Combinations for the treatment of cancer

A method of treating cancer in a subject with an anti-EGFR antibody in combination with a VEGFR inhibitor selected from

• a) compounds of Formula I
• wherein R is selected from unsubstituted or substituted 9- or 10-membered fused nitrogen-containing heteroaryl,
• wherein R is substituted with one or more substituents selected from halo, amino, hydroxy, C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, optionally substituted heterocyclylalkoxy, C1-6-alkylamino-C24-alkynyl, C1-6-alkylamino-C1-6-alkoxy, C1-6-alkylamino-C1-6-alkoxy-C1-6-alkoxy, and optionally substituted heterocyclyl-C2-4-alkynyl;
• wherein R1 is selected from unsubstituted or substituted
• aryl,
• cycloalkyl,
• 5-6 membered heteroaryl and
• 9-10 membered bicyclic and 13-14 membered tricyclic heterocyclyl,
• wherein substituted R1 is substituted with one or more substituents selected from halo, C1-6-alkyl, optionally substituted C3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C1-C4-alkylenyl, C1-2-haloalkoxy, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C1-C4-alkyl, optionally substituted 4-6 membered heterocyclyl-C2-C4-alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-C1-4-alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 4-6 membered heterocyclyl-C1-4-alkylcarbonyl, C1-2-haloalkyl, C1-4-aminoalkyl, nitro, amino, hydroxy, cyano, aminosulfonyl, C1-2-alkylsulfonyl, halosulfonyl, C1-4-alkylcarbonyl, C1-3-alkylamino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkoxy, C1-3-alkylamino-C1-3-alkoxy-C1-3-alkoxy, C1-4-alkoxycarbonyl, C1-4-alkoxycarbonylamino-C1-4-alkyl, C1-4-hydroxyalkyl
• and C1-4-alkoxy;
• wherein R2 is one or more substituents independently selected from H, halo, hydroxy, amino, C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, C1-2-alkylamino, aminosulfonyl, C3-6-cycloalkyl, cyano, C1-2-hydroxyalkyl, nitro, C2-3-alkenyl, C2-3-alkynyl, C1-6-haloalkoxy, C1-6-carboxyalkyl, 4-6-membered heterocyclyl-C1-6-alkylamino, unsubstituted or substituted phenyl and unsubstituted or substituted 4-6 membered heterocyclyl;
• wherein R4 is selected from a direct bond, C1-4-alkyl, and
• and
• wherein Re and Rf are independently selected from H and C1-2-haloalkyl;
• and
• wherein R7 is selected from H, C1-3-alkyl, optionally substituted phenyl, optionally substituted phenyl-C1-3-alkyl, 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C1-C3-alkyl, C1-3-alkoxy-C1-2-alkyl and C1-3-alkoxy-C1-3-alkoxy-C1-3-alkyl;
• b) inhibitor of Formula II
• wherein R is selected from
• a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and
• b) unsubstituted or substituted 9- or 10-membered fused heteroaryl,
• where substituted R is substituted with one or more substituents selected from halo, amino, hydroxy, C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, optionally substituted heterocyclyl-C1-6-alkoxy, optionally substituted heterocyclyl-C1-6-alkylamino, optionally substituted heterocyclyl-C1-6-alkyl, C1-4-alkylamino-C2-4-alkynyl, C1-6-alkylamino-C1-6-alkoxy, C1-6-alkylamino-C1-6-alkoxy-C1-6-alkoxy, and optionally substituted heterocyclyl-C2-4-alkynyl;
• wherein R1 is a ring selected from unsubstituted or substituted
• 4-6 membered saturated or partially un-saturated monocyclic heterocyclyl,
• 9-10 membered saturated or partially un-saturated bicyclic heterocyclyl, and
• 13-14 membered saturated or partially un-saturated tricyclic heterocyclyl,
• wherein substituted R1 is substituted with one or more substituents selected from halo, C1-6-alkyl, optionally substituted C3-6-cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C1-C4-alkylenyl, C1-2-haloalkoxy, optionally substituted 4-6 membered heterocyclyl-C1-C4-alkyl, optionally substituted 4-6 membered heterocyclyl-C2-C4-alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-C1-C4-alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 5-6 membered heterocyclyl-C1-4-alkylcarbonyl, C1-2-haloalkyl, C1-4-aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl, C1-2-alkylsulfonyl, halosulfonyl, C1-4-alkylcarbonyl, C1-3-alkylamino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkoxy, C1-3-alkylamino-C1-3-alkoxy-C1-3-alkoxy, C1-4-alkoxycarbonyl, C1-4-alkoxycarbonylamino-C1-4-alkyl, C1-4-hydroxyalkyl
• and C1-4-alkoxy;
• wherein R2 is one or more substituents independently selected from H, halo, hydroxy, amino, C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, C1-2-alkylamino, aminosulfonyl, C3-6-cycloalkyl, cyano, C1-2-hydroxyalkyl, nitro, C2-3-alkenyl, C2-3-alkynyl, C1-6-haloalkoxy, C1-6-carboxyalkyl, 5-6-membered heterocyclyl-C1-6-alkylamino, unsubstituted or substituted phenyl and unsubstituted or substituted 5-6 membered heterocyclyl;
• wherein R4 is selected from a direct bond, C1-4-alkyl, and
• wherein Rz is selected from C1-2-alkyl, C2-4-branched alkyl, C2-4-branched haloalkyl, amino-C1-4-alkyl and C1-2-alkylamino-C1-2-alkyl;
• wherein Re and Rf are independently selected from H and C1-2-haloalkyl;
• and
• wherein R7 is selected from H, C1-3-alkyl, optionally substituted phenyl, optionally substituted phenyl-C1-3-alkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C1-C3-alkyl, C1-3-alkoxy-C1-2-alkyl and C1-3-alkoxy-C1-3-alkoxy-C1-3-alkyl;
• c) inhibitor of Formula IV
• wherein R is selected from
• a) unsubstituted or substituted 5- or 6-membered rings-selected from 4-pyridyl, 2-pyridyl, 4-pyrimidinyl, and tetrahydro-2H-pyran-4-yl, and
• b) unsubstituted or substituted 9- or 10-membered fused rings selected from 4-quinolyl, 6-quinolyl, 2,3-dihydro-5-benzofuryl, 5-benzoxazolyl, 1H-pyrrolo[2,3-b]pyridin-4-yl, and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl,
• where substituted R is substituted with one or more substituents selected from methylamino-, amino, methoxy, methylaminocarbonyl, morpholino, and trifluoromethoxy;
• wherein R1 is 4,4-dimethyl-3,4-dihydro-2-oxo-1H-quinolinyl;
• or wherein R1 is 4,4-dimethyl-1,2,3,4-tetrahydro-1H-quinolinyl;
• or wherein R1 is 4,4-dimethyl-3,4-dihydro-2-oxo-1H-[1,8]naphthyridinyl;
• or wherein R1 is 3,3-dimethyl-2,3-dihydro-1H-indolyl optionally substituted with a substituent selected from pyrrolidin-1-yl-carbonyl, methylcarbonyl, and methylsulfonyl;
• or wherein R1 is 4,4-dimethyl-1,2,3,4-tetrahydro-1H-isoquinolinyl;
• or wherein R1 is 2-oxo-3,3-bis(trifluoromethyl)-2,3-dihydro-1H-indol-6-yl;
• or wherein R1 is 1′,2′-dihydro-spiro[cyclopropane-1,3′-[3H]indol]-6′-yl;
• and
• wherein R2 is H;
• and pharmaceutically acceptable isomers and derivatives thereof.