)-Quinazolinone, 2-[[4-amino-3-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl) 4(3H)-Quinazolinone, 2-[[4-amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl) 4(3H)-Quinazolinone, 2-[[4-amino-3-(4-chloro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl) 4(3H)-Quinazolinone, 2-[[4-amino-3-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl) 4(3H)-Quinazolinone, 2-[[4-amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl) 4(3H)-Quinazolinone, 2-[[4-amino-3-[4-(phenylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl) 4(3H)-Quinazolinone, 2-[[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl) 4(3H)-Quinazolinone, 2-[[4-amino-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl) 4(3H)-Quinazolinone, 2-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-3-(2-chlorophenyl)-5-methyl or 4(3H)-Quinazolinone, 2-[[4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-5-methyl-3-(2-methylphenyl).