Substituted 3-(5-membered unsaturated heterocyclyl-1, 3-dihydro-indol-2-one's and derivatives thereof as kinase inhibitors

Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

1 . A compound represented by one of the general formulae: 
       
         
           
           
               
               
           
         
         wherein 
         X is O or S; 
         Y is selected from the group consisting of O, S, NR 3  and CR 3 R 4 ; 
       
       and wherein the ring system represented by A in formula V, below, is a 5 or 6 membered aryl group, 
       
         
           
           
               
               
           
         
       
       wherein said aryl group is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and wherein the ring system represented by B in formula VI, above, is a five membered unsaturated heterocyclic ring wherein said unsaturated heterocyclic ring is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein Z is selected from the group consisting of [C(R 2 ) 2 ] c , O, NR 3  and S; 
       
         
           
           
               
               
           
         
       
       and wherein the ring system represented by C in formula VII, above, is a 5 or 6 membered aryl group e.g. a carbocyclic aryl or heterocyclic aryl, wherein said aryl group is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of halogen, aryl, C 1  to C 8  alkyl, C 2  to C 8  alkenyl; CF 3 , OCF 3 , OCF 2 H, S(O) f R 2 , (CR 3 R 4 ) d C(O)OR 2 , O(CR 3 R 4 ) e C(O)OR 2 , NR 2 (CR 3 R 4 ) d C(O)R 2 , NR 2 (CR 3 R 4 ) d C(O)OR 2 , OP(O)(OR 2 ) 2 , OC(O)OR 2 , OCH 2 O, NR 2 (CH 2 ) e N(R 2 ) 2 , O(CH 2 ) e N(R 2 ) 2 , (CR 3 R 4 ) d CN, O(CR 3 R 4 ) e CN, (CR 3 R 4 ) g Ar, NR 2 (CR 3 R 4 ) e Ar, O(CR 3 R 4 ) e Ar, S(O) f (CR 3 R 4 ) e Ar, (CR 3 R 4 ) e SO 2 R 2 , (CR 3 R 4 ) e C(O)N(R 2 ) 2 , NR 2 (CR 3 R 4 ) e C(O)N(R 2 ) 2 , O(CR 3 R 4 ) d C(O)N(R 2 ) 2 , C(O)(CR 2 CR 3 ) e Ar, S(O) f (CR 3 R 4 ) e C(O)N(R 2 ) 2 , (CR 3 R 4 ) d OR 2 , NR 2 (CR 3 R 4 ) e OR 2 , O(CR 3 R 4 ) e OR 2 , S(O) f (CR 3 R 4 ) d OR 2 , C(O)(CR 3 R 4 ) d R 3 , NR 2 C(O)(CR 3 R 4 ) e R 3 , OC(O)(CR 3 R 4 ) d N(R 2 ) 2 , C(O)(CR 3 R 4 ) e N(R 2 ) 2 , NR 2 C(O)(CR 3 R 4 ) d N(R 2 ) 2 , OC(O)(CR 3 R 4 ) d N(R 2 ) 2 , (CR 3 R 4 ) d R 3 , NR 2 (CR 3 R 4 ) d R 3 , O(CR 3 R 4 ) d R 3 , S(O) f (CR 3 R 4 ) d R 3 , (CR 3 R 4 ) e N(R 2 ) 2 , NR 2 (CR 3 R 4 ) e N(R 2 ) 2 , O(CR 3 R 4 ) e N(R 2 ) 2 , S(O) f  (CR 3 R 4 ) d N(R 2 ) 2 ; 
       R 2  is selected from the group consisting of hydrogen, C 1  to C 8  alkyl, C 2  to C 8  alkenyl, C 2  to C 8  alkynyl, C 1  to C 4  alkylol, lower alkylphenyl, phenyl, (CR 3 R 4 ) d Ar, (CR 3 R 4 ) d C(O)OR 6 , (CR 3 R 4 ) d SO 2 R 6 , (CR 3 R 4 ) d OR 6 , (CR 3 R 4 ) d OSO 2 R 6 , (CR 3 R 4 ) d P(O)(OR 6 ) 2 , (CR 3 R 4 ) d R 6 , (CR 3 R 4 ) e N(R 6 ) 2  and (CR 3 R 4 ) e NR 6 C(O)N(R 6 ) 2 ; 
       wherein N(R 6 ) 2  may form a 3-7 membered heterocyclic ring, for example, pyrrolidine, 3-fluoropyrrolidine, piperidine, 4-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be substituted with one or more of R 3 ; and 
       [C(R 2 ) 2 ] c  may form a 3-7 membered carbocyclic or heterocyclic ring; 
       R is selected from the group consisting of halogen, C 1  to C 8  alkyl, C 2  to C 8  conjugated alkenyl, (CR 2 ═CR 2 ) d CON(R 2 ) 2 , CF 3 , OCF 3 , OCF 2 H, (CR 3 R 4 ) d CN, NR 2 (CR 3 R 4 ) e CN, O(CR 3 R 4 ) e CN, S(O) f R 2 , (CR 3 R 4 ) d C(O)OR 2 , NR 2 (CR 3 R 4 ) d C(O)OR 2 , O(CR 3 R 4 ) d C(O)OR 2 , S(O) f (CR 3 R 4 ) d C(O)OR 2 , (CR 3 R 4 ) d Ar, NR 2 (CR 3 R 4 ) d Ar, O(CR 3 R 4 ) d Ar, S(O) f (CR 3 R 4 ) d Ar, (CR 3 R 4 ) d SO 2 R 2 , NR 2 (CR 3 R 4 ) d S(O) f R 2 , O(CR 3 R 4 ) d  S(O) f R 2 , S(O) f (CR 3 R 4 ) e S(O) f R 2 , (CR 3 R 4 ) d C(O)N(R 2 ) 2 , NR 2 (CR 3 R 4 ) d C(O)N(R 2 ) 2 , O(CR 3 R 4 ) d C(O)N(R 2 ) 2 , S(O) f (CR 3 R 4 ) e C(O)N(R 2 ) 2 , (CR 3 R 4 ) d OR 2 , NR 2  (CR 3 R 4 ) e OR 2 , O(CR 