Derivatives of n-(arylamino) sulfonamides as inhibitors of mek

Abstract

This invention concerns N-(2-arylamino) aryl sulfonamides, which are inhibitors of MEK and are useful in treatment of cancer and other hyperproliferative diseases.

1 . A compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof 
       
         
           
           
               
               
           
         
       
       wherein
 Z is H or F; 
 X is F, Cl, CH 3 , CH 2 OH, CH 2 F, CHF 2 , or CF 3 ; 
 Y is I, Br, Cl, CF 3 , C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, where Het is a 5- to 10-membered mono- or bicyclic heterocyclic group, which group is saturated, olefinic, or aromatic, containing 1-5 ring heteroatoms selected independently from N, O, and S; where
 all said phenyl or Het groups are optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO 2 , CO 2 H, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  alkyl-C(═O)—, C 1 -C 3  alkyl-C(═S)—, C 1 -C 3  alkoxy-C(═S)—, C 1 -C 3  alkyl-C(═O)O—, C 1 -C 3  alkyl-O—(C═O)—, C 1 -C 3  alkyl-C(═O)NH—, C 1 -C 3  alkyl-C(═NH)NH—, C 1 -C 3  alkyl-NH—(C═O)—, di-C 1 -C 3  alkyl-N—(C═O)—, C 1 -C 3  alkyl-C(═O)N(C 1 -C 3  alkyl)-, C 1 -C 3  alkyl-S(═O) 2 NH— or trifluoromethyl; 
 all said methyl, ethyl, C 1 -C 3  alkyl, and cyclopropyl groups are optionally substituted with OH; 
 all said methyl groups are optionally substituted with one, two, or three F atoms; 
 
 R 0  is H, F, Cl, Br, I, CH 3 NH—, (CH 3 ) 2 N—, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, phenyl, monosubstituted phenyl, O(C 1 -C 4  alkyl), O—C(═O)(C 1 -C 4  alkyl) or C(═O)O(C 1 -C 4  alkyl); where
 said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl; 
 said C 1 -C 6  alkyl and C 1 -C 4  alkoxy groups also optionally substituted with OCH 3  or OCH 2 CH 3 ; 
 
 G is G 1 , G 2 , R 1a , R 1b , R 1c , R 1d , R 1e , Ar 1 , Ar 2  or Ar 3 ; where
 G 1  is C 1 -C 6  alkyl optionally substituted with one amino, C 1 -C 3  alkylamino, or dialkylamino group, said dialkylamino group comprising two C 1 -C 4  alkyl groups which may be identical or non-identical; or 
 G 1  is a C 3 -C 8  diamino alkyl group; 
 G 2  is a 5- or 6-membered ring, which is saturated, unsaturated, or aromatic, containing 1-3 ring heteroatoms selected independently from N, O, and S, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, O(C 1 -C 3  alkyl), OCH 3 , OCH 2 CH 3 , CH 3 C(═O)NH, CH 3 C(═O)O, CN, CF 3 , and a 5-membered aromatic heterocyclic group containing 1-4 ring heteroatoms selected independently from N, O, and S; 
 R 1a  is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C 1 -C 3  alkoxy, where said cyclopropoxy group or the C 1 -C 3  alkyl moieties of said C 1 -C 3  alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C 3 -alkyl groups within said C 1 -C 4  alkoxy are optionally further substituted with a second OH group; 
 R 1b  is CH(CH 3 )—C 1-3  alkyl or C 3 -C 6  cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, OCH 3 , and CN; 
 R 1c  is (CH 2 ) n O m R′; where
 m is 0 or 1; and where
 when m is 0, n is 1 or 2; 
 when m is 1, n is 2 or 3; 
 
 R′ is C 1 -C 6  alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH 3 , OCH 2 CH 3 , and C 3 -C 6  cycloalkyl; 
 
 R 1d  is C(A)(A′)(B)—; where
 B is H or C 1-4  alkyl, optionally substituted with one or two OH groups; 
 A and A′ are independently H or C 1-4  alkyl, optionally substituted with one or two OH groups; or 
 A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring; 
 
 R 1e  is 
 
 
       
         
           
           
               
               
           
         
         
           where
 q is 1 or 2; 
 R 2  and R 3  are each independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl; 
 R 4  is H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl amino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino; 
 R 5  is H, F, Cl or methyl; 
 R 6  is H, F, Cl or methyl; 
 
