Phosphatidylinositol 3-kinase inhibitors and methods of their use
The present invention comprises small molecule inhibitors of phosphatidylinositol 3-kinase (PI3K), which is associated with a number of malignancies such as ovarian cancer, cervical cancer, breast cancer, colon cancer, rectal cancer, and glioblastomas, among others. Accordingly, the compounds of the present invention are useful for treating, preventing, and/or inhibiting these diseases.
1. A Compound according to Formula I(a):
or a single stereoisomer or mixture of stereoisomers thereof and optionally as a pharmaceutically acceptable salt thereof, wherein:
W 1 , W 2 , W 3 , and W 4 are —C(H)—;
R 50 is hydrogen;
R 51 is methyl;
R 52 is hydrogen;
R 53 is hydrogen or alkoxy; and
R 54 is hydrogen, alkyl, alkoxy, or halo; or R 53 and R 54 together with the carbons to which they are attached form a 6-membered heteroaryl; and
R 3 is halo or methyl; and
R 3a is —N(R 7 )C(O)—C 1 -C 6 -alkylene-N(R 7a )(R 7b ) where R 7 is hydrogen and R 7a and R 7b are independently hydrogen, alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl.
2. The Compound of claim 1 where R 51 is methyl; and R 50 , R 52 , and R 53 are hydrogen and R 54 is halo or alkoxy or R 50 , R 52 , and R 54 are hydrogen and R 53 is alkoxy; or a single stereoisomer or mixture of stereoisomers thereof and optionally as a pharmaceutically acceptable salt thereof.
3. The Compound of claim 1 , wherein R 3a is —NHC(O)CH 2 NH(CH 3 ), —NHC(O)CH(CH 3 )NH 2 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 N(CH 3 ) 2 , —NHC(O)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , —NHC(O)CH(NH 2 )CH 2 CH 3 , —NHC(O)CH 2 N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , or —NHC(O)CH(CH 3 )NH(CH 3 ), or a single stereoisomer or mixture of stereoisomers thereof and optionally as a pharmaceutically acceptable salt thereof.
4. A Compound of claim 1 which is:
Structure
Name
N-(3-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}-phenyl)-N-2- methylglycinamide
N-(3-{[(3-{[3,5- bis(methoxy)phenyl]amino}quinoxalin- 2-yl)amino]sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide
N-(3-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin- 2-yl)amino]sulfonyl}-4-methylphenyl)- N-2-,N-2-dimethylglycinamide
N-(3-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl }phenyl)-L- alaninamide
N-(3-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-2- methylalaninamide
N-(3-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-N-2-[2- dimethylamino)ethyl]-N-2- methylglycinamide
N-(3-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide
N-(3-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)glycinamide
N-(2-chloro-5-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)-N-2- methylglycinamide
N-(5-{[3-{[3,5- bus(methoxy)phenyl]amino}quinoxalin- 2-yl)amino]sulfonyl}-2- mehtylphenyl)glycinamide
N-(5-{[(3-{[3,5- bis(methoxy)phenyl]amino}quinoxalin- 2-yl)amino]sulfonyl}-2-methylphenyl)- beta-alaninamide
N-(5-{[(3-{[2-chloro-5- (methoxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}-2-methylphenyl)-N- 2-,N-2-dimethylglycinamide
or a pharmaceutically acceptable salt thereof.
5. A compound of claim 3 which is
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.
7. A pharmaceutical composition comprising a compound of claim 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.