HETEROCYCLIC COMPOUNDS AND USES THEREOF
Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the heterocyclic entities, and methods of using these chemical entities for treating diseases and conditions associated with PI3 kinase activity are described herein.
1 . A method of preparing a compound of Formula A:
comprising the steps of:
a) reacting a compound of Formula A1 with a compound of Formula B1:
to result in a compound of Formula C1:
b) converting the compound of Formula C1 to a compound of Formula D1:
c) reacting the compound of Formula D1 with a compound of Formula E1:
and
to result in a compound of Formula A;
wherein:
X 1 is Br or I;
X 2 is Br, Cl or I;
one of W c and W d is N, and the other is O, NR 10 , or S;
n is 1, 2, or 3;
G is hydrogen, alkyl, alkenyl or aryl; or the G groups of
join together to form a 5- or 6-membered cyclic moiety; and
R 1 and R 2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
2 . The method of any preceding claim, wherein W c is 0 and W d is N.
3 . The method of any preceding claim, wherein R 2 is amino.
4 . The method of any preceding claim, wherein n is 1 or 2.
5 . The method of any preceding claim, wherein Ra and Rb taken together taken together with nitrogen form a 4, 5, 6 or 7-membered cyclic moiety, optionally substituted with alkyl.
6 . The method of claim 5 , wherein the cyclic moiety is a 4, 5, 6 or 7-membered heterocyclic group.
7 . The method of claim 6 , wherein the heterocyclic group is saturated.
8 . The method of claim 6 , wherein the heterocyclic group is a substituted piperazine.
9 . The method of any preceding claim, wherein G is hydrogen.
10 . The method of any preceding claim, wherein step a) is performed in the presence of a palladium catalyst system.
11 . The method of claim 10 , wherein the palladium catalyst system is Pd(dba) 2 /Xantphos.
12 . The method of any preceding claim, wherein step b) is performed in the presence of phosphorus oxychloride.
13 . The method of any preceding claim, wherein step c) is performed in the presence of a palladium catalyst system.
14 . The method of claim 13 , wherein the palladium catalyst system is Pd(PPh 3 ) 4 .