Combination Products with Tyrosine Kinase Inhibitors and their Use

Abstract

The present invention relates to pharmaceutical products comprising a combination of (i) a MET inhibitor and (ii) an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, respectively, or a prodrug thereof, which are jointly active in the treatment of proliferative diseases, corresponding pharmaceutical formulations, uses, methods, processes commercial packages and related invention embodiments.

1 . A pharmaceutical combination comprising (i) a MET tyrosine kinase inhibitor and (ii) an EGFR tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, respectively, or a prodrug thereof, respectively, and at least one pharmaceutically acceptable carrier. 
     
     
         2 . The pharmaceutical combination according to  claim 1  for simultaneous, separate or sequential use of the components (i) and (ii). 
     
     
         3 . The pharmaceutical combination according to  claim 1  in the form of a fixed combination. 
     
     
         4 . The pharmaceutical combination according to  claim 1  in the form or a kit of parts for the combined administration where the EGFR tyrosine kinase inhibitor and the MET tyrosine kinase inhibitor may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners are jointly active. 
     
     
         5 . The pharmaceutical combination according to  claim 1 ,
 wherein the EGFR tyrosine kinase inhibitor is selected from the following compounds, or pharmaceutically acceptable salts or prodrugs thereof:   a 4-(substituted phenylamino)quinazoline derivative of the formula   
       
         
           
           
               
               
           
         
         wherein each Ra, Rb, Rc and Rd is independently selected from hydrogen, halo, hydroxy, amino, 
         hydroxyamino, carboxy, C 1-4 alkoxycarbonyl, nitro, guanidino, ureido, carbamoyl, cyano, trifluoromethyl, (R 6 ) 2 N-carbonyl and phenyl-W-alkyl wherein W is selected from a single bond, O, S and NH; 
         or each Ra or Rb is independently selected from cyano-C 1-8 alkyl and R9 wherein R9 is selected from the group consisting of R5, R5O, (R5) 2 N, R7C(═O), R5ONH, A and R5Y; wherein 
         R5 is C 1-8 alkyl; 
         R6 is hydrogen or R5 wherein the R5s if more than one is present are the same or different; 
         R7 is R5, R5O or (R6) 2 N; 
         A is selected from piperidino, morpholino, pyrrolidino and 4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, carboxy-C 1-8 alkyl, phenoxy, phenyl, phenylsultfanyl, C 2-8 alkenyl, (R5) 2 N-carbonyl-C 1-5 alkyl; and 
         Y is selected from S, SO, SO 2 ; the alkyl moieties in R5, R5O and (R5) 2 N are optionally substituted with halo or R9 wherein R9 is defined as above, and wherein the resulting groups are optionally substituted with halo or R9 with the proviso that a nitrogen, oxygen or sulfur atom and another heteroatom can not be attached to the same carbon atom, and with the further proviso that Ra and Rb may not comprise more than three R9 units; 
         or each Ra or Rb is independently selected from R5-sulfonylamino, phthalimido-C 1-8 alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10-C 2-4 alkanoylamino wherein R10 is selected from halo, R5O, C 2-4 alkanoyloxy, B7C(═O) and (R6) 2 N; and wherein said benzamido or benzenesulfonylamino or phenyl or phenoxy or anilino or phenylsulfanyl substituent in Ra or Rb may optionally bear one or two halogens, C 1-8 alkyl, cyano, methansufonyl or C 1-8 alkoxy substituents; 
         or any two Ra and Rb taken together with the carbons to which they are attached comprise a 5-8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the alkyl groups and alkyl portions of the alkoxy or alkylamino groups may be straight chained or if comprised of at least three carbons may be branched or cyclic; each Rc and Rd is independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted amino, halo, hydroxy, optionally substituted hydroxy; or from azido or R11-ethynyl wherein R11 is selected from hydrogen, optionally substituted C 1-8 alkyl wherein the substituents are selected from hydrogen, amino, hydroxy, R5O, R5NH and (R5) 2 N; and X is N or C(CN), with the proviso that a substituent R5 may not comprise another substitutent R5; 
         a 4-(substituted phenylamino)quinazoline derivative of the formula 
       
       
         
           
           
               
               
           
         
         wherein 
         X is N; 
         Ra is C 1-8 alkyloxy; 
         Rb is di-(C 1-8 alkyl)-amino-C 1-8 alkoxy, pyrrolidin-1-yl-C 1-8 alkoxy, piperidino-C 1-8 alkoxy, morpholino-C 1-8 alkoxy, piperazin-1-yl-C 1-8 alkoxy, 4-C 1-8 alkylpiperazin-1-yl-C 1-8 alkoxy, imidazol-1-yl-C 1-8 alkoxy, di-(C 1-8 alkoxy-C 1-8 alkyl)-amino-C 1-8 alkoxy, thiomorpholino-C 1-8 alkoxy, 1-oxothiomorpholino-C 1-8 alkoxy or 1,1-dioxothiomorpholino-C 1-8 alkoxy, and wherein any of the above-mentioned Rb substituents comprising a CH 2  (methylene) group which is not attached to a N or O atom optionally bears on said CH 2  group a hydroxy substituent; 
         and each of Rc and Rd is independently of the other halo, trifluoromethyl or C 1-8 alkyl; a 4-(substituted phenylamino)quinazoline derivative of the formula 
       
       
         
           
           
               
               
           
         
         wherein X is N; 
         one of Ra and Rb is a group CH 3 SO 2 CH 2 CH 2 NHCH 2 —Ar—, wherein Ar is selected from phenyl, furanyl, thiophenyl, pyrrolyl and thiazolyl, each of which may optionally be substituted by one or two substituents selected from the group consisting of one or two halo, C 1-8 alkyl and C 1-8 alkoxy; the other of Ra and Rb is selected from the group consisting of hydrogen, halo, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino and di(C 1-8 alkyl)amino; 
         one of Rc and Rd represents benzyl, halo-, dihalo- or trihalobenzyl, trihalomethylbenzyl, benzoyl, pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- or trihalobenzyloxy, trihalomethylbenzyloxy, benzenesulphonyl or hydrogen; 
         the other of Rc and Rd is hydrogen or hydroxy, halo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, amino, C 1-8 alkylamino, di(C 1-8 alkyl)amino, C 1-8 alkylthio, C 1-8 alkylsulphinyl, C 1-8 alkylsulphonyl, C 1-8 alkylcarbonyl, carboxyl, carbamoyl, C 1-8 alkoxycarbonyl, C 1-8 alkanoylamino, N—(C 1-8 alkyl)carbamoyl, N,N-di(C 1-8 alkyl)carbamoyl, cyano, nitro or trifluoromethyl; 
         a 4-(substituted phenylamino)quinazoline derivative of the formula 
       
       
         
           
           
               
               
           
         
