Kinase Antagonists
The present invention provides novel compounds that are antagonists of PI3 kinase, PI3 kinase and tyrosine kinase, PI3 kinase and mTOR, or PI33 kinase, mTOR and tyrosine kinase.
1 . A compound having the formula:
wherein:
X is ═C(H)—;
R 1 is hydrogen, R 3 -substituted or unsubstituted alkyl, R 3 -substituted or unsubstituted heteroalkyl, R 3 -substituted or unsubstituted cycloalkyl, R 3 -substituted or unsubstituted heterocycloalkyl, R 3 -substituted or unsubstituted aryl, or R 3 -substituted or unsubstituted heteroaryl;
R 2 is R 4 -substituted heteroaryl;
R 3 is halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , ═N—NH 2 , —NR 10 —C(O)R 11 , —NR 12 —C(O)—OR 13 , —C(O)NR 14 R 15 , —NR 16 S(O) 2 NR 17 , —S(O) 2 NR 18 , R 19 -substituted or unsubstituted alkyl, R 19 -substituted or unsubstituted heteroalkyl, R 19 -substituted or unsubstituted cycloalkyl, R 19 -substituted or unsubstituted heterocycloalkyl, R 19 -substituted or unsubstituted aryl, or R 19 -substituted or unsubstituted heteroaryl, wherein n is an integer from 0 to 2;
R 36 is —NR 37 R 38 ;
R 4 is halogen, —OR 20 , or —NR 22 R 23 ;
R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are independently hydrogen, R 35 -substituted or unsubstituted alkyl, R 35 -substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, R 35 -substituted or unsubstituted heterocycloalkyl, R 35 -substituted or unsubstituted aryl, or R 35 -substituted or unsubstituted heteroaryl;
R 20 , R 22 and R 23 are hydrogen;
R 19 and R 35 are independently hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; and
R 37 and R 38 are hydrogen.
2 . The compound of claim 1 , wherein R 2 is:
wherein:
W 1 , W 2 , W 3 , and W 4 are independently ═CH—, ═CR 4 —, or ═N—; and
ring A is a partially or fully unsaturated 6- or 7- membered ring.
3 . The compound of claim 1 , wherein R 2 is R 4 -substituted pyridinyl, R 4 -substituted pyrimidinyl, R 4 -substituted thiophenyl, R 4 -substituted furanyl, R 4 -substituted indolyl, R 4 -substituted benzoxadiazolyl, R 4 -substituted benzodioxolyl, R 4 -substituted benzodioxanyl, R 4 -substituted thianaphthanyl, R 4 -substituted pyrrolopyridinyl, R 4 -substituted indazolyl, R 4 -substituted quinolinyl, R 4 -substituted quinoxalinyl, R 4 -substituted pyridopyrazinyl, R 4 -substituted quinazolinonyl, R 4 -substituted chromenonyl, R 4 -substituted benzoisoxazolyl, R 4 -substituted imidazopyridinyl, R 4 -substituted benzofuranyl, R 4 -substituted dihydro-benzofuranyl, R 4 -substituted dihydro-benzodioxinyl, R 4 -substituted benzoimidazolonyl, or R 4 -substituted benzothiophenyl.
4 . The compound of claim 1 , wherein R 2 is R 4 -substituted pyrrolpyridinyl, R 4 -substituted quinolinyl, R 4 -substituted indazolyl, or R 4 -substituted indolyl.
5 . The compound of claim 1 , wherein R 2 is R 4 -substituted indolyl.
6 . The compound of claim 5 , wherein R 2 is 5-hydroxyindol-2-yl.
7 . The compound of claim 6 , wherein R 1 is isopropyl.
8 . Thecompound of claim 1 , wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are independently hydrogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
9 . The compound of claim 1 , wherein R 1 is R 3 -substituted or unsubstituted alkyl, R 3 -substituted or unsubstituted cycloalkyl, or R 3 -substituted or unsubstituted aryl.
10 . The compound of claim 1 , wherein R 1 is R 3 -substituted or unsubstituted C 1 -C 4 alkyl, or R 3 -substituted or unsubstituted C 3 -C 6 cycloalkyl.
11 . The compound of claim 1 , wherein R 1 is methyl or unsubstituted C 3 -C 6 branched alkyl.
12 . The compound of claim 1 , wherein R 1 is isopropyl.
13 . The compound of claim 1 , wherein R 3 is R 19 -substituted or unsubstituted alkyl, R 19 -substituted or unsubstituted cycloalkyl, or R 19 -substituted or unsubstituted aryl.
14 . The compound of claim 1 , wherein R 3 is R 19 -substituted or unsubstituted alkyl or R 19 -substituted or unsubstituted cycloalkyl.
15 . The compound of claim 1 , wherein R 19 is unsubstituted alkyl or unsubstituted cycloalkyl.
16 . The compound of claim 16 , wherein R 19 is unsubstituted C 1 -C 4 alkyl or unsubstituted cyclopentyl.
17 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.