Arylamino N-heteraryl compounds as MEK inhibitors
The invention provides novel arylamino N-heteroaryl MEK inhibitors of Formula (I): Such compounds are MEK inhibitors that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation. Also disclosed is the treatment of a hyperproliferative disease in mammals, and pharmaceutical compositions containing such compounds.
1. A method of inhibiting MEK in a cancer cell selected from the group consisting of human melanoma cells and human pancreatic cancer cells comprising administering to said cancer cell a therapeutically effective amount of a compound of Formula (I),
as well as tautomers, pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein:
Het is selected from
wherein
* is the connecting position;
W is selected from: 1) heteroaryl containing 1-4 heteroatoms or heterocycloalkyl containing 1-4 heteroatoms each of which is optionally substituted by 1 to 5 substituents R 11 ; and 2) aryl, halogen, C 1 -C 10 -alkyl-OR 6 , C 1 -C 10 -alkyl-NR 7 R 8 , —C═NNR 6 R 7 , —C═NOR 7 , C 1 -C 10 alkyl(NR 7 )(NR 7 R 8 ), —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 8 , —C(O)NR 7 OR 6 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)NR 7 (C 1 -C 10 alkyl)heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocycloalkyl), —CN, —C(O)NR 7 NR 8 R 6 , —C(O)C(O)R 6 , —NR 7 R 8 , —C(O)CR 6 R 7 C(O)R 8 , —NR 7 C(O)R 8 , —NRC(O)NR 7 R 8 or —C(O)NR 7 NR 8 C(O)R 6 ;
R 1 and R 9 are independently selected from: hydrogen, halogen, cyano, azido, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR 6 , C 1 -C 4 alkyl-OR 6 , C 1 -C 4 alkyl-C(O)NR 7 R 8 , —C(O)OR 6 , —C(O)R 6 , —NR 7 C(O)OR 6 , —OC(O)R 6 , —NR 7 R 8 , —SR 6 , and —NR 7 S(O) 2 R 6 , wherein said alkyl, aryl, heteroaryl and heterocycloalkyl are substituted or unsubstituted;
R 2 and R 3 are independently halogen;
R 4 and R 5 are independently selected from: hydrogen, halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, wherein said alkyl or alkoxy is substituted or unsubstituted;
R 6 , R 7 and R 8 are independently selected from: hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, C 1 -C 4 alkyl-C(O)OR′, C 1 -C 4 alkyl-OR′, C 1 -C 4 alkyl-(heterocycloalkyl), C 1 -C 4 alkyl-diol, and C 1 -C 4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl are substituted or unsubstituted; or
R 7 and R 8 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocycloalkyl ring, with 1-4 heteroatoms, each of which is substituted or unsubstituted;
R 10 is selected from hydrogen, halogen or C 1 -C 6 alkyl; wherein said alkyl is substituted or unsubstituted;
R 11 is selected from: hydrogen, C 1 -C 6 -alkyl, —OR 6 , —NR 7 R 8 , —SR 6 , and —NR 7 S(O)(O)R′; and
R′ and R″ are independently selected from hydrogen, C 1 -C 6 -alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted, wherein said cancer is susceptible to MEK inhibition.