US2018118754A1PendingUtilityA1
Compounds
Est. expiryOct 19, 2029(~3.3 yrs left)· nominal 20-yr term from priority
Inventors:John King-UnderwoodKazuhiro ItoPeter John MurrayGeorge HardyFrederick Arthur BrookfieldChristopher John Brown
A61P 35/00A61P 37/08A61P 35/04A61P 27/02A61P 29/00A61P 11/06A61P 17/00A61P 1/18A61P 11/00A61P 11/02A61P 17/06A61P 19/00A61P 1/04A61P 1/00A61P 19/02A61K 31/4965A61K 31/517C07D 239/88A61K 31/519C07D 487/04C07D 403/06
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Claims
Abstract
The present invention relates to compounds of formula (I) and to compositions comprising the same and to the use of the compounds and their compositions in treatment, for example in the treatment of inflammatory diseases, in particular respiratory inflammatory disease. The invention also extends to methods of making said compounds.
Claims
exact text as granted — not AI-modified1 - 22 . (canceled)
23 . A combination therapeutic agent comprising a compound of formula (I) and an additional active ingredient, wherein the compound of formula (I) is:
wherein
R 1 is H, a saturated or unsaturated, branched or unbranched C 1-15 alkyl chain, wherein optionally one or more carbons is/are replaced by a heteroatom selected from O, N, S(O) p , wherein said chain is optionally substituted by one or more groups independently selected from oxo, halogen, an aryl group, a heteroaryl group, a carbocyclyl group or a heterocyclyl group,
each aryl, heteroaryl, carbocyclyl or heterocyclyl group bearing:
0 to 3 substituents selected from halogen, -hydroxyl, —C 1-6 alkyl, —C 1-6 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 2-3 alkylOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 1-6 haloalkyl, amino, —C 1-4 mono or —C 2-8 di-alkyl amino, —C 1-4 mono or —C 2-8 di-acyl amino, —C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OC 0-6 alkyl, —NR 8 C 0-6 alkylC(O)NR 6 R 7 , —NR 8 C 0-6 alkylC(O)C 0-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 , and —C 0-6 alkylC(O)C 1-6 alkyl; and/or one aryl, heterocyclyl or carbocyclyl;
X is C 6-10 aryl or a C 5-9 heteroaryl each substituted by R 2a and by R 2b wherein R 2a is selected from hydrogen, —C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 2-3 alkylOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 0-6 alkylS(O) q C 1-3 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OH, —C 0-6 alkylC(O)OC 1-6 alkyl, —NR 8 C 0-6 alkylC(O)NR 6 R 7 , —NR 8 C 0-6 alkylC(O)C 1-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 and —C 0-6 alkylC(O)C 1-6 alkyl; and
R 2b is selected from hydrogen, C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, and —C 0-6 alkylS(O) q C 1-3 alkyl;
R 3a is hydroxyl;
R 3b is selected from hydrogen, hydroxyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 hydroxyalkyl, —C 1-3 alkoxy, and —S(O) q C 1-3 alkyl;
R 4 is hydrogen or —C 1-3 alkyl;
R 5 is hydrogen or —C 1-3 alkyl;
R 6 is hydrogen or —C 1-6 alkyl;
R 7 is hydrogen or —C 1-6 alkyl;
R 8 is hydrogen or —C 1-6 alkyl;
p is 0 or an integer 1 or 2;
q is 0 or an integer 1 or 2
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
24 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I):
R 1 is H, a saturated or unsaturated, branched or unbranched C 1-10 alkyl chain, wherein optionally one or more carbons is/are replaced by a heteroatom selected from O, N, S(O) p , wherein said chain is optionally substituted by one or more groups independently selected from oxo, halogen, an aryl group, a heteroaryl group, a carbocyclyl group or a heterocyclyl group,
each aryl, heteroaryl, carbocyclyl or heterocyclyl group bearing:
0 to 3 substituents selected from halogen, —C 1-6 alkyl, —C 1-6 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 1-6 haloalkyl, amino, —C 1-4 mono or —C 2-8 di-alkyl amino,
—C 1-4 mono or —C 2-8 di-acyl amino, —C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OC 0-6 alkyl, —NC 0-6 alkylC(O)NR 6 R 7 —NC 0-6 alkylC(O)C 0-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 , and —C 0-6 alkylC(O)C 1-6 alkyl; and/or one aryl, heterocyclyl or carbocyclyl;
X is C 6-10 aryl or a C 5-9 heteroaryl each substituted by R 2a and optionally by R 2b wherein R 2a is selected from hydrogen, —C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 0-6 alkylS(O) q C 1-3 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OH, —C 0-6 alkylC(O)OC 1-6 alkyl, —NC 0-6 alkylC(O)NR 6 R 7 ,
—NR 8 C 0-6 alkylC(O)C 1-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 and —C 0-6 alkylC(O)C 1-6 alkyl; and
R 2b is selected from hydrogen, C 1-3 alkyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy and —C 0-6 alkylS(O) q C 1-3 alkyl;
R 3a is hydroxyl;
R 3b is hydrogen, hydroxyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 hydroxyalkyl, —C 1-3 alkoxy, —S(O) q C 1-3 alkyl;
R 4 is hydrogen or —C 1-3 alkyl;
R 5 is hydrogen or —C 1-3 alkyl;
R 6 is hydrogen or —C 1-6 alkyl;
R 7 is hydrogen or —C 1-6 alkyl;
R 8 is hydrogen or —C 1-6 alkyl
p is 0 or an integer 1 or 2;
q is 0 or an integer 1 or 2
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
25 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 1 is hydrogen.
26 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 1 is:
27 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 1 is —CH 2 CH 2 CH 2 C(O)OH.
28 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 1 is —CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 .
29 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 1 is —CH 2 CH 2 CH 2 C(O)N(CH 2 CH 2 OCH 3 ) 2 .
30 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 2a is selected from the group comprising chloro, fluoro, cyano, methoxy, trifluoromethyl and SO 2 CH 3 .
31 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 4 is hydrogen.
32 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 5 is hydrogen.
33 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 3 is in the meta position.
34 . The combination therapeutic agent of claim 23 wherein, in the compound of formula (I), R 3 is in the para position.
35 . The combination therapeutic agent of claim 23 wherein the compound of formula (I) is selected from:
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-(2-(2-methoxyethoxy)ethoxy)prop-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)hex-5-ynoic acid;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
3-((2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(3-(2-(2-hydroxyethoxy)ethoxy)prop-1-yn-1-yl)-4-oxoquinazolin-3(4H)-yl)methyl)benzonitrile;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-(2-morpholinoethoxy)prop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-fluorobenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-fluorobenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-methoxybenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-methoxybenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(4-chlorobenzyl)-5-ethynyl quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-(methylsulfonyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-(methylsulfonyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
3-((2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-4-oxoquinazolin-3(4H)-yl)methyl)benzonitrile;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-(methylsulfonyl)benzyl)quinazolin-4(3H)-one;
3-((2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-4-oxoquinazolin-3(4H)-yl)methyl)benzonitrile;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(4-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(4-chlorobenzyl)-5-(3-methoxyprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-methoxybenzyl)-5-(3-methoxyprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-methoxyprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-(2-methoxyethoxy)prop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-((5-methylisoxazol-3-yl)methyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-((5-methylisoxazol-3-yl)methyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-chloro-2-fluorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2,6-difluorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(4-chloro-2-fluorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(3-methoxyprop-1-ynyl)-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-fluorobenzyl) quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-cyclopentylprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(3-(benzyloxy)prop-1-ynyl)-3-(2-chlorobenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(5-hydroxypent-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-fluoro-5-methoxybenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3,4-dichlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-benzyl-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-trifluoromethylbenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-methoxybenzyl)quinazolin-4(3H)-one;
4-((2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-4-oxoquinazolin-3(4H)-yl)methyl)benzonitrile;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-fluoro-4-methoxybenzyl)quinazolin-4(3H)-one;
1-(3-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)prop-2-ynyl)urea;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-fluorobenzyl)-5-(3-(2-(2-methoxyethoxy)ethoxy)prop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-phenoxyprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-fluorobenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(2-methoxyethyl)hex-5-ynamide;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(7-morpholino-7-oxohept-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(5-morpholino-5-oxopent-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-((5-methylpyrazin-2-yl)methyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-oxo-6-(piperidin-1-yl)hex-1-yn-1-yl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-diethylhex-5-ynamide;