         wherein 
         X is N, 
         Ra is -D-E-F and Rb is —SR 4* , halo, —OR 4* , —NHR 3*  or hydrogen, or 
         Rb is -D-E-F and Ra is —SR 4* , halo, —OR 4* , —NHR 3*  or hydrogen, 
         wherein, respectively, 
         D is —N(R 2* )—, —O—, —CH(R 2* )—, —N(R 2* )—NH—, —N(R 2* )—O—, —CH(R 2* )—NH—, —CH(R 2* )—O—, —CH(R 2* )—CH 2 —, —NH—CH(R 2* )—, —O—CH(R 2* )—, —S—CH(R 2* )— or absent; 
         E is —C(═O)—, —S(═O) 2 —, —P(═O)(OR 2* )— or —S(═O)—, 
         F is —C(R 1* )—CHR 5* , —C≡C—R 5* , or —C(R 1* )═C═CHR 5* ; 
         provided that when E is S(═O) 2 — or —S(═O)—, D is not —NH—CH(R 2* )— or —O—CH(R 2* )—; 
         R 1*  is hydrogen, halogen or C 1-8 alkyl, 
         R 2* , R 3*  and R 4*  are independently hydrogen, C 1-8 alkyl, —(CH 2 ) n —N-piperidinyl, —(CH 2 ) n* —N-piperazinyl, —(CH 2 ) n* —N 1 -piperazinyl(N 4 —C 1-6 alkyl), —(CH 2 ) n* —N-pyrrolidinyl, —(CH 2 ) n* —N-pyridinyl, —(CH 2 ) n* —N-imidazolyl, —(CH 2 ) n* —N-morpholinyl, —(CH 2 ) n* —N-thiomorpholinyl, —(CH 2 ) n* —N-hexohydroazepinyl or substituted C 1-8 alkyl, wherein the substituents are selected from —OH, —NH 2 , or —N(B*)(A*), wherein A* and B* are independently hydrogen, C 1-8 alkyl, —(CH 2 ) n* —OH, —(CH 2 ) n* —N-piperidinyl, —(CH 2 ) n* —N-piperazinyl, —(CH 2 ) n* —N-piperazinyl(N 4 —C 1-8 alkyl), —(CH 2 ) n* —N-pyrrolidinyl, —(CH 2 )-pyridyl and —(CH 2 ) n* —N-imidazolyl; 
         Rc and Rd are independently hydrogen, halo, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 3-8 cycloalkoxy, nitro, C 1-8 perfluoroalkyl, hydroxy, C 1-8 acyloxy, amino, —NH(C 1-8 alkyl), —N(C 1-8 alkyl) 2 , —NH(C 3-8 cycloalkyl), —NH(C 3-8 cycloalkyl) 2 , hydroxymethyl, C 1-8 acyl, cyano, azido, C 1-8 thioalkyl, C 1-8 sulfinylalkyl, C 1-8 sulfonylalkyl, C 3-8 thiocycloalkyl, C 3-8 sulfinylcycloalkyl, C 3-8 sulfonylcycloalkyl, mercapto, C 1-8 alkoxycarbonyl, C 3-8 cycloalkoxycarbonyl, C 2-8 alkenyl, C 4-8 cycloalkenyl, or C 2-8 alkynyl; 
         R 5*  is hydrogen, halo, C 1-6 perfluoroalkyl, 1,1-difluoro-C 1-6 alkyl, C 1-6 alkyl, —(CH 2 ) n* —N-piperidinyl, —(CH 2 ) n* —N-piperazinyl, —(CH 2 ) n* —N 1 -piperazinyl(N 4 —C 1-8 alkyl), —(CH 2 ) n* —N-pyrrolidinyl, —(CH 2 ) n* —N-pyridyl, —(CH 2 ) n* —N-imidazolyl, —(CH 2 ) n* —N-morpholinyl, —(CH 2 ) n* —N-thiomorpholinyl, —CH═CH 2 , —CH═CH—C 1-8 alkyl, —(CH 2 ) n* —N-hexahydroazepinyl, —(CH 2 ) n* —NH 2 , —(CH 2 ) n* —NH—(C 1-8 )alkyl, —(CH 2 ) n* —N(C 1-8 alkyl) 2 , -1-oxo-C 1-8 alkyl, carboxy, C 1-8 alkoxycarbonyl, N—C 1-8 alkyl-carbamoyl, phenyl or substituted phenyl, wherein the phenyl can have from one to three substituents independently selected from Rc and Rd or a monocyclic heteroaryl group selected from the group consisting of pyridyl, thienyl and imidazolyl, and each C 1-8 alkyl group above in R 5*  can be substituted with —OH, —NH 2  or NA*B*, where A* and B* are as defined above; 
         R 6*  is hydrogen or C 1-8 alkyl; 
         and n* is 1 to 8, especially 1 to 4; 
         a 4-(substituted phenylamino)quinazoline derivative of the formula 
       
       
         
           
           
               
               
           
         
         wherein X is C—CN; 
         Ra is C 1-8 alkoxy; 
         Rb is amino- or N—[N′-mono- or N′,N′-di(C 1-8 alkyl)]amino)-C 1-8 alkenoyl)-amino; 
         Rc is halo or R 2 **—(CH 2 ) n* —R 3 **— 
         wherein R 2 ** is a pyridyl, thiophenyl, pyrimidinyl, thiazolyl or phenyl, each optionally substituted with up to three substituents selected from C 1-8 alkyl, C 1-8 alkoxy and halogen, R 3 ** is —O— or —S— and n** is 0 to 8, preferably 0 or 1; 
         and Rd is halo; 
         or a pharmaceutically acceptable salt or prodrug thereof; 
         and an antibody inhibiting EGFR; 
         and the MET tyrosine kinase inhibitor is one of the formula (I), 
       
       
         
           
           
               
               
           
         
         wherein 
         Y is C or N; 
         X is CH or N; 
         B is CH or N; 
         A is a ring; 
         such that when X is CH and B is N, ring A is ring Ai or ring Aii; 
       
       
         
           
           
               
               
           
         
         when X is N and B Is N, ring A is Aiii; 
       
       
         
           
           
               
               
           
         
         and when X is N and B is N, or X is N and B is CH, ring A is Ai; 
       
       
         
           
           
               
               
           
         
         R 1  is a group selected from i, ii and iii: 
       
       
         
           
           
               
               
           
         
         wherein R 5  is heteroaryl; 
         R 6  is hydrogen, deuterium, OH, methyl or halo; 
         R 7  is hydrogen, deuterium, halo, or (C 1 -C 3 )alkyl, wherein said (C 1 -C 3 )alkyl is optionally substituted by one or more substituents independently selected from OH and halo; 
         or R 6  and R 7 , together with the carbon to which they are attached form cyclopropyl, wherein said cyclopropyl is optionally substituted by methyl; 
         n is 0, 1 or 2; 
         R 2  is hydrogen, NH 2 , or (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is optionally substituted by one or more substituents independently selected from OH, NH 2  and halo; 
         R 3  is hydrogen, —CONH 2 , —CONH(C 1 -C 4 )alkyl, —CONHphenyl, wherein the phenyl of said CONHphenyl is optionally substituted by one or more halo, —(C 1 -C 4 )alkyl, —CO(C 1 -C 4 )alkyl, —CO 2 (C 1 -C 4 )alkyl, phenyl, heteroaryl, —COheteroaryl, —CSNH 2 , —CSNH(C 1 -C 4 )alkyl, —CSNHbenzyl, —SO 2 (C 1 -C 4 )alkyl or —COCH 2 heterocyclyl, said heterocyclyl being optionally substituted by (C 1 -C 3 )alkyl; 
         R 4  is hydrogen or (C 1 -C 3 )alkyl; 
         or R 3  and R 4  together with the nitrogen to which they are attached form a 5 or 6 membered saturated or partially unsaturated monocyclic group comprising 1 ring N atom to which R 3  and R 4  are attached and optionally 1 additional ring heteroatom independently selected from N, O and S, wherein said monocyclic group is substituted by one or two ═O substituents; 
         or a pharmaceutically acceptable salt or prodrug cerivative thereof; 
         or is a MET tyrosine kinase inhibitor of the formula III: 
       
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof or prodrugs thereof, wherein:
 A is N or CR 3 ; 
 Cy 1  is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 —W—X—Y—Z; 
 Cy 2  is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z; 
 L 1  is (CR 4 R 5 ) q , (CR 4 R 5 ) p -(cycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(arylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heterocycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heteroarylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p O(CR 4 R 5 ) q , (CR 4 R 5 ) p S(CR 4 R 5 ) q , (CR 4 R 5 ) p C(O)(CR 4 R 5 ) q , (CR 4 R 5 ) p C(O)NR 6 (CR 4 R 5 ) q , (CR 4 R 5 ) p C(O)O(CR 4 R 5 ) q , (CR 4 R 5 ) p OC(O)(CR 4 R 5 ) q , (CR 4 R 5 ) p OC(O)NR(CR 4 R 5 ) q , (CR 4 R 5 ) p NR(CR 4 R 5 ) q , (CR 4 R 5 ) p NR 6 C(O)NR 6 (CR 4 R 5 ) q , (CR 4 R 5 ) p S(O)(CR 4 R 5 ) q , (CR 4 R 5 ) p S(O)NR(CR 4 R 5 ) q , (CR 4 R 5 ) p S(O) 2 (CR 4 R 5 ) q , or (CR 4 R 5 ) p S(O) 2 NR(CR 4 R 5 ) q , wherein said cycloalkylene, arylene, heterocycloalkylene, or heteroarylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR d , C(═NR)NR c R d , NR c C(═NR g )NR c R d , P(R f ), P(OR e ), P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d ; 
 
