Claims for Patent: 8,193,229

Summary for Patent: 8,193,229

Title:	Method of treatment using N3 alkylated benzimidazole derivatives as MEK inhibitors
Abstract:	Disclosed are methods of treating a hyperproliferative disorder or a disease related to vasculogenesis or angiogenesis in a mammal, comprising administering to said mammal an effective amount of a compound of the formula or a pharmaceutically accepted salt thereof, wherein A, R1, R2, R7, R8, and R9 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.
Inventor(s):	Eli M. Wallace, Joseph P. Lyssikatos, Allison L. Marlow, T. Brian Hurley
Assignee:	AstraZeneca AB, Array Biopharma Inc
Application Number:	US12/824,521
Patent Claims:	1. A method of alleviating or inhibiting the progress of cancer in a mammal, wherein said cancer is lung cancer, squamous cell cancer, pancreatic cancer, breast cancer, head cancer, neck cancer, colorectal cancer or melanoma, said method comprising administering to said mammal in need thereof an effective amount of a compound of the formula or a pharmaceutically accepted salt thereof, wherein: R1, R2, and R9 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR3, —C(O)R3, —C(O)OR3, NR4C(O)OR6, —OC(O)R3, —NR4SO2R6, —SO2NR3R4, NR4C(O)R3, —C(O)NR3R4, —NR5C(O)NR3R4, —NR5C(NCN)NR3R4, —NR3R4, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, —S(O)j(C1-C6 alkyl), —S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylheterocyclylalkyl, —O(CR4R5)m-aryl, —NR4(CR4R5)m-aryl, —O(CR4R5)m-heteroaryl, —NR4(CR4R5)m-heteroaryl, —O(CR4R5)m-heterocyclyl and —NR4(CR4R5)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, —NR4SO2R6, —SO2NR3R4, —C(O)R3, —C(O)OR3, —OC(O)R3, —NR4C(O)OR6, —NR4C(O)R3, —C(O)NR3R4, —NR3R4, —NR5C(O)NR3R4, —NR5C(NCN)NR3R4, —OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R3 is selected from hydrogen, trifluoromethyl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 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′SO2R″″, —SO2NR′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″″, —SO2R′, —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, C1-C10 alkyl, C2-C10 alkenyl, aryl and arylalkyl; R″″ is selected from C1-C10 alkyl, C2-C10 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 R3 and R4 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′SO2R″″, —SO2NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)R″″, —NR′C(O)R″, —C(O)NR′R″, —SO2R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R4 and R5 independently represent hydrogen or C1-C6 alkyl; or R4 and R5 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′SO2R″″, —SO2NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO2R″″, —NR′R″, —NR′C(O)NR″R′″, —NR′C(NCN)NR′R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R6 is selected from trifluoromethyl, C1-C10 alkyl, C3-C10 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′SO2R″″, —SO2NR′R″, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″″, —NR′C(O)R″, —C(O)NR′R″, —SO2R″″, —NR′R′, —NR′C(O)NR″R′″, —NR′C(NCN)NR″R′″, —OR′, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R7 is selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 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, —NR4SO2R6, —SO2NR3R4, —C(O)R3, —C(O)OR3, —OC(O)R3, —NR4C(O)OR6, —NR4C(O)R3, —C(O)NR3R4, —SO2R6, —NR3R4, —NR5C(O)NR3R4, —NR5C(NCN)NR3R4, —OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; A is selected from —OR3 and —NR4OR3; R8 is selected from —SCF3, —Cl, —Br, —F, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR3, —C(O)R3, —C(O)OR3, —NR4C(O)OR6, —OC(O)R3, —NR4SO2R6, —SO2NR3R4, —NR4C(O)R3, —C(O)NR3R4, —NR5C(O)NR3R4, —NR3R4, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C1o cycloalkylalkyl, —S(O)j(C1-C6 alkyl), —S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR4R5)m-aryl, —NR4(CR4R5)m-aryl, —O(CR4R5)m-heteroaryl, —NR4(CR4R5)m-heteroaryl, —O(CR4R5)m-heterocyclyl and —NR4(CR4R5)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, —NR4SO2R6, —SO2NR3R4, —C(O)R3, —C(O)OR3, —OC(O)R3, —NR4C(O)OR6, —NR4C(O)R3, —C(O)NR3R4, —NR3R4, —NR5C(O)NR3R4, —NR5C(NCN)NR3R4, —OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; m is 0, 1, 2, 3, 4 or 5; and j is 1 or 2. 2. The method according to claim 1, wherein said compound has the formula wherein: R7 is C1-C10 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, C3-C7 heterocycloalkyl or C3-C7 heterocycloalkylalkyl, each of which can be optionally substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR4SO2R6, —SO2NR3R4, —C(O)R3, —C(O)OR3, —OC(O)R3, —SO2R6, —NR4C(O)OR6, —NR4C(O)R3, —C(O)NR3R4, —NR3R4, —NR5C(O)NR3R4, —NR5C(NCN)NR3R4, —OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R9 is hydrogen or halogen; R1 is C1-C10 alkyl or halogen; and R8 is —OCF3, —Cl, —Br, or —F. 3. The method according to claim 2 wherein R9 is fluoro. 4. The method according to claim 3 wherein R1 is methyl or chloro. 5. The method according to claim 4 wherein R8 is chloro or bromo. 6. The method according to claim 3, wherein R1 is methyl or fluoro. 7. The method according to claim 6, wherein R8 is chloro or bromo. 8. The method according to claim 2 wherein A is —NR4OR3. 9. The method according to claim 1 wherein R7 is C1-C10 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, C3-C7 heterocycloalkyl or C3-C7 heterocycloalkylalkyl, each of which can be optionally substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR4SO2R6, —SO2NR3R4, —C(O)R3, —C(O)OR3, —OC(O)R3, —SO2R6, —NR4C(O)OR6, —NR4C(O)R3, —C(O)NR3R4, —NR3R4, —NR5C(O)NR3R4, —NR5C(NCN)NR3R4, —OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R8 is —OCF3, —Br or —Cl, R2 is hydrogen, and R1 is C1-C10 alkyl or halogen; and R9 is hydrogen or halogen. 10. The method according to claim 9 wherein A is —NR4OR3. 11. The method according to claim 1, wherein said mammal is administered an effective amount of a compound selected from: 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide; 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2,3-dihydroxypropoxy)-amide; 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethylethoxy)-amide; 6-(2,4-Dichloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-(tetrahydropyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide; and 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-furan-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; and pharmaceutically acceptable salts thereof. 12. The method according to claim 1, wherein said mammal is administered an effective amount of a compound selected from 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide and pharmaceutically acceptable salts thereof. 13. The method according to claim 1, wherein said mammal is administered an effective amount of a compound of the formula or a pharmaceutically accepted salt thereof, wherein: R1 is C1-C10 alkyl or halogen; R2 is hydrogen; R8 is —OCF3, —Cl, —Br, or —F; R9 is hydrogen or halogen; R7 is C1-C10 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkylalkyl, C3-C7 heterocycloalkyl or C3-C7 heterocycloalkylalkyl, each of which can be optionally substituted with 1-3 groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR4SO2R6, —SO2NR3R4, —C(O)R3, —C(O)OR3, —OC(O)R3, —SO2R6, —NR4C(O)OR6, —NR4C(O)R3, —C(O)NR3R4, —NR3R4, —NR5C(O)NR3R4, —NR5C(NCN)NR3R4, —OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; and A is —NR4OR3. 14. The method according to claim 1, wherein said mammal is administered an effective amount of a compound selected from: and pharmaceutically acceptable salts thereof.