7-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)hept-6-ynoic acid;
2-Acetamido-N-(3-(2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)prop-2-yn-1-yl)acetamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-methoxy-5-(trifluoromethyl)benzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-methoxyphenethyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(benzo[b]thiophen-2-ylmethyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-fluoro-3-methoxybenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
Methyl 3-((2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)-4-oxoquinazolin-3(411)-yl)methyl)benzoate;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(benzofuran-5-ylmethyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-((2-methylthiazol-4-yl)methyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-methylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-morpholinopiperidin-1-yl)-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
5-(6-(4-Acetylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)-2-((4-amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)quinazolin-4(3H)-one;
N-(4-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)but-3-yn-1-yl)morpholine-4-carboxamide;
5-(6-(4-Acetylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)-2-((4-amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)quinazolin-4(3H)-one;
N-(4-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)but-3-yn-1-yl)morpholine-4-carboxamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(5-(bis(2-methoxyethy)amino)pent-1-ynyl)-3-(2-chlorobenzyl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-cyclopentylhex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl) hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(2-morpholinoethyl)hex-5-ynamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-(2-methoxyethyl)piperazin-1-yl)-6-oxohex-1-ynyl) quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(2-(dimethylamino)ethyl) hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(pyridin-4-yl)hex-5-ynamide;
6-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(pyridin-4-yl)hex-5-ynamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-(dimethylamino)piperidin-1-yl)-6-oxohex-1-ynyl) quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-methyl-N-(2-(4-methyl piperazin-1-yl)ethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-isopropylhex-5-ynamide;
6-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-isopropylhex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-dimethylhex-5-ynamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-oxo-6-(pyrrolidin-1-yl)hex-1-yn-1-yl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(pyrrolidin-3-yl)hex-5-ynamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(3-(dimethylamino)pyrrolidin-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(3-(dimethylamino)pyrrolidin-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-methyl-1,4-diazepan-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-methyl-1,4-diazepan-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxy-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-morpholino-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
36 . The combination therapeutic agent of claim 23 , wherein the additional active ingredient is selected from the group consisting of steroids, beta agonists, xanthines, muscarinic antagonists and p38 MAP kinase inhibitors.
37 . The combination therapeutic agent of claim 36 , wherein the steroid is selected from the group consisting of budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate and fluticasone furoate.
38 . The combination therapeutic agent of claim 36 , wherein the beta agonist is selected from the group consisting of terbutaline, salbutamol, salmeterol, formoterol and indacaterol.
39 . The combination therapeutic agent of claim 36 , wherein the xanthine is theophylline.
40 . The combination therapeutic agent of claim 36 , wherein the muscarinic antagonist is ipratropium.
41 . The combination therapeutic agent of claim 23 , wherein the additional active ingredient is an antiviral agent.
42 . The combination therapeutic agent of claim 41 , wherein the antiviral agent is selected from the group consisting of acyclovir, tamiflu, relenza and interferon.
43 . The combination therapeutic agent of claim 23 , wherein the compound of formula (I) and the additional active ingredient are co-formulated.
44 . The combination therapeutic agent of claim 23 , wherein the compound of formula (I) and the additional active ingredient are co-administered.
45 . A method for the treatment of a respiratory disorder comprising administering to a patient in need of such treatment an effective amount of the combination therapeutic agent of claim 36 .
