Benzoxazepin PI3K inhibitor compounds and methods of use

Patent metadata

Field	Value
Publication number	US-9546178-B2
Application number	US-201514930929-A
Country	US
Kind code	B2
Filing date	Nov 3, 2015
Priority date	Sep 28, 2009
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

Benzoxazepin compounds of Formula I, including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, wherein: Z 1 is CR 1 or N; Z 2 is CR 2 or N; Z 3 is CR 3 or N; Z 4 is CR 4 or N; and B is a pyrazolyl, imidazolyl, or triazolyl ring fused to the benzoxepin ring, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

First claim

We claim:

1. A compound selected from Formula I:

stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
Z 1 is CR 1 or N;
Z 2 is CR 2 or N;
Z 3 is CR 3 or N;
Z 4 is CR 4 or N;
B is a pyrazolyl, imidazolyl, or triazolyl ring fused to the benzoxepin ring and selected from the structures:

R 1 , R 2 , R 3 , and R 4 are independently selected from H, F, Cl, Br, I, —CN, —COR 10 , —CO 2 R 10 , —C(═O)N(R 10 )OR 11 , —C(═NR 10 )NR 10 R 11 , —C(═O)NR 10 R 11 , —NO 2 , —NR 10 R 11 , —NR 12 C(═O)R 10 , —NR 12 C(═O)OR 11 , —NR 12 C(═O)NR 10 R 11 , —NR 12 C(═O)(C 1 -C 12 alkylene)NR 10 R 11 , —NR 12 (C 1 -C 12 alkylene)NR 10 R 11 , —NR 12 (C 1 -C 12 alkylene)OR 10 , —NR 12 (C 1 -C 12 alkylene)C(═O)NR 10 R 11 , —OR 10 , —SR 10 , —S(O) 2 R 10 ,
—C(═O)NR 10 (C 1 -C 12 alkylene)NR 10 R 11 ,
—C(═O)NR 10 (C 1 -C 12 alkylene)NR 10 C(═O)OR 11 ,
—C(═O)NR 10 (C 1 -C 12 alkylene)NR 10 C(═O)R 11 ,
—C(═O)NR 10 (C 1 -C 12 alkylene)R 10 ,
C 1 -C 12 alkyl,
C 2 -C 8 alkenyl,
C 2 -C 8 alkynyl,
C 3 -C 12 carbocyclyl,
C 2 -C 20 heterocyclyl,
C 6 -C 20 aryl,
C 1 -C 20 heteroaryl,
—(C 3 -C 12 carbocyclyl)-(C 1 -C 12 alkyl),
—(C 2 -C 20 heterocyclyl)-(C 1 -C 12 alkyl),
—(C 6 -C 20 aryl)-(C 1 -C 12 alkyl),
—(C 1 -C 20 heteroaryl)-(C 1 -C 12 alkyl),
—(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 2 -C 20 heterocyclyl)-(C 2 -C 20 heterocyclyl),
—(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl)-(C 3 -C 12 carbocyclyl),
—(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl)-C(═O)—(C 2 -C 20 heterocyclyl),
—(C 1 -C 12 alkylene)-(C 1 -C 20 heteroaryl),
—(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl)-(C 1 -C 12 alkyl),
—(C 1 -C 12 alkylene)-(C 6 -C 20 aryl)-(C 1 -C 12 alkyl),
—(C 1 -C 12 alkylene)-(C 1 -C 20 heteroaryl)-(C 1 -C 12 alkyl),
—(C 1 -C 12 alkylene)-C(═O)—(C 2 -C 20 heterocyclyl),
—(C 1 -C 12 alkylene)C(═O)OR 10 ,
—(C 1 -C 12 alkylene)C(═O)NR 10 R 11 ,
—(C 1 -C 12 alkylene)-NR 10 R 11 ,
—(C 1 -C 12 alkylene)NR 12 C(═O)R 10 ,
—(C 1 -C 12 alkylene)OR 10 ,
—(C 1 -C 12 alkylene)-NR 10 —(C 1 -C 12 alkylene)-(C 1 -C 20 heteroaryl),
—(C 1 -C 12 alkylene)-NR 10 —(C 1 -C 12 alkylene)-(C 1 -C 20 heterocyclyl),
—(C 1 -C 12 alkylene)-NR 10 —(C 1 -C 12 alkylene)-NHC(═O)—(C 1 -C 20 heteroaryl),
—(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl)-NR 10 R 11 , and
—(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl)-(C 1 -C 12 alkyl)-NR 10 R 11 ,
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, R 10 , —SR 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 12 C(O)R 10 , —CO 2 R 10 , —C(O)R 10 , —CONR 10 R 11 , oxo, and —OR 10 ;
A is selected from the structures:

