Oxindoles as kinase inhibitors

Abstract

The present invention relates to oxindoles of the formula I, their use as protein kinase activators or inhibitors, a method for their manufacture, their use for the preparation of a medicament for the treatment of diseases and their use for the manufacture of a pharmaceutical composition.

1 - 28 . (canceled) 
   
   
       29 . A method for activating or inhibiting protein kinase is MEK1 or MEK2, or for treating or preventing cancer, or for treating or preventing melanoma, brain cancer, lung cancer, non-small cell lung carcinoma, squamous cell cancer, colon cancer, duodenal cancer, ductal cancer, colorectal cancer, gastric cancer, stomach cancer, pancreatic cancer, hepatic cancer, renal cancer, bladder cancer, endometrial cancer, ovarian cancer, uterine cancer, prostate cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynecological cancer, dysplastic oral mucosa, polyposis, invasive oral cancer, thyroid cancer, lymphoma, chronic leukaemia or acute leukaemia,
 comprising administering to a subject in need thereof an effective amount of a compound of formula I   
     
       
         
         
             
             
         
       
     
     wherein
 X is (CH 2 ) p . 
 R 1  is Ar or Het, 
 R 2  is H, A, Ar, (CH 2 ) m CON(R 8 ) 2  or (CH 2 ) m CONHAr, 
 R 3 , R 4 , R 6 , and R 7  are independently from each other H, A, Ar, OR 8 , SR a , OAr, SAr, N(R 8 ) 2 , NHAr, NAr 2 , Hal, NO 2 , CN, COR S , COAr, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, SO 2 N(R 8 ) 2 , O(CH 2 ) n N(R 8 ) 2  or O(CH 2 ) n NHR 8 , 
 R 5  is H, A, Ar, OR 8 , SR 8 , OAr, SAr, N(R 8 ) 2 , NHAr, NAr 2 , Hal, NO 2 , CN, COAr, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, SO 2 N(R 8 ) 2 , O(CH 2 ),N(R 5 ) 2  or O(CH 2 ) n NHR 8 , 
 R 8  is H, A or A-Ar, 
 A is a linear or branched alkyl or a cycloalkyl which is optionally substituted by Hal, 
 Ar is aryl, 
 Het is heteroaryl, 
 Hal Cl, Br, I or F, 
 n, and p are independently from each other 0-5, and 
 m is 0-2, 
 
     with the provisio, that one of the residues R 2 , R 3 , R 4 , R 5 , R 6  or R 7  is other than H and that 3-(1-Amino-2-phenyl-ethylidene)-1-methyl-1,3-dihydro-indol-2-one is excluded, or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, or a mixtures thereof. 
   
   
       30 . A method according to  claim 29 , wherein in the compound of formula I
 X is (CH 2 ) p ,   p is 0-5,   R 1  is Ar or Het,   R 2 , R 3 , R 4 , R 6 , and R 7  are H, and   R 5  is Hal.   
   
   
       31 . A method according to  claim 29 , wherein in the compound of formula I
 X is (CH 2 ) p ,   p is 0-5,   R 1  is Ar or Het,   R 2 , R 3 , R 5 , R 6 , and R 7  are H, and   R 4  is Hal.   
   
   
       32 . A method according to  claim 29 , wherein in the compound of formula I
 X is (CH 2 ) p ,   p is 0-5,   R 1  is Ar or Het,   R 3 , R 4 , R 5 , R 6 , and R 7  are H, and   R 2  is A or Ar.   
   
   
       33 . A method according to  claim 29 , wherein in the compound of formula I
 X is (CH 2 ) p ,   p is 0-5,   R 1  is Ar or Het,   R 2 , R 3 , R 4 , and R 6  are H,   R 5  is Hal,   R 7  is Hal or OR 8 , and   R 8  is H or A.   
   
   
       34 . A method according to  claim 29 , wherein in the compound of formula I
 X is (CH 2 ) p ,   p is 0-5,   R 1  is Ar or Het,   R 2 , R 3 , R 5 , and R 6  are H,   R 4  is Hal,   R 7  is Hal or OR 8 , and   R 8  is H or A.   
   
   
       35 . A method according to  claim 29 , wherein in the compound of formula I
 X is (CHO 2 ) p ,   p is 0-5,   R 1  is Ar or Het,   R 2 , R 3 , R 4 , and R 6  are H,   R 5  is Hal,   R 7  is Hal or OR 8 , and   R 8  is H or A.   
   
   
       36 . A method according to  claim 29 , wherein in the compound of formula I
 X is (CH 2 ) p ,   p is 0,   R 1  is phenyl,   R 3 , R 4 , R 5 , and R 6  are H,   R 2  is A or Ar,   R 7  is Hal or OR 8 , and   R 8  is H or A.   
   