46 . A method for the treatment of viral exacerbations of asthma and/or COPD, flu virus, rhinovirus and/or respiratory syncytial virus comprising administering to a patient in need of such treatment an effective amount of the combination therapeutic agent of claim 41 .
47 . A process for the preparation of a compound of formula (I)
wherein
R 1 is H, a saturated or unsaturated, branched or unbranched C 1-15 alkyl chain, wherein optionally one or more carbons is/are replaced by a heteroatom selected from O, N, S(O) p , wherein said chain is optionally substituted by one or more groups independently selected from oxo, halogen, an aryl group, a heteroaryl group, a carbocyclyl group or a heterocyclyl group,
each aryl, heteroaryl, carbocyclyl or heterocyclyl group bearing:
0 to 3 substituents selected from halogen, -hydroxyl, —C 1-6 alkyl, —C 1-6 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 2-3 alkylOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 1-6 haloalkyl, amino, —C 1-4 mono or —C 2-8 di-alkyl amino, —C 1-4 mono or —C 2-8 di-acyl amino, —C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OC 0-6 alkyl, —NR 8 C 0-6 alkylC(O)NR 6 R 7 , —NR 8 C 0-6 alkylC(O)C 0-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 , and —C 0-6 alkylC(O)C 1-6 alkyl; and/or one aryl, heterocyclyl or carbocyclyl;
X is C 6-10 aryl or a C 5-9 heteroaryl each substituted by R 2a and by R 2b wherein R 2a is selected from hydrogen, —C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 2-3 alkylOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 0-6 alkylS(O) q C 1-3 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OH, —C 0-6 alkylC(O)OC 1-6 alkyl, —NR 8 C 0-6 alkylC(O)NR 6 R 7 , —NR 8 C 0-6 alkylC(O)C 1-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 and —C 0-6 alkylC(O)C 1-6 alkyl; and
R 2b is selected from hydrogen, C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, and —C 0-6 alkylS(O) q C 1-3 alkyl;
R 3a is hydroxyl;
R 3b is selected from hydrogen, hydroxyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 hydroxyalkyl, —C 1-3 alkoxy, and —S(O) q C 1-3 alkyl;
R 4 is hydrogen or —C 1-3 alkyl;
R 5 is hydrogen or —C 1-3 alkyl;
R 6 is hydrogen or —C 1-6 alkyl;
R 7 is hydrogen or —C 1-6 alkyl;
R 8 is hydrogen or —C 1-6 alkyl;
p is 0 or an integer 1 or 2;
q is 0 or an integer 1 or 2
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof;
comprising reacting a compound of formula (II):
or a protected derivate thereof wherein X, R 3a , R 3b , R 4 and R 5 are as defined above for compounds of formula (I) and LG 1 represents a leaving group, with a compound of formula (III):
≡—R 1 (III)
or a protected derivative thereof, wherein R 1 is as defined above for compounds of formula (I), in the presence of a suitable catalyst, an organic base and a polar aprotic solvent, under an inert atmosphere; and
optionally deprotecting to reveal a compound of formula (I); and
optionally converting one compound of formula (I) into another compound of formula (I) by standard functional group transformations.
48 . The process of claim 47 wherein, in the compound of formula (I):
R 1 is H, a saturated or unsaturated, branched or unbranched C 1-10 alkyl chain, wherein optionally one or more carbons is/are replaced by a heteroatom selected from O, N, S(O) p , wherein said chain is optionally substituted by one or more groups independently selected from oxo, halogen, an aryl group, a heteroaryl group, a carbocyclyl group or a heterocyclyl group,
each aryl, heteroaryl, carbocyclyl or heterocyclyl group bearing:
0 to 3 substituents selected from halogen, —C 1-6 alkyl, —C 1-6 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 1-6 haloalkyl, amino, —C 1-4 mono or —C 2-8 di-alkyl amino,
—C 1-4 mono or —C 2-8 di-acyl amino, —C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OC 0-6 alkyl, —NC 0-6 alkylC(O)NR 6 R 7 —NC 0-6 alkylC(O)C 0-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 , and —C 0-6 alkylC(O)C 1-6 alkyl; and/or one aryl, heterocyclyl or carbocyclyl;
X is C 6-10 aryl or a C 5-9 heteroaryl each substituted by R 2a and optionally by R 2b wherein R 2a is selected from hydrogen, —C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 0-6 alkylS(O) q C 1-3 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OH, —C 0-6 alkylC(O)OC 1-6 alkyl, —NC 0-6 alkylC(O)NR 6 R 7 ,
—NR 8 C 0-6 alkylC(O)C 1-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 and —C 0-6 alkylC(O)C 1-6 alkyl; and
R 2b is selected from hydrogen, C 1-3 alkyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy and —C 0-6 alkylS(O) q C 1-3 alkyl;
R 3a is hydroxyl;
R 3b is hydrogen, hydroxyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 hydroxyalkyl, —C 1-3 alkoxy, —S(O) q C 1-3 alkyl;
R 4 is hydrogen or —C 1-3 alkyl;
R 5 is hydrogen or —C 1-3 alkyl;
R 6 is hydrogen or —C 1-6 alkyl;
R 7 is hydrogen or —C 1-6 alkyl;
R 8 is hydrogen or —C 1-6 alkyl
p is 0 or an integer 1 or 2;
q is 0 or an integer 1 or 2
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
49 . The process of claim 47 wherein, in the compound of formula (I), R 1 is hydrogen.
50 . The process of claim 47 wherein, in the compound of formula (I), R 1 is:
51 . The process of claim 47 wherein, in the compound of formula (I), R 1 is CH 2 CH 2 CH 2 C(O)OH.
52 . The process of claim 47 wherein, in the compound of formula (I), R 1 is CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 .
53 . The process of claim 47 wherein, in the compound of formula (I), R 1 is CH 2 CH 2 CH 2 C(O)N(CH 2 CH 2 OCH 3 ) 2 .
54 . The process of claim 47 wherein, in the compound of formula (I), R 2a is selected from the group comprising chloro, fluoro, cyano, methoxy, trifluoromethyl and SO 2 CH 3 .
55 . The process of claim 47 wherein, in the compound of formula (I), R 4 is hydrogen.
56 . The process of claim 47 wherein, in the compound of formula (I), R 5 is hydrogen.
57 . The process of claim 47 wherein, in the compound of formula (I), R 3 is in the meta position.
58 . The process of claim 47 wherein, in the compound of formula (I), R 3 is in the para position.
59 . The process of claim 47 wherein the compound of formula (I) is selected from:
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-(2-(2-methoxyethoxy)ethoxy)prop-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)hex-5-ynoic acid;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
3-((2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(3-(2-(2-hydroxyethoxy)ethoxy)prop-1-yn-1-yl)-4-oxoquinazolin-3(4H)-yl)methyl)benzonitrile;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-(2-morpholinoethoxy)prop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-fluorobenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-fluorobenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-methoxybenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-methoxybenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(4-chlorobenzyl)-5-ethynyl quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-(methylsulfonyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-(methylsulfonyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
3-((2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-4-oxoquinazolin-3(4H)-yl)methyl)benzonitrile;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(3-(methylsulfonyl)benzyl)quinazolin-4(3H)-one;
3-((2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-4-oxoquinazolin-3(4H)-yl)methyl)benzonitrile;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(4-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(4-chlorobenzyl)-5-(3-methoxyprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-methoxybenzyl)-5-(3-methoxyprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-methoxyprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-(2-methoxyethoxy)prop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-((5-methylisoxazol-3-yl)methyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-((5-methylisoxazol-3-yl)methyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-chloro-2-fluorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2,6-difluorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(4-chloro-2-fluorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(3-methoxyprop-1-ynyl)-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-fluorobenzyl) quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-cyclopentylprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(3-(benzyloxy)prop-1-ynyl)-3-(2-chlorobenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(5-hydroxypent-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-fluoro-5-methoxybenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3,4-dichlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-benzyl-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-trifluoromethylbenzyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(4-methoxybenzyl)quinazolin-4(3H)-one;