           Ar 1  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 U and V are, independently, N, CR 2  or CR 3 ; 
 R 2 , R 3  and R 4  are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonylamino, and methylsulfonyl; 
 R 5  and R 6  are, independently, H, F, Cl or methyl; 
 
           Ar 2  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 the dashed line represents alternative formal locations for the second ring double bond; 
 U is —S—, —O— or —N═, and where
 when U is —O— or —S—, V is —CH═, —CCl═ or —N═; 
 when U is —N═, V is —CH═, —CCl═, or —N═; 
 
 R 7  is H or methyl; 
 R 8  is H, acetamido, methyl, F or Cl; 
 
           Ar 3  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 U is —NH—, —NCH 3 — or —O—; 
 R 7  and R 8  are, independently, H, F, Cl, or methyl. 
 
         
       
     
     
         2 . The compound of  claim 1 , or its pharmaceutically acceptable salt. 
     
     
         3 - 68 . (canceled) 
     
     
         69 . A method for inhibiting MEK enzymes comprising contacting said MEK enzyme with a composition comprising a compound of formula I or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, sufficient to inhibit said enzyme, wherein said enzyme is inhibited 
       
         
           
           
               
               
           
         
       
       wherein
 Z is H or F; 
 X is F, Cl, CH 3 , CH 2 OH, CH 2 F, CHF 2 , or CF; 
 Y is I, Br, Cl, CF 3 , C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, where Het is a 5- to 10-membered mono- or bicyclic heterocyclic group, which group is saturated, olefinic, or aromatic, containing 1-5 ring heteroatoms selected independently from N, 0, and S; where
 all said phenyl or Het groups are optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO 2 , CO 2 H, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  alkyl-C(═O)—, C 1 -C 3  alkyl-C(═S)—, C 1 -C 3  alkoxy-C(═S)—, C 1 -C 3  alkyl-C(═O)O—, C 1 -C 3  alkyl-O—(C═O)—, C 1 -C 3  alkyl-C(═O)NH—, C 1 -C 3  alkyl-C(═NH)NH—, C 1 -C 3  alkyl-NH—(C═O)—, di-C 1 -C 3  alkyl-N—(C═O)—, C 1 -C 3  alkyl-C(═O)N(C 1 -C 3  alkyl)-, C 1 -C 3  alkyl-S(═O) 2 NH— or trifluoromethyl; 
 all said methyl, ethyl, C 1 -C 3  alkyl, and cyclopropyl groups are optionally substituted with OH, 
 all said methyl groups are optionally substituted with one, two, or three F atoms; 
 
 R 0  is H, F, Cl, Br, I, CH 3 NH—, (CH 3 ) 2 N—, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, phenyl, monosubstituted phenyl, O(C 1 -C 4  alkyl), O—C(═O)(C 1 -C 4  alkyl) or C(═O)O(C 1 -C 4  alkyl); where
 said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl; 
 said C 1 -C 6  alkyl and C 1 -C 4  alkoxy groups also optionally substituted with OCH 3  or OCH 2 CH 3 ; 
 
 G is G 1 , G 2 , R 1a , R 1b , R 1c , R 1d , R 1e , Ar 1 , Ar 2  or Ar 3 ; where
 G 1  is C 1 -C 6  alkyl optionally substituted with one amino, C 1 -C 3  alkylamino, or dialkylamino group, said dialkylamino group comprising two C 1 -C 4  alkyl groups which may be identical or non-identical; or 
 G 1  is a C 3 -C 8  diamino alkyl group; 
 G 2  is a 5- or 6-membered ring, which is saturated, unsaturated, or aromatic, containing 1-3 ring heteroatoms selected independently from N, O, and S, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, O(C 1 -C 3  alkyl), OCH 3 , OCH 2 CH 3 , CH 3 C(═O)NH, CH 3 C(═O)O, CN, CF 3 , and a 5-membered aromatic heterocyclic group containing 1-4 ring heteroatoms selected independently from N, O, and S; 
 R 1a  is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C 1 -C 3  alkoxy, where said cyclopropoxy group or the C 1 -C 3  alkyl moieties of said C 1 -C 3  alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C 3 -alkyl groups within said C 1 -C 4  alkoxy are optionally further substituted with a second OH group; 
 R 1b  is CH(CH 3 )—C 1-3  alkyl or C 3 -C 6  cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, OCH 3 , and CN; 
 R 1c  is (CH 2 ) n O m R′; where
 m is 0 or 1; and where
 when m is 0, n is 1 or 2: 
 when m is 1, n is 2 or 3: 
 