where R 9 is independently selected from H, F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 CO 2 H, —CH(CH 3 )CH 2 OCH 3 , —CN, —CF 3 , —CH 2 CF 3 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —C(═O)CH 3 , —CH 2 C(═O)NHCH 3 , —C(═O)NHCH 3 , —CO 2 H, —CH 2 CO 2 CH 3 , —NH 2 , —OH, —OCH 3 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclopropylmethyl, 1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, 4-morpholinyl, morpholin-4-yl-ethyl, benzyl, and phenyl, where benzyl and phenyl are optionally substituted with one or more groups selected from F, Cl, Br, I, —CH 2 OH, —CH 2 CO 2 H, —CN, —CH 2 NH 2 , —CH 3 , —C(═O)CH 3 , —C(═O)NHCH 3 , —CO 2 H, —CH 2 CO 2 CH 3 , —NH 2 , —OCH 3 , —S(O) 2 CH 3 , 1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, and 4-morpholinyl; and where the wavy line indicates the site of attachment;
R 5 is selected from H, and C 1 -C 12 alkyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CO 2 H, —CONH 2 , —CONHCH 3 , —NH 2 , —NO 2 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —S(O) 2 NH 2 , and —S(O) 2 CH 3 ;
R 6 is selected from C 1 -C 12 alkyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, and C 6 -C 20 aryl, each optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 OH, —CH 2 C 6 H 5 , —CN, —CF 3 , —CO 2 H, —C(O)CH 3 , —NH 2 , —NO 2 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —OH, oxo, —OCH 3 , —OCH 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 CH 3 , —C(═O)NR 10 (C 1 -C 12 alkylene)NR 10 R 11 , phenyl, pyridinyl, tetrahydro-furan-2-yl, 2,3-dihydro-benzofuran-2-yl, 1-isopropyl-pyrrolidin-3-ylmethyl, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, —C≡CR 13 , —CH═CHR 13 , and —C(═O)NR 10 R 11 ;
or R 5 and R 6 together with the nitrogen atom to which they are attached form C 2 -C 20 heterocyclyl or C 1 -C 20 heteroaryl, optionally substituted with one or more groups selected from F, Cl, Br, I, CH 3 , C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 C 6 H 5 , pyridin-2-yl, 6-methyl-pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyrimidin-2-yl, pyrazin-2-yl, tetrahydro-furan-carbonyl, 2-methoxy-phenyl, benzoyl, cyclopropylmethyl, (tetrahydrofuran-2-yl)methyl, 2,6-dimethyl-morpholin-4-yl, 4-methyl-piperazine-carbonyl, pyrrolidine-1-carbonyl, cyclopropanecarbonyl, 2,4-difluoro-phenyl, pyridin-2-ylmethyl, morpholin-4-yl, —CN, —CF 3 , —CO 2 H, —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —COCF 3 , —COCH 3 , —COCH(CH 3 ) 2 , —NO 2 , NHCH 3 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NHCOCH 3 , —NCH 3 COCH 3 , —NHS(O) 2 CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 S(O) 2 NHCH 3 , —CH 2 S(O) 2 CH 2 CH 3 , —S(O) 2 NHCH 3 , —S(O) 2 CH 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 N(CH 3 ) 2 and —S(O) 2 CH 3 ;
R 10 , R 11 and R 12 are independently selected from H, C 1 -C 12 alkyl, —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), —(C 1 -C 12 alkylene)-(C 6 -C 20 aryl), —(C 1 -C 12 alkylene)-(C 3 -C 12 carbocyclyl), C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, and C 1 -C 20 heteroaryl, each of which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CH(CH 3 )OH, —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , —CH 2 NH 2 , —(CH 2 ) 2 N(CH 3 ) 2 , —CH 2 C 6 H 5 , —CN, —CF 3 , —CO 2 H, —C(O)CH 3 , —C(O)CH(OH)CH 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NO 2 , —N(CH 3 ) 2 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NHCOCH 3 , —NHS(O) 2 CH 3 , ═O (oxo), —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OP(O)(OH) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 N(CH 3 ) 2 , —CH 2 S(O) 2 NHCH 3 , —CH 2 S(O) 2 CH 2 CH 3 , —S(O) 2 NHCH 3 , —S(O) 2 CH 2 CH 3, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, cyclopropyl, cyclopentyl, oxetanyl, 4-methylpiperazin-1-yl, and 4-morpholinyl;
or R 10 and R 11 together with the nitrogen atom to which they are attached form a C 2 -C 20 heterocyclyl ring or C 1 -C 20 hete

Assignees

• Genentech Inc

Inventors

• Blaquiere Nicole
• Do Steven
• Dudley Danette
• FOLKES Adrian
• Heald Robert
• Heffron Timothy
• Jones Mark
• Kolesnikov Aleksandr
• Ndubaku Chudi
• Olivero Alan G
• Price Stephen
• Staben Steven
• Wang Lan

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title