Arylamino N-heteraryl compounds as MEK inhibitors

摘要

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.

主权项

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 R11; and 2) aryl, halogen, C1-C10-alkyl-OR6, C1-C10-alkyl-NR7R8, —C═NNR6R7, —C═NOR7, C1-C10 alkyl(NR7)(NR7R8), —C(O)R6, —C(O)OR6, —C(O)NR7R8, —C(O)NR7OR6, —C(O)(C3-C10 cycloalkyl), —C(O)(C1-C10 alkyl), —C(O)(aryl), —C(O)NR7(C1-C10 alkyl)heterocycloalkyl, —C(O)(heteroaryl), —C(O)(heterocycloalkyl), —CN, —C(O)NR7NR8R6, —C(O)C(O)R6, —NR7R8, —C(O)CR6R7C(O)R8, —NR7C(O)R8, —NRC(O)NR7R8 or —C(O)NR7NR8C(O)R6; R1 and R9 are independently selected from: hydrogen, halogen, cyano, azido, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, aryl, heteroaryl, heterocycloalkyl, C1-C4 alkyl-C(O)OR6, C1-C4 alkyl-OR6, C1-C4 alkyl-C(O)NR7R8, —C(O)OR6, —C(O)R6, —NR7C(O)OR6, —OC(O)R6, —NR7R8, —SR6, and —NR7S(O)2R6, wherein said alkyl, aryl, heteroaryl and heterocycloalkyl are substituted or unsubstituted; R2 and R3 are independently halogen; R4 and R5 are independently selected from: hydrogen, halogen, C1-C6 alkyl and C1-C6 alkoxy, wherein said alkyl or alkoxy is substituted or unsubstituted; R6, R7 and R8 are independently selected from: hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, C1-C4 alkyl-C(O)OR′, C1-C4 alkyl-OR′, C1-C4 alkyl-(heterocycloalkyl), C1-C4 alkyl-diol, and C1-C4 alkyl-C(O)NR′R″, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl are substituted or unsubstituted; or R7 and R8 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; R10 is selected from hydrogen, halogen or C1-C6 alkyl; wherein said alkyl is substituted or unsubstituted; R11 is selected from: hydrogen, C1-C6-alkyl, —OR6, —NR7R8, —SR6, and —NR7S(O)(O)R′; and R′ and R″ are independently selected from hydrogen, C1-C6-alkyl or aryl, wherein said alkyl or aryl is substituted or unsubstituted, wherein said cancer is susceptible to MEK inhibition.