US2019330235A1PendingUtilityA1
Tricyclic p13k inhibitor compounds and methods of use
Est. expiryDec 16, 2030(~4.4 yrs left)· nominal 20-yr term from priority
Inventors:Jennafer DotsonRobert Andrew HealdTimothy HeffronGraham Elgin JonesSussie Lerche KrintelNeville James McleanChudi NdubakuAlan G. OliveroLaurent SalphatiLan WangBinqing Wei
A61P 43/00A61P 37/04A61P 9/00A61P 3/10A61P 37/00A61P 7/00A61P 37/02A61P 31/12A61P 35/00A61P 35/02A61P 29/00A61P 1/16A61P 25/00A61K 31/5383C07D 487/14A61K 39/3955C07D 491/14C07D 498/14C07D 491/147C07D 471/14C07D 495/14C07D 498/20C07K 16/22C07D 519/00C07K 2317/24C07D 471/22C07D 498/22A61K 31/5386A61K 2039/505A61K 31/5377
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Claims
Abstract
Formula I compounds include stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof. The dashed lines indicate an optional double bond, and at least one dashed line is a double bond. The substituents are as described.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound selected from Formula I:
and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
the dashed lines indicate an optional double bond, and at least one dashed line is a double bond;
X 1 is S, O, N, NR a , CR 1 , C(R 1 ) 2 , or —C(R 1 ) 2 O—;
X 2 is C, CR 2 or N;
X 3 is C, CR 3 or N;
A is a 5, 6, or 7-membered carbocyclyl or heterocyclyl ring fused to X 2 and X 3 , optionally substituted with one or more R 5 groups;
R a is H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 12 alkylene)-(C 3 -C 12 carbocyclyl), —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), —(C 1 -C 12 alkylene)-C(═O)—(C 2 -C 20 heterocyclyl), —(C 1 -C 12 alkylene)-(C 6 -C 20 aryl), and —(C 1 -C 12 alkylene)-(C 1 -C 20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl;
R 1 , R 2 , and R 3 are independently selected from H, F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OOH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl;
R 4 is selected from C 6 -C 20 aryl, C 2 -C 20 heterocyclyl and C 1 -C 20 heteroaryl, each of which are optionally substituted with one or more groups R 6 groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH 3 , —CH 2 CN, —CN, —CF 3 , —CH 2 OH, —CO 2 H, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —NHCOCH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(═O)NHCH 3 , —NHC(═O)NHCH 2 CH 3 , —NHC(═O)NHCH(CH 3 ) 2 , —NHS(O) 2 CH 3 , —N(CH 3 )C(═O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , benzyl, benzyloxy, morpholinyl, morpholinomethyl, and 4-methylpiperazin-1-yl; and
R 5 is independently selected from C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 12 alkylene)-(C 3 -C 12 carbocyclyl), —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), —(C 1 -C 12 alkylene)-C(═O)—(C 2 -C 20 heterocyclyl), —(C 1 -C 12 alkylene)-(C 6 -C 20 aryl), and —(C 1 -C 12 alkylene)-(C 1 -C 20 heteroaryl); or two geminal R 5 groups form a 3, 4, 5, or 6-membered carbocyclyl or heterocyclyl ring, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl;
mor is selected from:
optionally substituted with one or more R 7 groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OCH 3 , —CHF 2 , —CN, —CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH(CH 3 )OH, —CH(CH 2 CH 3 )OH, —CH 2 CH(OH)CH 3 , —C(CH 3 ) 2 OH—, —C(CH 3 ) 2 OCH 3 , —CH(CH 3 )F, —C(CH 3 )F 2 , —CH(CH 2 CH 3 )F, —C(CH 2 CH 3 ) 2 F, —CO 2 H, —CONH 2 , —CON(CH 2 CH 3 ) 2 , —COCH 3 , —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 OCH 3 , —NHCOCH 3 , —NHCOCH 2 CH 3 , —NHCOCH 2 OH, —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(═O)NHCH 3 , —NHC(═O)NHCH 2 CH 3 , —S(O)CH 3 , —S(O)CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —S(O) 2 N(CH 3 ) 2 , and —CH 2 S(O) 2 CH 3 .
2 . The compound of claim 1 selected from Formulas Ia-n:
3 . The compound of claim 1 wherein Formula Ia is selected from the structures:
where the A heterocyclyl ring is optionally substituted with one or more R 5 groups.
4 . The compound of claim 1 wherein Formula If is selected from the structures:
where the A heterocyclyl ring is optionally substituted with one or more R 5 groups.
5 . The compound of claim 1 wherein R 4 is phenyl substituted with one or more groups selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CN, —CF 3 , —CH 2 OH, —CO 2 —, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —NHCOCH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(═O)NHCH 3 , —NHC(═O)NHCH 2 CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(═O)OC(CH 3 ) 3 , and —S(O) 2 CH 3 .
6 . The compound of claim 1 wherein R 4 is an optionally substituted bicyclic heteroaryl group selected from 1H-indazole, 1H-indole, indolin-2-one, 1-(indolin-1-yl)ethanone, 1H-benzo[d][1,2,3]triazole, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-benzo[d]imidazole, 1H-benzo[d]imidazol-2(3H)-one, 1H-pyrazolo[3,4-e]pyridine, 1H-pyrrolo[2,3-e]pyridine, 3H-imidazo[4,5-e]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, 7H-purine, 1H-pyrazolo[4,3-d]pyrimidine, 5H-pyrrolo[3,2-d]pyrimidine, 2-amino-1H-purin-6(9H)-one, quinoline, quinazoline, quinoxaline, isoquinoline, isoquinolin-1(2H)-one, 3,4-dihydroisoquinolin-(2H)-one, 3,4-dihydroquinolin-2(1H)-one, quinazolin-2(1H)-one, quinoxalin-2(1H)-one, 1,8-naphthyridine, pyrido[3,4-d]pyrimidine, and pyrido[3,2-b]pyrazine.
7 . The compound of claim 1 wherein optionally substituted R 4 is selected from:
where the wavy line indicates the site of attachment.
8 . The compound of claim 7 wherein R 4 is 1H-indazol-4-yl.
9 . The compound of claim 1 wherein R 4 is an optionally substituted monocyclic heteroaryl group selected from 2-furanyl, 3-furanyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 5-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-triazolyl, and 1-triazolyl.
10 . The compound of claim 9 wherein R 4 is 2-aminopyrimidin-5-yl.
11 . The compound of claim 1 wherein optionally substituted R 4 is selected from:
where the wavy line indicates the site of attachment.
12 . The compound of claim 1 wherein one or more R 5 groups are independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl.
13 . The compound of claim 1 wherein two geminal R 5 groups form cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuryl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, cyclohexyl, morpholino, or 1,1-dioxo-thiopyran-4-yl.
14 . The compound of claim 1 wherein mor is
15 . A compound of claim 1 selected from:
1-[4-(3a,8-dimethyl-7-morpholin-4-yl-3,3a,8,8a-tetrahydro-2h-1-oxa-4,6,8-triaza-cyclopenta[a]inden-5-yl)-phenyl]-3-ethyl-urea;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)-4-methylpyrimidin-2-amine;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)-4-(trifluoromethyl)pyridyl-2-amine;
5-(4-morpholino-8,9-dihydro-7h-[1,3]oxazino[2,3-e]purin-2-yl)pyrimidin-2-amine;
5-(4-morpholino-6,7,8,9-tetrahydropyrido[2,1-e]purin-2-yl)pyrimidin-2-amine;
5-(4-morpholino-6,7,8,9-tetrahydropyrido[2,1-e]purin-2-yl)pyridin-2-amine;
5-(4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)-4-(trifluoromethyl)pyridyl-2-amine;
5-(4-morpholino-7,8-dihydro-6h-pyrrolo[2,1-e]purin-2-yl)pyrimidin-2-amine;
6,6-dimethyl-4-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridin-2-amine;
5-(4-morpholino-8,9-dihydrospiro[[1,3]oxazino[2,3-e]purine-7,1′-cyclopropane]-2-yl)pyrimidin-2-amine;
5-(4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
5-(4-morpholino-8,9-dihydrospiro[[1,4]oxazino[3,4-e]purine-6,3′-oxetane]-2-yl)pyrimidin-2-amine;
5-(7,7-dimethyl-4-morpholino-8,9-dihydro-7h-[1,3]oxazino[2,3-e]purin-2-yl)pyrimidin-2-amine;
5-(4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridin-2-amine;
5-(6,6-(hexadeuterio)dimethyl-4-morpholino-8,9-dihydro-6h-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
(S)-5-(6-ethyl-6-methyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
5-(6,6,9-trimethyl-4-morpholino-6h-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
(R)-5-(6-ethyl-6-methyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
5-(1-morpholin-4-yl-5,6,8a,9-tetrahydro-8h-7,10-dioxa-2,4,4b-triaza-phenanthren-3-yl)-pyrimidin-2-yl amine;
5-((S)-6-Morpholin-4-yl-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalen-8-yl)-pyrimidin-2-ylamine;
4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)aniline;
1-(4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)-3-methylurea;
6,6-dimethyl-4-morpholino-2-(1H-pyrazol-4-yl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyri din-2-amine;
6,6-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
3-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenol;
2-(1H-indazol-5-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
6,6-dimethyl-2-(2-(4-methylpiperazin-1-yl) yridine-4-yl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
N-(2-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)methanesulfonamide;
6,6-dimethyl-4-morpholino-2-(6-morpholinopyridin-3-yl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
2-(1-benzyl-1H-pyrazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