         L 2  is (CR 7 R 8 ) t , (CR 7 R 8 ) s -(cycloalkylene)(CR 7 R 8 ) t , (CR 7 R 8 ) s -(arylene)-(CR 7 R 8 ) t , (CR 7 R 8 ) s -(heterocycloalkylene)-(CR 7 R 8 ) t , (CR 7 R 8 ) s -(heteroarylene)-(CR 7 R 8 ) t , (CR 7 R 8 ) s O((CR 7 R 8 ) t , (CR 7 R 8 ) s S(CR 7 R 8 ) t , (CR 7 R 8 ) s C(O)(CR 7 R 8 ) t , (CR 7 R 8 ) s C(O)NR 9 (CR 7 R 8 ) t , (CR 7 R 8 ) s C(O)O(CR 7 R 8 ) t , (CR 7 R 8 ) s OC(O)(CR 7 R 8 ) t , (CR 7 R 8 ) s OC(O)NR(CR 7 R 8 ) t , (CR 7 R 8 ) s NR 9 (CR 7 R 8 ) t , (CR 7 R 8 ) s NR 9 C(O)NR(CR 7 R 8 ) t , (CR 7 R 8 ) s S(O)(CR 7 R 8 ) t , (CR 7 R 8 ) s S(O)NR 9 (CR 7 R 8 ) t , (CR 7 R 8 ) s S(O) 2 (CR 7 R 8 ) t , or (CR 7 R 8 ) s S(O) 2 NR(CR 7 R 8 ) t , wherein said cycloalkylene, arylene, heterocycloalkylene, or heteroarylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR g )NR c1 R d1 , NR c1 C(═NR g )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; 
         R 1  is H or —W″—X″—Y″—Z″; 
         R 2  is H, halo, C 1-5  alkyl, C 2-5  alkenyl, C 2-5  alkynyl, C 1-6  haloalkyl, CN, NO 2 , OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , S(O)R B , S(O)NR C R D , S(O) 2 R B , NR C S(O) 2 R B , or S(O) 2 NR C R D ; 
         R 3  is H, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, CN, NO 2 , OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , S(O)R B , S(O)NR C R D , S(O) 2 R B , NR C S(O) 2 R B , and S(O) 2 NR C R D : wherein said cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or C 1-6  alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 5 , halo, C 1-8  alkyl, C 2-8  alkenyl, C 2-8 , alkynyl, C 1-8 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR 9 )NR c1 R d1 , NR c1 C(═NR 9 )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; 
         or R 2  and -L 2 -Cy 2  are linked together to form a group of formula: 
       
       
         
           
           
               
               
           
         