 R′ is C 1 -C 6  alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH 3 , OCH 2 CH 3 , and C 3 -C 6  cycloalkyl; 
 
 R 1d  is C(A)(A′)(B)—; where
 B is H or C 1-4  alkyl, optionally substituted with one or two OH groups; 
 A and A′ are independently H or C 1-4  alkyl, optionally substituted with one or two OH groups; or 
 A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring; 
 
 R 1e  is 
 
 
       
         
           
           
               
               
           
         
         
           where
 q is 1 or 2; 
 R 2  and R 3  are each independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl; 
 R 4  is H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl amino, N-morpholylsulfonyl and N-pyrrolidinylcarbonylamino; 
 R 5  is H, F, Cl or methyl: 
 R 6  is H, F, Cl or methyl; 
 
           A 1  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 U and V are, independently, N, CR 2  or CR 3 ; 
 R 2 , R 3  and R 4  are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonylamino, and methylsulfonyl; 
 R 5  and R 6  are, independently, H, F, Cl or methyl; 
 
           Ar 2  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 the dashed line represents alternative formal locations for the second ring double bond; 
 U is —S—, —O— or —N═, and where
 when U is —O— or —S—, V is —CH═, —CCl═ or —N═; 
 when U is —N═, V is —CH═, —CCl═, or —N═; 
 
 R 7  is H or methyl: 
 R 8  is H, acetamido, methyl, F or Cl; 
 
           Ar 3  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 U is —NH—, —NCH 3 — or —O—; 
 
         
       
       R 7  and R 8  are, independently, H, F, Cl, or methyl. 
     
     
         70 - 101 . (canceled) 
     
     
         102 . A method for the treatment of an oncologic disease, a proliferative disease or an inflammatory disease in an individual or a method for inhibiting tumor size increase, reducing the size of a tumor, or reducing tumor proliferation in an individual,
 comprising administering to said individual an effective amount of a compound of formula I or a pharmaceutically acceptable salt, ester, or tautomer thereof:   
       
         
           
           
               
               
           
         
       
       wherein
 Z is H or F; 
 X is F, Cl, CH 3 , CH 2 OH, CH 2 F, CHF 2 , or CF 3 ; 
 Y is I, Br, Cl, CF 3 , C 1 -C 3  alkyl, C 2 -C 3  alkenyl, C 2 -C 3  alkynyl, cyclopropyl, O-Methyl, O-Ethyl, S-Methyl or phenyl; where
 said phenyl group is optionally substituted with F, Cl, Br, I, acetyl, methyl, CN, NO 2 , CO 2 H, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, C 1 -C 3  alkyl-C(═O)—, C 1 -C 3  alkyl-C(═S)—, C 1 -C 3  alkoxy-C(═S)—, C 1 -C 3  alkyl-C(═O)O—, C 1 -C 3  alkyl-O—(C═O)—, C 1 -C 3  alkyl-C(═O)NH—, C 1 -C 3  alkyl-C(═NH)NH—, C 1 -C 3  alkyl-NH—(C═O)—, di-C 1 -C 3  alkyl-N—(C═O)—, C 1 -C 3  alkyl-C(═O)N(C 1 -C 3  alkyl)-, C 1 -C 3  alkyl-S(═O) 2 NH— or trifluoromethyl; 
 all said methyl, ethyl, C 1 -C 3  alkyl, and cyclopropyl groups are optionally substituted with OH; 
 all said methyl groups are optionally substituted with one, two, or three F atoms; 
 
 R 0  is H, F, Cl, Br, I, CH 3 NH—, (CH 3 ) 2 N—, C 1 -C 6  alkyl, C 1 -C 4  alkoxy, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, phenyl, monosubstituted phenyl, O(C 1 -C 4  alkyl), O—C(═O)(C 1 -C 4  alkyl) or C(═O)O(C 1 -C 4  alkyl); where
 said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl and phenyl groups are optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, CN, cyanomethyl, nitro, phenyl and trifluoromethyl; 
 said C 1 -C 6  alkyl and C 1 -C 4  alkoxy groups are also optionally substituted with OCH 3  or OCH 2 CH 3 ; 
 