2-(2-isopropoxypyridin-3-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
N-(2-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)acetamide;
2-(3,5-dimethyl-1H-pyrazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridine-2-ol;
6-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridine-3-amine;
(R)-5-(4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine
(S)-5-(4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
2-(1-ethyl-1H-pyrazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)-N,N-dimethylbenzamide;
tert-butyl 4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl(methyl)carbamate;
2-(3-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)acetonitrile;
6,6-dimethyl-4-morpholino-2-(3-morpholinophenyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
6,6-dimethyl-4-morpholino-2-(3-(morpholinomethyl)phenyl)-8,9-dihydro-6-[1,4]oxazino[3,4-e]purine;
2-(3-(benzyloxy)phenyl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
2-(1-isobutyl-1H-pyrazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
6,6-dimethyl-2-(6-(4-methylpiperazin-1-yl) yridine-3-yl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
2-(1H-indazol-4-yl)-6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)benzonitrile;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)nicotinamide;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)-N-methylpicolinamide;
2-(4-(benzyloxy)phenyl)-6,6-dimeth yl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
3-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)-N,N-dimethylaniline;
6,6-dimethyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
6,6-dimethyl-4-morpholino-2-(4-(piperidin-1-yl)phenyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine;
N-(5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridine-2-yl)acetamide;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)picolinamide;
6-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyridine-3-ol;
(4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)(4-methylpiperazin-1-yl)methanone;
N-cyclopropyl-3-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)benzamide;
5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)-N,N-dimethylpyrazin-2-amine;
1-(4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)-3-ethylurea;
1-(4-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenyl)-3-isopropyl urea;
(2-(2-aminopyrimidin-5-yl)-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purine-6,6-diyl)dimethanol;
2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholino-8,9-dihydropyrazino[2,1-e]purin-6(7H)-one;
5-(8,8-Dimethyl-1-morpholin-4-yl-5,8-dihydro-6H-7-oxa-9-thia-2,4-diaza-fluoren-3-yl)-pyrimidin-2-ylamine;
2-(1H-indazol-4-yl)-4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6-[1,4]oxazino[3,4-e]purine;
3-(4-morpholino-6-(trifluoromethyl)-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)phenol;
5-(4-((2S,6R)-2,6-dimethylmorpholino)-6,6-dimethyl-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
5-(4-(2,2-dimethylmorpholino)-6,6-dimethyl-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
N-(5-(6,6-dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-yl)acetamide;
5-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6,6-dimethyl-8,9-dihydro-6H-[1,4]oxazino[3,4-e]purin-2-yl)pyrimidin-2-amine;
2-(2-aminopyrimidin-5-yl)-6-methyl-4-morpholino-6,7-dihydropyrazino[2,1-e]purin-8(9H)-one;
5-(6,7-dimethyl-4-morpholino-6,7,8,9-tetrahydropyrazino[2,1-e]purin-2-yl)pyrimidin-2-amine; and
5-(8,8-Dimethyl-1-morpholin-4-yl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluoren-3-yl)-pyrimidin-2-ylamine.
16 . A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
17 . The pharmaceutical composition according to claim 16 , further comprising an additional therapeutic agent selected from a chemotherapeutic agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.
18 . A method of treating cancer in a patient comprised of administering to said patient a therapeutically effective amount of a compound of claim 1 wherein the cancer is breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, renal, pancreatic, myeloid disorders, lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx, lip, tongue, mouth, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's or leukemia.
19 . The method of claim 18 wherein the cancer is a brain cancer.
20 . The method of claim 18 further comprising administering to the patient an additional therapeutic agent selected from a chemotherapeutic agent, an anti-angiogenesis therapeutic agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.
21 . The method of claim 20 wherein the additional therapeutic agent is bevacizumab.
22 . A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier.
23 . A kit for treating a PI3K-mediated condition, comprising:
a) a first pharmaceutical composition comprising a compound of claim 1 ; and b) instructions for use.Cited by (0)
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