       
       wherein ring B is a fused aryl or fused heteroaryl ring, each optionally substituted with 1, 2, or 3 —W′—X′—Y′—Z′;
 R 4  and R 5  are independently selected from H, halo, OH, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C 1-6  haloalkyl, CN, and NO 2 ; 
 or R 4  and R 5  together with the C atom to which they are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C 1-6  haloalkyl, CN, and NO 2 ; 
 R 6  is H, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl; 
 R 7  and R 4  are independently selected from H, halo, OH, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  haloalkyl, CN, and NO 2 ; 
 or R 7  and R 8  together with the C atom to which they are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituent independently selected from halo, OH, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, C 1-6  haloalkyl, CN, and NO 2 ; 
 R 9  is H, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl; 
 W, W′, and W″ are independently absent or independently selected from C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, O, S, NR h , CO, COO, CONR h , SO, SO 2 , SONR h  and NR h CONR i , wherein each of the C 1-6  alkylene, C 2-6  alkenylene, and C 2-6  alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-6  alkyl, C 1-6  haloalkyl, OH, C 1-6  alkoxy, C 1-6  haloalkoxy, amino, C 1-6  alkylamino, and C 2-6  dialkylamino; 
 X, X′, and X″ are independently absent or independently selected from C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkoxyalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 2-6  alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR i , C(O)NR h R i , amino, C 1-6  alkylamino, and C 2-6  dialkylamino; 
 Y, Y′, and Y″ are independently absent or independently selected from C 1-6  alkylene, C 2-6  alkenylene, C 2-6  alkynylene, O, S, NR h , CO, COO, CONR h , SO, SO 2 , SONR h , and NR h CONR i , wherein each of the C 1-6  alkylene, C 2-6  alkenylene, and C 2-6  alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6  haloalkyl, OH, C 1-6  alkoxy, C 1-6  haloalkoxy, amino, C 1-6  alkylamino, and C 2-6  dialkylamino; 
 Z, Z′, and Z″ are independently selected from H, halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R d2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR)NR c2 R d2 , NR c2 C(═NR g )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , S(O) 2 NR c2 R d2 , aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR g )NR c2 R d2 , NR c2 C(═NR g )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; 
 wherein two adjacent —W—X—Y—Z, together with the atoms to which they are attached, optionally form a fused 4-20 membered cycloalkyl ring or a fused 4-20 membered heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, halosulfanyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR g )NR c3 R d3 , NR c3 C(═NR g )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , S(O) 2 NR c3 R d3 , aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; 
 wherein two adjacent —W′—X′—Y′—Z′, together with the atoms to which they are attached, optionally form a fused 4-20 membered cycloalkyl ring or a fused 4-20 membered heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, halosulfanyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR g )NR c3 R d3 , NR c3 C(═NR g )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , S(O) 2 NR c3 R d3 , aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; 
 Cy 3 , Cy 4 , and Cy 5  are independently selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR g )NR c4 R d4 , NR c4 C(═NR g )NR c4 R d4 , P(R f4 ) 2 , P(OR 4 ) 2 , P(O)R e4 R f4 , P(O)OR e4 OR f4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , and S(O) 2 NR c4 R d4 ; 
 R A  is H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4  alkyl: 
 R B  is H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said C 1-4  alkyl, C 2-4  alkenyl, or C 2-4  alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4  alkyl; 
 R C  and R D  are independently selected from H, C 1-4  alkyl, C 2-4  alkenyl, or C 2-4  alkynyl, wherein said C 1-4  alkyl, C 2-4  alkenyl, or C 2-4  alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4  alkyl; 
 or R C  and R D  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4  alkyl; 
 R a , R a1 , R a2 , R a3 , and R a4  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 R b , R b1 , R b2 , R b3 , and R b4  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloakcylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 R c  and R d  are independently selected from H, C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 or R c  and R d  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 R c1  and R d1  are independently selected from H, C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 or R c1  and R d1  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 R c2  and R d2  are independently selected from H, C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl, wherein said C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, aryheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C(O)OR a4 , C(O)R b4 , S(O) 2 R b3 , alkoxyalkyl, and alkoxyalkoxy; 
 or R c2  and R d2  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C(O)OR a4 , C(O)R b4 , S(O) 2 R b3 , alkoxyalkyl, and alkoxyalkoxy; 
 R c3  and R d3  are independently selected from H, C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 or R c3  and R d3  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 R c4  and R d4  are independently selected from H, C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 or R c4  and R d4  together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, and C 1-6  haloalkoxy; 
 R e , R e1 , R e2 , and R e4  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, (C 1-6  alkoxy)-C 1-6  alkyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl; 
 R f , R f1 , R f2 , and R f4  are independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; 
 R g  is H, CN, and NO 2 ; 
 R h  and R i  are independently selected from H and C 1-6  alkyl; 
 R j  is H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl; 
 m is 0, 1, 2, 3, 4, 5, or 6; 
 p is 0, 1, 2, 3, or 4; 
 q is 0, 2, 3, or 4; 
 r is 0, 1, 2, 3, 4, 5, or 6; 
 s is 0, 1, 2, 3, or 4; and 
 t is 0, 1, 2, 3, or 4. 
 
     
     
         6 . A pharmaceutical combination according to  claim 5 , wherein the EGFR tyrosine kinase inhibitor is a compound of the formula 
       
         
           
           
               