   
       37 . A method according to  claim 29 , wherein a compound of formula I or a pharmaceutically acceptable salt thereof is administered. 
   
   
       38 . A method according to  claim 29 , which is for activating or inhibiting protein kinase is MEK1 or MEK2. 
   
   
       39 . A method according to  claim 29 , which is for treating or preventing cancer. 
   
   
       40 . A method according to  claim 29 , which is for treating or preventing melanoma, brain cancer, lung cancer, non-small cell lung carcinoma, squamous cell cancer, colon cancer, duodenal cancer, ductal cancer, colorectal cancer, gastric cancer, stomach cancer, pancreatic cancer, hepatic cancer, renal cancer, bladder cancer, endometrial cancer, ovarian cancer, uterine cancer, prostate cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynecological cancer, dysplastic oral mucosa, polyposis, invasive oral cancer, thyroid cancer, lymphoma, chronic leukaemia or acute leukaemia. 
   
   
       41 . A method according to  claim 29 , which is for treating melanoma, brain cancer, lung cancer, non-small cell lung carcinoma, squamous cell cancer, colon cancer, duodenal cancer, ductal cancer, colorectal cancer, gastric cancer, stomach cancer, pancreatic cancer, hepatic cancer, renal cancer, bladder cancer, endometrial cancer, ovarian cancer, uterine cancer, prostate cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynecological cancer, dysplastic oral mucosa, polyposis, invasive oral cancer, thyroid cancer, lymphoma, chronic leukaemia or acute leukaemia. 
   
   
       42 . A method according to  claim 29 , which further comprises administering an estrogen receptor modulator, androgen receptor modulator, retinoid receptor modulator, cytotoxic agent, anti-proliferative agent, prenyl protein protease inhibitor, HMG CoA reductase inhibitor, HIV protease inhibitor, reverse transcriptase inhibitor, growth factor receptor inhibitor or angiogenesis inhibitor. 
   
   
       43 . A method according to  claim 29 , which further comprises administering an anti-metastatic, antitumor or anti-angiogenic agent, which is not a compound of formula I. 
   
   
       44 . A method according to  claim 29 , which further comprises providing radio therapy to the subject in need thereof. 
   
