Pyrimidine derivatives used as PI-3 kinase inhibitors
Phosphatidylinositol (PI) 3-kinase inhibitor compounds (I), their pharmaceutically acceptable salts, and prodrugs thereof; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases.
1. A compound having Formula I:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein,
W is CR w or N, wherein R w is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) halogen,
(4) methyl,
(5) trifluoromethyl,
(6) sulfonamido;
R 1 is substituted or unsubstituted morpholinyl;
R 2 is selected from the group consisting
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) hydroxy,
(6) amino,
(7) substituted and unsubstituted alkyl,
(8) —COR 2a , and
(9) —NR 2a COR 2b ,
wherein R 2a , and R 2b are independently selected from the group consisting of
(a) hydrogen, and
(b) substituted or unsubstituted alkyl;
R 3 is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) substituted and unsubstituted alkyl,
(6) substituted and unsubstituted alkenyl,
(7) substituted and unsubstituted alkynyl,
(8) substituted and unsubstituted aryl,
(9) substituted and unsubstituted heteroaryl,
(10) substituted and unsubstituted heterocyclyl,
(11) substituted and unsubstituted cycloalkyl,
(12) —COR 3a ,
(13) —NR 3a R 3b ,
(14) —NR 3a COR 3b ,
(15) —NR 3a SO 2 R 3b ,
(16) —OR 3a ,
(17) —SR 3a ,
(18) —SOR 3a ,
(19) —SO 2 R 3a , and
(20) —SO 2 NR 3a R 3b ,
wherein R 3a , and R 3b are independently selected from the group consisting of
(a) hydrogen,
(b) substituted or unsubstituted alkyl,
(c) substituted and unsubstituted aryl,
(d) substituted and unsubstituted heteroaryl,
(e) substituted and unsubstituted heterocyclyl, and
(f) substituted and unsubstituted cycloalkyl; and
R 4 is selected from the group consisting of
(1) hydrogen, and
(2) halogen.
2. The compound of claim 1 , wherein W is CH.
3. The compound of claim 1 , wherein R 1 is unsubstituted N-linked morpholinyl.
4. The compound of claim 1 , wherein R 2 is hydrogen or halogen.
5. The compound of claim 1 , wherein R 2 is hydrogen.
6. The compound of claim 1 , wherein R 3 is trifluoromethyl.
7. A compound having Formula II:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein,
W is CR w or N, wherein R w is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) halogen,
(4) methyl,
(5) trifluoromethyl, and
(6) sulfonamido;
X is O, S, NH, or a direct bond;
R 2 is selected from the group consisting
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) hydroxy,
(6) amino,
(7) substituted and unsubstituted alkyl,
(8) —COR 2a , and
(9) —NR 2a COR 2b ,
wherein R 2a , and R 2b are independently selected from the group consisting of
(a) hydrogen, and
(b) substituted or unsubstituted alkyl;
R 3 is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) substituted and unsubstituted alkyl,
(6) substituted and unsubstituted alkenyl,
(7) substituted and unsubstituted alkynyl,
(8) substituted and unsubstituted aryl,
(9) substituted and unsubstituted heteroaryl,
(10) substituted and unsubstituted heterocyclyl,
(11) substituted and unsubstituted cycloalkyl,
(12) —COR 3a ,
(13) —NR 3a R 3b ,
(14) —NR 3a COR 3b ,
(15) —NR 3a SO 2 R 3b ,
(16) —OR 3a ,
(17) —SR 3a ,
(18) —SOR 3a ,
(19) —SO 2 R 3a , and
(20) —SO 2 NR 3a R 3b ,
wherein R 3a , and R 3b are independently selected from the group consisting of
(a) hydrogen,
(b) substituted or unsubstituted alkyl,
(c) substituted and unsubstituted aryl,
(d) substituted and unsubstituted heteroaryl,
(e) substituted and unsubstituted heterocyclyl, and
(f) substituted and unsubstituted cycloalkyl;
R 4 is selected from the group consisting of
(1) hydrogen, and
(2) halogen; and
R 5 is selected from the group consisting of
(1) substituted or unsubstituted morpholinyl,
(2) substituted or unsubstituted tetrahydropyranyl, and
(3) substituted or unsubstituted tetrahydrofuranyl.
8. The compound of claim 7 , wherein W is CH.
9. The compound of claim 7 , wherein R 2 is H.
10. The compound of claim 7 , wherein X is a direct link and R 5 is unsubstituted N-linked morpholinyl.
11. A compound having Formula III:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein,
W is CR w or N, wherein R w is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) halogen,
(4) methyl,
(5) trifluoromethyl, and
(6) sulfonamido;
R 2 is selected from the group consisting
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) hydroxy,
(6) amino,
(7) substituted and unsubstituted alkyl,
(8) —COR 2a , and
(9) —NR 2a COR 2b ,
wherein R 2a , and R 2b are independently selected from the group consisting of
(a) hydrogen, and
(b) substituted or unsubstituted alkyl;
R 3 is selected from the group consisting of
(1) hydrogen,
(2) cyano,
(3) nitro,
(4) halogen,
(5) substituted and unsubstituted alkyl,
(6) substituted and unsubstituted alkenyl,
(7) substituted and unsubstituted alkynyl,
(8) substituted and unsubstituted aryl,
(9) substituted and unsubstituted heteroaryl,
(10) substituted and unsubstituted heterocyclyl,
(11) substituted and unsubstituted cycloalkyl,
(12) —COR 3a ,
(13) —NR 3a R 3b ,
(14) —NR 3a COR 3b ,
(15) —NR 3a SO 2 R 3b ,
(16) —OR 3a ,
(17) —SR 3a ,
(18) —SOR 3a ,
(19) —SO 2 R 3a , and
(20) —SO 2 NR 3a R 3b ,
wherein R 3a , and R 3b are independently selected from the group consisting of
(a) hydrogen,
(b) substituted or unsubstituted alkyl,
(c) substituted and unsubstituted aryl,
(d) substituted and unsubstituted heteroaryl,
(e) substituted and unsubstituted heterocyclyl, and
(f) substituted and unsubstituted cycloalkyl;
R 4 is selected from the group consisting of
(1) hydrogen, and
(2) halogen; and
R 6 is selected from the group consisting of
(1) hydrogen,
(2) substituted and unsubstituted alkyl, and
(3) substituted and unsubstituted cycloalkyl.
12. The compound of claim 11 , wherein R 2 is hydrogen and R 3 is trifluoromethyl.
13. The compound of claim 11 , wherein R 6 is selected from the group consisting
(1) hydrogen,
(2) methyl, and
(3) ethyl.
14. A compound of formula:
or a pharmaceutically acceptable salt thereof.
15. A compound, or a pharmaceutically acceptable salt thereof, selected from:
16. A compound, or a pharmaceutically acceptable salt thereof, selected from: