Claims for Patent: 8,178,693

Summary for Patent: 8,178,693

Title:	N3 alkylated benzimidazole derivatives as MEK inhibitors
Abstract:	Disclosed are compounds of the Formula ##STR00001## and pharmaceutically acceptable salts and prodrugs thereof, wherein A, R.sup.1, R.sup.2, R.sup.7, R.sup.8, and R.sup.9 are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed is a method of using such compounds in the treatment of hyperproliferative diseases in mammals, and pharmaceutical compositions containing such compounds.
Inventor(s):	Wallace; Eli M. (Boulder, CO), Lyssikatos; Joseph P. (Piedmont, CA), Marlow; Allison L. (Boulder, CO), Hurley; T. Brian (Boulder, CO)
Assignee:	Array Biopharma Inc. (Boulder, CO)
Application Number:	12/824,559
Patent Claims:	1. A compound of the formula ##STR00104## and pharmaceutically accepted salts thereof, wherein: R.sup.1, R.sup.2, and R.sup.9 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3, NR.sup.4C(O)OR.sup.6, --OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4, --NR.sup.3R.sup.4, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkylalkyl, --S(O).sub.jC.sub.1-C.sub.6 alkyl), --S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, --O(CR.sup.4R.sup.5).sub.m-aryl, --NR.sup.4(CR.sup.4R.sup.5).sub.m-aryl, --O(CR.sup.4R.sup.5).sub.m-heteroaryl, --NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl, --O(CR.sup.4R.sup.5).sub.m-heterocyclyl and --NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4, --C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3, --NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4, --OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R.sup.3 is selected from hydrogen, trifluoromethyl, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R, --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'', --SR'''', --S(O)R'''', --SO.sub.2R', --NR'R'', --NRC(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R', R'' and R''' independently are selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, aryl and arylalkyl; R'''' is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, aryl and arylalkyl; or any two of R', R'', R''' or R'''' 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 optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R.sup.3 and R.sup.4 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 optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R.sup.4 and R.sup.5 independently represent hydrogen or C.sub.1-C.sub.6 alkyl; or R.sup.4 and R.sup.5 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 optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R'', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R.sup.6 is selected from trifluoromethyl, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR'SO.sub.2R'''', --SO.sub.2NR'R'', --C(O)R', --C(O)OR', --OC(O)R', --NR'C(O)OR'''', --NR'C(O)R'', --C(O)NR'R'', --SO.sub.2R'''', --NR'R', --NR'C(O)NR''R''', --NR'C(NCN)NR''R''', --OR', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R.sup.7 is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4, --C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3, --NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4, --SO.sub.2R.sup.6, --NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4, --OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; A is selected from --OR.sup.3 and --NR.sup.4OR.sup.3; R.sup.8 is selected from --SCF.sub.3, --Cl, --Br, --F, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --OR.sup.3, --C(O)R.sup.3, --C(O)OR.sup.3, --NR.sup.4C(O)OR.sup.6, --OC(O)R.sup.3, --NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4, --NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 cycloalkylalkyl, --S(O).sub.j(C.sub.1-C.sub.6 alkyl), --S(O).sub.j(CR.sup.4R.sup.5).sub.m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, --O(CR.sup.4R.sup.5).sub.m-aryl, --NR.sup.4(CR.sup.4R.sup.5).sub.m-aryl, --O(CR.sup.4R.sup.5).sub.m-heteroaryl, --NR.sup.4(CR.sup.4R.sup.5).sub.m-heteroaryl, --O(CR.sup.4R.sup.5).sub.m-heterocyclyl and --NR.sup.4(CR.sup.4R.sup.5).sub.m-heterocyclyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl portion is optionally substituted with one to five groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4, --C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3, --NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4, --OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 0, 1, 2, 3, 4 or 5; and j is 1 or 2. 2. A compound according to claim 1 which is ##STR00105## wherein: R.sup.7 is C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7 cycloalkylalkyl, C.sub.3-C.sub.7 heterocycloalkyl or C.sub.3-C.sub.7 heterocycloalkylalkyl, each of which can be optionally substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4, --C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3, --SO.sub.2R.sup.6, --NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4, --NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4, --OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R.sup.9 is hydrogen or halogen; R.sup.1 is C.sub.1-C.sub.10 alkyl or halogen; and R.sup.8 is --OCF.sub.3, --Cl, --Br, or --F. 3. A compound according to claim 2 wherein R.sup.9 is fluoro. 4. A compound according to claim 3 wherein R.sup.1 is methyl or chloro. 5. A compound according to claim 4 wherein R.sup.8 is chloro or bromo. 6. A compound according to claim 3 wherein R.sup.1 is methyl or fluoro. 7. A compound according to claim 6 wherein R.sup.8 is chloro or bromo. 8. A compound according to claim 2 wherein A is --NR.sup.4OR.sup.3. 9. A compound according to claim 1 wherein R.sup.7 is C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7 cycloalkylalkyl, C.sub.3-C.sub.7 heterocycloalkyl or C.sub.3-C.sub.7 heterocycloalkylalkyl, each of which can be optionally substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, --NR.sup.4SO.sub.2R.sup.6, --SO.sub.2NR.sup.3R.sup.4, --C(O)R.sup.3, --C(O)OR.sup.3, --OC(O)R.sup.3, --SO.sub.2R.sup.6, --NR.sup.4C(O)OR.sup.6, --NR.sup.4C(O)R.sup.3, --C(O)NR.sup.3R.sup.4,--NR.sup.3R.sup.4, --NR.sup.5C(O)NR.sup.3R.sup.4, --NR.sup.5C(NCN)NR.sup.3R.sup.4, --OR.sup.3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R.sup.8 is --OCF.sub.3, --Br or --Cl, R.sup.2 is hydrogen, and R.sup.1 is C.sub.1-C.sub.10 alkyl or halogen; R.sup.9 is hydrogen or halogen; and R.sup.10 is hydrogen. 10. A compound according to claim 9 wherein A is --NR.sup.4OR.sup.3. 11. A compound according to claim 1 which is selected from: ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130## and pharmaceutically acceptable salts thereof. 12. A compound according to claim 1 which is selected from: ##STR00131## and pharmaceutically acceptable salts thereof. 13. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 14. A composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier.