Biaryl compositions and methods for modulating a kinase cascade
The invention relates to compounds of formula IB and methods for modulating one or more components of a kinase cascade using these compounds.
1. A method of treating a brain cancer, comprising administering to a subject a compound according to Formula IB:
or a salt thereof, wherein:
T is a bond;
X y is CY;
X z is CZ;
Y is selected from hydrogen, hydroxyl, halogen, (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, and O-benzyl;
X a is CR a , N, or N—O;
X b is CR b , N, or N—O;
X c is CR c , N, or N—O;
X d is CR d , N, or N—O;
X e is CR e , N, or N—O;
R a , R b , R c , R d , R e , R 4 , R 5 , and R 6 are each independently selected from hydrogen, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, COOH, COO—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 —(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,
W is H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl;
V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —;
Z is
wherein:
R 1 , R 2 , and R 3 are each independently H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl;
R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O—(C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O—C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl,
and
n and m are each independently 0, 1, or 2,
provided that at least one of X a , X b , X c , X d , and X e is N,
wherein the brain cancer is a primary tumor selected from glioblastoma, astrocytoma, and medullablastoma.
2. The method according to claim 1 , wherein the compound is administered with at least one pharmaceutically acceptable excipient or carrier.
3. The method according to claim 1 , wherein R 4 and R 6 are each H.
4. The method according to claim 1 , wherein at least one of R 7 , R 8 , R 9 , R 10 and R 11 is halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or O-benzyl.
5. The method according to claim 1 , wherein m and n are each 1 and R 2 and R 3 are each H.
6. The method according to claim 5 , wherein the compound is selected from
7. The method according to claim 1 , wherein the compound is a pharmaceutically acceptable salt.
8. The method according to claim 1 , wherein the compound is a hydrochloride salt.
9. A method of treating a brain cancer in a patient wherein the brain cancer is a primary tumor selected from glioblastoma, astrocytoma, and medullablastoma, comprising administering the compound
or a pharmaceutically acceptable salt thereof to the patient having said brain cancer.
10. The method according to claim 1 , wherein the brain cancer is glioblastoma.
11. The method according to claim 9 , wherein the brain cancer is glioblastoma.