   
       45 . A method for activating or inhibiting protein kinase is MEK1 or MEK2, or for treating or preventing cancer, or for treating or preventing melanoma, brain cancer, lung cancer, non-small cell lung carcinoma, squamous cell cancer, colon cancer, duodenal cancer, ductal cancer, colorectal cancer, gastric cancer, stomach cancer, pancreatic cancer, hepatic cancer, renal cancer, bladder cancer, endometrial cancer, ovarian cancer, uterine cancer, prostate cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynecological cancer, dysplastic oral mucosa, polyposis, invasive oral cancer, thyroid cancer, lymphoma, chronic leukaemia or acute leukaemia,
 comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of   a) 3-(Amino-phenyl-methylene)-6-chloro-1,3-dihydro-indol-2-one,   b) 3-(Amino-phenyl-methylene)-5-chloro-1,3-dihydro-indol-2-one,   c) 3-[Amino-(4-hydroxy-phenyl)methylene]-1,3-dihydro-indol-2-one,   d) 3-[Amino-(4-iodo-phenyl)methylene]-1,3-dihydro-indol-2-one,   e) 3-(Amino-(4-iodo-phenyl)-methylene)-6-chloro-1,3-dihydro-indol-2-one,   f) 3-(Amino-(4-iodo-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one,   g) 3-[Amino-(3-iodo-phenyl)-methylene]-1,3-dihydro-indol-2-one,   h) 3-(Amino-(3-iodo-phenyl)-methylene)-6-chloro-1,3-dihydro-indol-2-one,   i) 3-(Amino-(3-iodo-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one,   j) 3-(Amino-(3-iodo-phenyl)-methylene)-1-methyl-1,3-dihydro-indol-2-one,   k) 3-(Amino-phenyl-methylene)-5-bromo-1,3-dihydro-indol-2-one,   l) 3-(Amino-(4-iodo-phenyl)-methylene)-1-methyl-1,3-dihydro-indol-2-one,   m) 3-(Amino-(4-iodo-phenyl)-methylene)-5-bromo-1,3-dihydro-indol-2-one,   n) 3-(Amino-(3-iodo-phenyl)-methylene)-5-bromo-1,3-dihydro-indol-2-one,   o) 3-[Amino-(4-methoxy-phenyl)-methylene]-1,3-dihydro-indol-2-one,   p) 3-(Amino-(4-methoxy-phenyl)-methylene)-6-chloro-1,3-dihydro-indol-2-one,   q) 3-(Amino-(4-methoxy-phenyl)-methylene)-5-bromo-1,3-dihydro-indol-2-one,   r) 3-(Amino-(4-hydroxy-phenyl)-methylene)-6-chloro-1,3-dihydro-indol-2-one,   s) 3-(Amino-(4-hydroxy-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one,   t) 3-(Amino-phenyl-methylene)-1-methyl-1,3-dihydro-indol-2-one,   u) 3-(Amino-(4-hydroxy-phenyl)-methylene)-1-methyl-1,3-dihydro-indol-2-one,   v) 3-(Amino-(4-hydroxy-phenyl)-methylene)-5-bromo-1,3-dihydro-indol-2-one,   w) 3-(Amino-(4-methoxy-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one,   x) 3-[Amino-(4-fluoro-phenyl)methylene]-1,3-dihydro-indol-2-one,   y) 3-(Amino-(4-fluoro-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one, and   z) 3-(Amino-(4-methoxy-phenyl)-methylene)-1-methyl-1,3-dihydro-indol-2-one,   
     and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       46 . A method according to  claim 45 , wherein
 a) 3-(Amino-phenyl-methylene)-6-chloro-1,3-dihydro-indol-2-one,   b) 3-(Amino-phenyl-methylene)-5-chloro-1,3-dihydro-indol-2-one,   c) 3-[Amino-(4-hydroxy-phenyl)-methylene]-1,3-dihydro-indol-2-one,   d) 3-[Amino-(4-iodo-phenyl)-methylene]-1,3-dihydro-indol-2-one,   e) 3-(Amino-(4-iodo-phenyl)-methylene)-6-chloro-1,3-dihydro-indol-2-one,   f) 3-(Amino-(4-iodo-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one,   g) 3-[Amino-(3-iodo-phenyl)-methylene]-1,3-dihydro-indol-2-one,   h) 3-(Amino-(3-iodo-phenyl)-methylene)-6-chloro-1,3-dihydro-indol-2-one,   i) 3-(Amino-(3-iodo-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one,   j) 3-(Amino-(3-iodo-phenyl)-methylene)-1-methyl-1,3-dihydro-indol-2-one,   k) 3-(Amino-phenyl-methylene)-5-bromo-1,3-dihydro-indol-2-one,   l) 3-(Amino-(4-iodo-phenyl)-methylene)-1-methyl-1,3-dihydro-indol-2-one,   m) 3-(Amino-(4-iodo-phenyl)-methylene)-5-bromo-1,3-dihydro-indol-2-one,   n) 3-(Amino-(3-iodo-phenyl)-methylene)-5-bromo-1,3-dihydro-indol-2-one,   o) 3-(Amino-(4-methoxy-phenyl)-methylene]-1,3-dihydro-indol-2-one,   p) 3-(Amino-(4-methoxy-phenyl)-methylene)-6-chloro-1,3-dihydro-indol-2-one,   q) 3-(Amino-(4-methoxy-phenyl)methylene)-5-bromo-1,3-dihydro-indol-2-one,   r) 3-(Amino-(4-hydroxy-phenyl)-methylene)-6-chloro-1,3-dihydro-indol-2-one,   s) 3-(Amino-(4-hydroxy-phenyl)methylene)-5-chloro-1,3-dihydro-indol-2-one,   t) 3-(Amino-phenyl-methylene)-1-methyl-1,3-dihydro-indol-2-one,   u) 3-(Amino-(4-hydroxy-phenyl)-methylene)-1-methyl-1,3-dihydro-indol-2-one,   v) 3-(Amino-(4-hydroxy-phenyl)-methylene)-5-bromo-1,3-dihydro-indol-2-one,   w) 3-(Amino-(4-methoxy-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one,   x) 3-(Amino-(4-fluoro-phenyl)-methylene]-1,3-dihydro-indol-2-one,   y) 3-(Amino-(4-fluoro-phenyl)-methylene)-5-chloro-1,3-dihydro-indol-2-one, or   z) 3-(Amino-(4-methoxy-phenyl)-methylene)-1-methyl-1,3-dihydro-indol-2-one,   
     or a physiologically acceptable salt thereof is administered. 
   
   
       47 . A method according to  claim 45 , which is for treating melanoma, brain cancer, lung cancer, non-small cell lung carcinoma, squamous cell cancer, colon cancer, duodenal cancer, ductal cancer, colorectal cancer, gastric cancer, stomach cancer, pancreatic cancer, hepatic cancer, renal cancer, bladder cancer, endometrial cancer, ovarian cancer, uterine cancer, prostate cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynecological cancer, dysplastic oral mucosa, polyposis, invasive oral cancer, thyroid cancer, lymphoma, chronic leukaemia or acute leukaemia.