Biaryl compositions and methods for modulating a kinase cascade
The invention relates to compounds and methods for modulating one or more components of a kinase cascade.
1. A method of treating psoriasis in a subject, comprising administering to the subject a compound having Formula I:
or a salt, solvate, hydrate, or prodrug thereof, wherein:
T is a bond, CR 12 R 13 , C(O), O, S, S(O), S(O) 2 , NR 14 , C(R 15 R 16 )C(R 17 R 18 ), CH 2 O, or OCH 2 ;
X y is N;
X z is CZ;
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 independently H, hydroxyl, halogen, P, 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-lower (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-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (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;
P is SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 20 R 21 ,
tetrazole, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 , and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring;
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 —;
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are independently H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl;
Z is selected from
R 1 is H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl;
R 2 and R 3 are each H;
n and m are each 1; and
R 7 , R 8 , R 9 , R 10 , and R 11 are independently hydrogen, hydroxyl, halogen, P, 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-lower (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-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,
2. The method of claim 1 , wherein T is a bond.
3. The method of claim 1 , wherein Z is
wherein:
R 7 , R 8 , R 9 , R 10 , and R 11 are independently H, 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-lower (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,
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; and
V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —.
4. The method of claim 3 , 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 of claim 1 , wherein X b is CR b ; X c is CR c ; and X d is CR d .
6. A method of treating psoriasis in a subject, comprising administering to the subject a compound selected from:
or a salt, solvate, hydrate, or prodrug thereof.
7. A method of treating psoriasis in a subject, comprising administering to the subject a compound selected from:
or a salt, solvate, hydrate, or prodrug thereof.
8. The method of claim 1 , wherein the compound is administered topically.
9. The method of claim 1 , wherein the compound is administered with a pharmaceutically acceptable carrier.
10. The method of claim 6 , wherein the compound is administered topically.
11. The method of claim 6 , wherein the compound is administered with a pharmaceutically acceptable carrier.
12. The method of claim 7 , wherein the compound is administered topically.
13. The method of claim 7 , wherein the compound is administered with a pharmaceutically acceptable carrier.