Substituted pyridinone compounds as MEK inhibitors

Patent metadata

Field	Value
Publication number	US-9617261-B2
Application number	US-201514977011-A
Country	US
Kind code	B2
Filing date	Dec 21, 2015
Priority date	Jun 20, 2013
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

The invention provides novel substituted heterocyclic compounds represented by Formula I and Formula II, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of MEK and are useful in the treatment of inflammatory diseases, cancer and other hyperproliferative diseases. The invention further provides a method of treatment for inflammatory diseases, cancer and other hyperproliferative diseases in mammals, especially humans.

First claim

The invention claimed is:

1. A compound of formula II

wherein
R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 5 -C 6 cycloalkenyl or C 2 -C 6 alkynyl; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, and one or two ring carbon atoms of said C 3 -C 6 cycloalkyl groups are optionally replaced with, independently, O, N, or S; and
R 2 , R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —SR 9 , —OR 9 , —C(O)R 9 , —NR 10 C(O)OR 12 , —OC(O)R 9 , —NR 10 , —S(O) j R 12 , —S(O) j NR 9 R 10 , —S(O) j NR 10 C(O)R 9 , —C(O)NR 10 S(O) j R 12 , —S(O) j R 12 , —NR 10 C(O)R 9 , —C(O)NR 9 R 10 , —NR 11 C(O)NR 9 R 10 , —NR 11 C(NCN)NR 9 R 10 , —NR 9 R 10 and C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, —S(O) j (C 1 -C 6 alkyl), —S(O) j (CR 10 R 11 ) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR 10 R 10 ) m -aryl, —NR 10 (CR 10 R 11 ) m -aryl, —O(CR 10 R 11 ) m -heteroaryl, —NR 10 (CR 10 R 11 ) m -heteroaryl, —O(CR 10 R 11 ) m -heterocyclyl, —NR 10 (CR 10 R 11 ) m -heterocyclyl, and —S(C 1 -C 2 alkyl) optionally substituted with fluorine atoms;
R 9 is selected from the group consisting of hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 4 alkyl, hydroxyl and amino;
R 10 is selected from hydrogen or C 1 -C 6 alkyl where alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 4 alkyl, hydroxyl and amino; or
R 9 and R 10 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 4 alkyl, hydroxyl and amino;
R 11 is selected from hydrogen or C 1 -C 6 alkyl where alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 4 alkyl, hydroxyl and amino; or
R 10 and R 11 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 4 alkyl, hydroxyl and amino, and
R 12 is selected from trifluoromethyl, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1 -C 4 alkyl, hydroxyl and amino;
W is —C(O)OR 6 , —C(O)NR 6 R 7 , —C(O)NR 7 OR 6 , —C(O)R 7 OR 6 , heteroaryl, heterocyclyl, —NHSO 2 R 6 , —NHC(O)OR 6 , —NHC(O)NR 6 R 7 , —NHC(O)R 6 , —NR 6 R 7 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)NHSO 2 CH 3 , or —CR 6 OR 6 , wherein any of said heteroaryl, heterocyclyl, —C(O)OR 6 , —C(O)NR 6 R 7 , —C(O)NR 7 OR 6 , —C(O)R 7 OR 6 , —NHSO 2 R 6 , —NHC(O)OR 6 , —NHC(O)NR 6 R 7 , —NHC(O)R 6 , —NR 6 R 7 , —C(O)(C 3 -C 10 cycloalkyl), —C(O)(C 1 -C 10 alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)NHSO 2 CH 3 and —CR 6 OR 6 are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, azide, —NR 6 R 7 , —OR 6 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, and C 2 -C 10 alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted independently with 1 or more groups independently selected from —NR 6 R 7 and —OR 6 ;
R 6 is hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that is not substituted on a aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 13 SO 2 R 16 , —SO 2 NR 13 R 14 , —C(O)R 13 , —C(O)OR 13 , —OC(O)R 13 , —NR 13 C(O)OR 16 , —NR 13 C(O)R 14 , —C(O)NR 13 R 14 , —SR 13 , —S(O)R 16 , —SO 2 R 16 , —NR 13 R 14 , —NR 13 C(O)NR 14 R 15 , —NR 13 C(NCN)NR 14 R 15 , —OR 13 , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl,
or R 6 and R 7 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 13 SO 2 R 16 , —SO 2 NR 13 R 14 , —C(O)R 13 , —C(O)OR 13 , —OC(O)R 13 , —NR 13 C(O)OR 16 , —NR 13 C(O)R 14 , —C(O)NR 13 R 14 , —SO 2 R 16 , —NR 13 R 14 , —NR 13 C(O)NR 14 R 15 , —NR 13 C(NCN)NR 14 R 15 , —OR 13 , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R 7 is hydrogen or C 1 -C 6 alkyl;
each Y is independently CH 2 , C(CH 3 ) 2 or CR 17 R 17 ;
m is 0, 1, 2, 3, 4 or 5; and
j is 1 or 2;
R 5 is H, F, Cl, Br, CF 3 , CN, —C(O)R 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —NR 6 R 7 , —NR 6 C(O)R 7 , —NR 8 C(O)OR 7 , —NR 8 C(O)NR 6 R 7 , —NR 8 , —SO 2 NR 6 R 7 , —OC(O)R 6 , —OC(O)OR 6 , —OC(O)NR 6 R 7 , —SR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , C 1 -C 12 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl;
R 8 is selected from the group consisting of trifluoromethyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarycycloalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heteroarycycloalkyl, and heterocyclyl is unsubstituted or substituted with 1-3 substituents selected independently from halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, trifluoromethyl, difluoromethoxy, phenyl or substituted phenyl with 1-3 substituents selected independently from halogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano trifluoromethyl, or difluoromethoxy;
R 13 , R 14 and R 15 independently are hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl, and R 16 is lower alkyl, lower alkenyl, aryl and ar

Assignees

• Asan Found
• Cmg Pharmaceutical Co Ltd

Inventors

• Lee Gilnam
• Jeon Hye Sun
• Jeon Ki Joon
• Rhim Chul Yun
• Kim Jin Sung
• Seo Jeongbeob
• Cho Suk Young
• Kim Choung Soo
• Lee Jung Shin
• Choi Eun Kyung
• Hwang Jung Jin
• Kim Bongcheol

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D221/04

  Ortho- or peri-condensed ring systems · CPC title

• C07D271/10

  1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D271/113

  with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical · CPC title