Combinations Comprising Heterocyclic Inhibitors of MEK and Methods of Use Thereof

Abstract

Disclosed are combinations comprising (a) a compound of the Formula: wherein R 1 , R 2 , R 7 , R 8 , R 9 and W are as defined in the specification, and (b) at least one additional therapeutic agent. Such combinations are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, and inflammatory conditions in mammals. Also disclosed are methods of using such combinations in the treatment of hyperproliferative diseases and inflammatory conditions in mammals.

1 . A combination comprising:
 (a) a compound having the formula:   
       
         
           
           
               
               
           
         
         including tautomers, resolved enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein: 
         R 1 , R 2 , and R 9  are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —SR 11 , —OR 3 , —C(O)R 3 , —C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 SO 2 R 6 , —SO 2 NR 3 R 4 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, C 4 -C 10  cycloalkylalkyl, —S(O) j (C 1 -C 6  alkyl), —S(O) j (CR 4 R 5 ) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR 4 R 5 ) m -aryl, —NR 4 (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -heteroaryl, —NR 4 (CR 4 R 5 ) m -heteroaryl, —O(CR 4 R 5 ) m -heterocyclyl or —NR 4 (CR 4 R 5 ) m -heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted independently with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 4 SO 2 R 6 , —SO 2 NR 3 R 4 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 C(O)OR 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —OR 3 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionally substituted independently with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, NR 3 R 4  and OR 3 ; 
         R 7  is hydrogen or C 1 -C 10  alkyl, wherein said alkyl is optionally substituted independently with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionally substituted independently with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, NR 11 R 12  and OR 11 ; 
         R 8  is Br, I or SR 11 ; 
         R 3  is hydrogen, trifluoromethyl, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, C 4 -C 10  cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted independently with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl heterocyclyl, and heterocyclylalkyl, 
         or R 3  and R 4  together with the atom to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryl and heterocyclic rings are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; 
         R 4  and R 5  independently are hydrogen or C 1 -C 6  alkyl, or 
         R 4  and R 5  together with the atom to which they are attached form a 4 to 10 membered carbocyclic ring, wherein said alkyl and carbocyclic ring are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; 
         R 6  is trifluoromethyl, C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted independently with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; 
         R 11 , R 12  and R 13  independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R 14  is lower alkyl, lower alkenyl, aryl or arylalkyl, 
         or any two of R 11 , R 12 , R 13  and R 14  together with the atom to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring and heterocyclic ring are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; 
         W is heteroaryl, heterocyclyl, —C(O)OR 3 , —C(O)NR 4 OR 3 , —C(O)NR 4 SO 2 R 3 , —C(O)(C 3 -C 10  cycloalkyl), —C(O)(C 1 -C 10  alkyl), —C(O)(heterocyclyl) or CR 3 R 4 OR 3 , wherein any of said cycloalkyl, alkyl, heteroaryl and heterocyclyl portions are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, azido, —NR 3 R 4 , —OR 3 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, cycloalkyl and heterocycloalkyl, 
         provided that when W is C(O)OR 3  and R 9  is F, R 7  cannot be H; 
         m is 0, 1, 2, 3, 4 or 5; and
 j is 0, 1 or 2; and 
 (b) at least one additional therapeutic agent. 
 
       
     
     
         2 . The combination of  claim 1 , wherein R 9  is hydrogen, halogen, cyano, amino, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or anilino. 
     
     
         3 . The combination of  claim 1 , wherein W is selected from heteroaryl, —C(O)OR 3, —C(O)NR 4 OR 3  and —C(O)NR 4 S(O) 2 R 3 , wherein said heteroaryl is optionally substituted independently with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, amino, aminomethyl, dimethylamino, aminoethyl, diethylamino, ethoxy, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 6  cycloalkyl and C 3 -C 6  heterocycloalkyl. 
     
     
         4 . The combination of  claim 1 , wherein R 9  is hydrogen, halogen, cyano, amino, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or anilino. 
     
     
         5 . The combination of  claim 1 , wherein the at least one additional therapeutic agent is an anti-tumor agent. 
     
     
         6 . The combination of  claim 5 , wherein the anti-tumor agent is selected from the group consisting of antiproliferative/antineoplastic drugs, cytostatic agents, agents which inhibit cancer invasion, inhibitors of growth factor function, antiangiogenic agents, vascular damaging agents, antisense therapies, gene therapy, interferon, and immunotherapy approaches. 
     
     
         7 . The combination of  claim 5 , wherein the anti-tumor agent is selected from the group consisting of alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents, topoisomerase inhibitors, antiestrogens, estrogen receptor down regulators, antiandrogens, LHRH antagonists or agonists, progestogens, inhibitors of 5α reductase, metalloproteinase inhibitors, inhibitors of urokinase plasminogne activator receptor function, trastuzumab, cetuximab, farnesyl transferase inhibitors, tyrosine kinase inhibitors, serine-threonine kinase inhibitors, inhibitors of the platelet-derived growth factor family and inhibitors of the hepatocyte growth factor family; bevacizumab, linomide, inhibitors of integrin αvβ3 function, MMP inhibitors, COX-2 inhibitors, angiostatin, Combretastatin A4, ISIS 2503, anti-ras antisense, GVAX™, and cytokines. 
     
     
         8 . The combination of  claim 5 , wherein the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. 
     