               
           
         
         wherein 
         X is N or C(CN); 
         Ra is selected from the group consisting of C 1-8 alkyloxy or (C 1-8 alkyloxy, 1-piperidin-1-yl, 1-piperazin-1-yl, 4-C 1-8 alkyl-piperazin-1-yl, morpholin-1-yl, thiomorpholino-1-yl, S-oxothiomorpholin-1-yl or S,S-dioxothiomorpholinyl-1-yl)-C 1-8 alkyloxy; 
         Rb is selected from C 3-8 alkenoyl, {amino- or N—[N′-mono- or N′,N′-di(C 1-8 alkyl)]amino}-C 4-8 alkenoyl)-amino, [(C 1-8 alkylsulfonyl-C 1-8 alkylamino)-C 1-8 alkyl]-fury or (C 1-8 alkyloxy, 1-piperidin-1-yl, 1-piperazin-1-yl, 4-C 1-8 alkyl-piperazin-1-yl, morpholin-1-yl, thiomorpholin-1-yl, S-oxothiomorpholin-1-yl or S,S-dioxothiomorpholinyl-1-yl)-C 1-8 alkyloxy; 
         Rc is halo or C 2-8 alkynyl; and 
         Rd is hydrogen, pyridinyl-C 1-8 alkyloxy or unsubstituted or halogen substituted phenyl-C 1-8 alkyloxy; 
         especially wherein: 
         X is N or C(CN); 
         Ra is methoxy, ethoxy, 3-morpholinopropyloxy or 2-methoxyethoxy; 
         Rb is 4-(dimethylamino)-but-2-enoylamino, prop-2-enoylamino, 5-((2-methylsulfonyl-ethyl)-aminomethyl)-furan-2-yl, 2-methoxyethoxy or 3-morpholinopropoxy; 
         Rc is chloro or ethynyl; and 
         Rd is hydrogen, fluoro, pyridin-2-ylmethoxy or 3-fluorophenyl-methoxy; 
         or a pharmaceutically acceptable salt or prodrug thereof, respectively. 
       
     
     
         7 . A pharmaceutical according to any one of  claims 1  to  6 , wherein the EGFR tyrosine kinase inhibitor is erlotinib, gefitinib, lapatinib, canertinib, pelitinib, neratinib or cetuximab; and wherein the MET inhibitor is (E)-2-(1-(3-((7-fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethylidene)hydrazinecarboxamide or 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide; or a pharmaceutically acceptable salt or prodrug thereof, respectively. 
     
     
         8 . The combination according to  claim 1 , comprising a further co-agent, or a pharmaceutically acceptable salt or a prodrug thereof. 
     
     
         9 . The combination according to  claim 1  comprising a quantity which is jointly therapeutically effective against an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, comprising the combination partners (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibitor, or, respectively, a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier material, and optionally a further co-agent or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The combination according to  claim 1  in the form of a combination product. 
     
     
         11 . A MET inhibitor and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for combined use in a method of treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer. 
     
     
         12 . The MET inhibitor and the EGFR inhibitor for use according to  claim 11 , where the MET tyrosine kinase inhibitor is selected from the group consisting of (E)-2-(1-(3-((7-fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethylidene)hydrazinecarboxamide and 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide, or a pharmaceutically acceptable salt or prodrug thereof, respectively,
 and the EGFR inhibitor is gefinitib, or a pharmaceutically acceptable salt or prodrug thereof.   
     
     
         13 . The use of a combination or combination product according to  claim 1  for treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer. 
     
     
         14 . A combination of (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor or, respectively, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament or a pharmaceutical product, especially a combination or combination product according to  claim 1 , for treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer. 
     
     
         15 . A method of treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, with a combination of (i) an EGFR tyrosine kinase inhibitor and (it) a MET tyrosine kinase inhibitor or, respectively, a pharmaceutically acceptable salt thereof, where the combination partners are defined in  claim 1 . 
     
     
         16 . A method for the treatment of an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, said method comprising administering an effective amount of a combination of or a combination product according to  claim 1  comprising (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor to a subject in need thereof, such as a warm-blooded animal, in particular a human. 
     
     
         17 . A pharmaceutical product or a commercial package comprising a combination or combination product according to  claim 1 , in particular together with instructions for simultaneous, separate or sequential use thereof in the treatment of an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, in particular for use in the treatment of an FGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer. 
     
     
         18 . The use of (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor or, respectively, a pharmaceutically acceptable salt thereof, for the preparation of a combination or combination product, especially according to  claim 1 , for the treatment of an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer. 
     
     
         19 . A pharmaceutical combination according to  claim 1  for use as a medicine. 
     
     
         20 . A pharmaceutical combination according to  claim 1  for use in the treatment of cancer. 
     
     
         21 . A MET inhibitor and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for combined use as a medicine.