 G is G 1 , G 2 , R 1a , R 1b , R 1c , R 1d , R 1e , Ar 1 , Ar 2  or Ar 3 ; where
 G 1  is C 1 -C 6  alkyl optionally substituted with one amino, or is a C 3 -C 8  diamino alkyl group; 
 G 2  is a 5- or 6-membered ring, which is saturated, unsaturated, or aromatic, containing 1-3 ring heteroatoms independently selected from the group consisting of O, and S, optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, OH, O(C 1 -C 3  alkyl), OCH 3 , OCH 2 CH 3 , CH 3 C(═O)NH, CH 3 C(═O)O, CN, CF 3 , and a 5-membered aromatic heterocyclic group containing 1-4 ring heteroatoms independently selected from the group consisting of N, O, and S; 
 R 1a  is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C 1 -C 3  alkoxy, where said cyclopropoxy group or the C 1 -C 3  alkyl moieties of said C 1 -C 3  alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C 3 -alkyl groups within said C 1 -C 3  alkoxy are optionally further substituted with a second OH group; 
 R 1b  is CH(CH 3 )—C 1-3  alkyl or C 3 -C 6  cycloalkyl, said alkyl and cycloalkyl groups optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, OCH 3 , and CN; 
 R 1c  is (CH 2 ) n O m R′; where
 m is 0 or 1; and where
 when m is 0, n is 1 or 2; 
 when m is 1, n is 2 or 3; 
 
 R′ is C 1 -C 6  alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of F, Cl, OH, OCH 3 , OCH 2 CH 3 , and C 3 -C 6  cycloalkyl; 
 
 R 1d  is C(A)(A′)(B)—; where
 B is H or C 1-4  alkyl, optionally substituted with one or two OH groups; 
 A and A′ are independently H or C 1-4  alkyl, optionally substituted with one or two OH groups; or 
 A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring; 
 
 R 1e  is 
 
 
       
         
           
           
               
               
           
         
         
           where
 q is 1 or 2; 
 R 2  and R 3  are each independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl or methylsulfonyl; 
 R 4  is H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, methylsulfonyl, nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholyl carbonyl amino, N-morpholylsulfonyl or N-pyrrolidinylcarbonylamino; 
 R 5  is H, F, Cl or methyl; 
 R 6  is H, F, Cl or methyl; 
 
           Ar 1  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 U and V are, independently, N, CR 2  or CR 3 ; 
 R 2 , R 3  and R 4  are, independently, H, F, Cl, Br, CH 3 , CH 2 F, CHF 2 , CF 3  OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazolyl, 1H-tetrazolyl, N-morpholylcarbonylamino, N-morpholylsulfonyl, N-pyrrolidinylcarbonylamino, or methylsulfonyl; 
 R 5  and R 6  are, independently, H, F, Cl or methyl; 
 
           Ar 2  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 the dashed line represents alternative formal locations for the second ring double bond; 
 U is —S—, —O— or —N═, and where
 when U is —O— or —S—, V is —CH═, —CCl═ or —N═; 
 when U is —N═, V is —CH═, —CCl═, or —N═; 
 
 R 7  is H or methyl; 
 R 8  is H, acetamido, methyl, F or Cl; 
 
           Ar 3  is 
         
       
       
         
           
           
               
               
           
         
         
           where
 U is —NH—, —NCH 3 — or —O—; and 
 R 7  and R 8  are, independently, H, F, Cl, or methyl. 
 
         
       
     
     
         103 . A method according to  claim 102 , which is for the treatment of an oncologic disease. 
     
     
         104 . A method according to  claim 102 , wherein the compound of formula I is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         105 . A method according to  claim 102 , wherein said proliferative disease is cancer, which is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, follicular lymphona, pre-B acute leukemia, chronic lymphocytic B-leukemia, mesothelioma, small cell line cancer, non-small-cell lung cancer, melanoma, pancreatic cancer, thyroid carcinoma, hepatocellular carcinoma, biliary carcinoma acute myeloid leukemia or multiple myeloma. 
     
     
         106 . A method according to  claim 102 , which is for inhibiting tumor size increase, reducing the size of a tumor, or reducing tumor proliferation in an individual, wherein said tumor occurs in the brain, breast, lung, ovaries, pancreas, prostate, kidney, colon or rectum.