     
         9 . A method for the treatment of a hyperproliferative disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         including tautomers, resolved enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, wherein: 
         R 1 , R 2 , and R 9  are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —SR 11 , —OR 3 , —C(O)R 3 , —C(O)OR 3 , —NR 4 C(O)OR 6 , —OC(O)R 3 , —NR 4 SO 2 R 6 , —SO 2 NR 3 R 4 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —NR 3 R 4 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, C 4 -C 10  cycloalkylalkyl, —S(O) j (C 1 -C 6  alkyl), —S(O) j (CR 4 R 5 ) m -aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —O(CR 4 R 5 ) m -aryl, —NR 4 (CR 4 R 5 ) m -aryl, —O(CR 4 R 5 ) m -heteroaryl, —NR 4 (CR 4 R 5 ) m -heteroaryl, —O(CR 4 R 5 ) m -heterocyclyl or —NR 4 (CR 4 R 5 ) m -heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted independently with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 4 SO 2 R 6 , —SO 2 NR 3 R 4 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —NR 4 C(O)OR 6 , —NR 4 C(O)R 3 , —C(O)NR 3 R 4 , —NR 3 R 4 , —NR 5 C(O)NR 3 R 4 , —NR 5 C(NCN)NR 3 R 4 , —OR 3 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionally substituted independently with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, NR 3 R 4  and OR 3 ; 
         R 7  is hydrogen or C 1 -C 10  alkyl, wherein said alkyl is optionally substituted independently with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl rings are optionally substituted independently with one or more groups selected from halogen, hydroxyl, cyano, nitro, azido, fluoromethyl, difluoromethyl, trifluoromethyl, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, C 3 -C 6  cycloalkyl, C 3 -C 6  heterocycloalkyl, NR 11 R 12  and OR 11 ; 
         R 8  is Br, I or SR 11 ; 
         R 3  is hydrogen, trifluoromethyl, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, C 4 -C 10  cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted independently with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl heterocyclyl, and heterocyclylalkyl, 
         or R 3  and R 4  together with the atom to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryl and heterocyclic rings are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; 
         R 4  and R 5  independently are hydrogen or C 1 -C 6  alkyl, or 
         R 4  and R 5  together with the atom to which they are attached form a 4 to 10 membered carbocyclic ring, wherein said alkyl and carbocyclic ring are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; 
         R 6  is trifluoromethyl, C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted independently with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR 11 SO 2 R 14 , —SO 2 NR 11 R 12 , —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)OR 14 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —SR 11 , —S(O)R 14 , —SO 2 R 14 , —NR 11 R 12 , —NR 11 C(O)NR 12 R 13 , —NR 11 C(NCN)NR 12 R 13 , —OR 11 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; 
         R 11 , R 12  and R 13  independently are hydrogen, lower alkyl, lower alkenyl, aryl or arylalkyl, and R 14  is lower alkyl, lower alkenyl, aryl or arylalkyl, 
         or any two of R 11 , R 12 , R 13  and R 14  together with the atom to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein said alkyl, alkenyl, aryl, arylalkyl, heteroaryl ring and heterocyclic ring are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; 
         W is heteroaryl, heterocyclyl, —C(O)OR 3 , —C(O)NR 4 OR 3 , —C(O)NR 4 SO 2 R 3 , —C(O)(C 3 -C 10  cycloalkyl), —C(O)(C 1 -C 10  alkyl), —C(O)(heterocyclyl) or CR 3 R 4 OR 3 , wherein any of said cycloalkyl, alkyl, heteroaryl and heterocyclyl portions are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, azido, —NR 3 R 4 , —OR 3 , C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, cycloalkyl and heterocycloalkyl, 
         provided that when W is C(O)OR 3  and R 9  is F, R 7  cannot be H;
 m is 0, 1, 2, 3, 4 or 5; and 
 j is 0, 1 or 2; 
 
         in combination with (b) at least one additional therapeutic agent. 
       
     
     
         10 . A method of treatment of  claim 9 , wherein the at least one additional therapeutic agent is an anti-tumor agent selected from the group consisting of antiproliferative/antineoplastic drugs, cytostatic agents, agents which inhibit cancer invasion, inhibitors of growth factor function, antiangiogenic agents, vascular damaging agents, antisense therapies, gene therapy, interferon, and immunotherapy approaches. 
     
     
         11 . A method of treatment of  claim 9 , wherein the at least one additional therapeutic agent is an anti-tumor agent selected from alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents, topoisomerase inhibitors, antiestrogens, estrogen receptor down regulators, antiandrogens, LHRH antagonists or agonists, progestogens, inhibitors of 5α reductase, metalloproteinase inhibitors, inhibitors of urokinase plasminogne activator receptor function, trastuzumab, cetuximab, farnesyl transferase inhibitors, tyrosine kinase inhibitors, serine-threonine kinase inhibitors, inhibitors of the platelet-derived growth factor family and inhibitors of the hepatocyte growth factor family; bevacizumab, linomide, inhibitors of integrin αvβ3 function, MMP inhibitors, COX-2 inhibitors, angiostatin, Combretastatin A4, ISIS 2503, anti-ras antisense, GVAX™, and cytokines. 
     
     
         12 . A method of treatment of  claim 9 , wherein the at least one additional therapeutic agent is an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.