4-((2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-4-oxoquinazolin-3(4H)-yl)methyl)benzonitrile;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-ethynyl-3-(2-fluoro-4-methoxybenzyl)quinazolin-4(3H)-one;
1-(3-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)prop-2-ynyl)urea;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-fluorobenzyl)-5-(3-(2-(2-methoxyethoxy)ethoxy)prop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-phenoxyprop-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-fluorobenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(2-methoxyethyl)hex-5-ynamide;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(7-morpholino-7-oxohept-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(5-morpholino-5-oxopent-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-((5-methylpyrazin-2-yl)methyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-oxo-6-(piperidin-1-yl)hex-1-yn-1-yl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-diethylhex-5-ynamide;
7-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)hept-6-ynoic acid;
2-Acetamido-N-(3-(2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)prop-2-yn-1-yl)acetamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(3-methoxy-5-(trifluoromethyl)benzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-methoxyphenethyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(benzo[b]thiophen-2-ylmethyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-fluoro-3-methoxybenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
Methyl 3-((2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)-4-oxoquinazolin-3(4H)-yl)methyl)benzoate;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(benzofuran-5-ylmethyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-((2-methylthiazol-4-yl)methyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-methylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-morpholinopiperidin-1-yl)-6-oxohex-1-yn-1-yl)quinazolin-4(3H)-one;
5-(6-(4-Acetylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)-2-((4-amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)quinazolin-4(3H)-one;
N-(4-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)but-3-yn-1-yl)morpholine-4-carboxamide;
5-(6-(4-Acetylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)-2-((4-amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)quinazolin-4(3H)-one;
N-(4-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)but-3-yn-1-yl)morpholine-4-carboxamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-5-(5-(bis(2-methoxyethy)amino)pent-1-ynyl)-3-(2-chlorobenzyl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-cyclopentylhex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(tetrahydro-2H-pyran-4-yl) hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(2-morpholinoethyl)hex-5-ynamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-(2-methoxyethyl)piperazin-1-yl)-6-oxohex-1-ynyl) quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(2-(dimethylamino)ethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(pyridin-4-yl)hex-5-ynamide;
6-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(pyridin-4-yl)hex-5-ynamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-(dimethylamino)piperidin-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-methyl-N-(2-(4-methylpiperazin-1-yl)ethyl)hex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-isopropylhex-5-ynamide;
6-(2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-isopropylhex-5-ynamide;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N,N-dimethylhex-5-ynamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-oxo-6-(pyrrolidin-1-yl)hex-1-yn-1-yl)quinazolin-4(3H)-one;
6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)-N-(pyrrolidin-3-yl)hex-5-ynamide;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(3-(dimethylamino)pyrrolidin-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(3-(dimethylamino)pyrrolidin-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-methyl-1,4-diazepan-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-(4-methyl-1,4-diazepan-1-yl)-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
2-((4-Amino-3-(4-hydroxy-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-morpholino-6-oxohex-1-ynyl)quinazolin-4(3H)-one;
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.
60 . The process of claim 47 , wherein LG 1 is halo.
61 . The process of claim 47 , wherein the catalyst is a palladium catalyst.
62 . The process of claim 60 , wherein the catalyst is bis(triphenylphosphine)palladium (II) dichloride, in the presence of copper iodide.
63 . The process of claim 47 , further including a preceding step of preparing the compound of formula (II) by reacting a compound of of formula (IV):
or a protected derivative thereof, wherein LG 1 and X are as defined above for compounds of formula (II) and LG 2 is a leaving group, with a compound of formula (V):
or a protected derivative thereof, wherein R 3a , R 3b , R 4 and R 5 are as defined above for compounds of formula (I), in the presence of a base, in a polar aprotic solvent.
64 . The process of claim 63 wherein LG 2 is halo.
65 . The process of claim 63 , wherein, in the compound of formula (V), R 3a is hydroxyl protected by a silyl ether protecting group.Cited by (0)
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