3 R 4 ) e OR 2 , S(O) f (CR 3 R 4 ) d OR 2 , (CR 3 R 4 ) d OSO 2 R 2 , NR 2  (CR 3 R 4 ) e OSO 2 R 2 , O(CR 3 R 4 ) e OSO 2 R 2 , S(O) f (CR 3 R 4 ) e OSO 2 R 2 (CR 3 R 4 ) d P(O)(OR 2 ) 2 , NR 2  (CR 3 R 4 ) d P(O)(OR 2 ) 2 , O(CR 3 R 4 ) d P(O)(OR 2 ) 2 , S(O) f (CR 3 R 4 ) e P(O)(OR 2 ) 2 , C(O)(CR 3 R 4 ) d R 3 , NR 2 C(O)(CR 3 R 4 ) d R 3 , OC(O)(CR 3 R 4 ) d N(R 2 ) 2 , C(O)(CR 3 R 4 ) d N(R 2 ) 2 , NR 2 C(O)(CR 3 R 4 ) d N(R 2 ) 2 , OC(O)(CR 3 R 4 ) d N(R 2 ) 2 , (CR 3 R 4 ) d R 3 , NR 2 (CR 3 R 4 ) d R 3 , O(CR 3 R 4 ) d R 3 , S(O) f (CR 3 R 4 ) d R 3 , HNC(O)R 2 , HN—C(O)OR 2 , (CR 3 R 4 ) d N(R 2 ) 2 , NR 2 (CR 3 R 4 ) e N(R 2 ) 2 , O(CR 3 R 4 ) e N(R 2 ) 2 , S(O) f  (CR 3 R 4 ) d N(R 2 ) 2 , OP(O)(OR 2 ) 2 , OC(O)OR 2 , OCH 2 O, HN—CH═CH, —N(COR 2 )CH 2 CH 2 , HC═N—NH, N═CH—S, (CR 3 R 4 ) d C═C(CR 3 R 4 ) d R 2 , (CR 3 R 4 ) d C═C(CR 3 R 4 ) d OR 2 , (CR 3 R 4 ) d C═C(CR 3 R 4 ) d N(R 2 ) 2 , (CR 3 R 4 ) d CC(CR 3 R 4 ) d R 2 , (CR 3 R 4 ) d CC(CR 3 R 4 ) e OR 2 , (CR 3 R 4 ) d CC(CR 3 R 4 ) e N(R 2 ) 2 , (CR 3 R 4 ) d C(O)(CR 3 R 4 ) d R 2 , (CR 3 R 4 ) d C(O)(CR 3 R 4 ) d OR 2  and (CR 3 R 4 ) d C(O)(CR 3 R 4 ) d N(R 2 ) 2 ; 
       R 3  and R 4  may be selected from the group consisting of H, F, hydroxy, and C 1 -C 4  alkyl or CR 3 R 4  may represent a carbocyclic or heterocyclic ring of from 3 to 6 carbons or alternatively, (CR 3 R 4 ) d  and (CR 3 R 4 ) e  may form a 3-7 membered carbocyclic or heterocyclic ring, preferably 
       R 3  and R 4  are H, F, CH 3  or hydroxy; 
       R 5  is Ar—R 1   b  wherein Ar is 5-7 membered carbocyclic aryl or 5-7 membered heterocyclic aryl; 
       R 6  is selected from the group consisting of hydrogen, C 1 -C 8  alkyl, hydroxylmethyl and phenyl; 
       R 7  is selected from the group consisting of hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, (R 2 CCR 2 )aCN and aryl; 
       a is 0 or an integer of from 1 to 3; 
       b is 0 or an integer of from 1 to 2; 
       c is an integer of from 1 to 2; 
       d is 0 or an integer of from 1 to 5; 
       e is an integer of from 1 to 4; 
       f is 0 or an integer of from 1 to 2; 
       g is an integer of from 2 to 5, and further provided said alkyl or aryl radicals may be substituted with one or two halo, hydroxy, lower alkyloxy, lower alkyl amino or cycloalkylamino radicals wherein the cycloalkyl ring can include an enchained oxygen, sulfur or additional nitrogen atom and may be substituted with one or two halo or lower alkyl radicals; and pharmaceutically acceptable salts thereof. 
     
     
         2 . The compound of  claim 1  wherein A is a carbocyclic aryl group. 
     
     
         3 . The compound of  claim 1  wherein A is a heterocyclic aryl group. 
     
     
         4 . The compound of  claim 1  wherein R 1  is a carbocyclic aryl group. 
     
     
         5 . The compound of  claim 1  wherein R 1  is a heterocyclic aryl group. 
     
     
         6 . The compound of  claim 1  wherein N(R 2 ) is selected from the group consisting of pyrrolidine, 3-fluoropyrrolidine, piperidine, 4-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine wherein said heterocyclic ring may be substituted with one or more of R 3 . 
     
     
         7 . A method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         8 . The method of  claim 7  wherein said disease is selected from the group consisting of cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases. 
     
     
         9 . The method of  claim 8  wherein the blood vessel proliferative disorder is selected from the group consisting of diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, arthritis and restenosis. 
     
     
         10 . The method of  claim 7  wherein the fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis. 
     
     
         11 . The method of  claim 7  wherein the mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies. 
     
     
         12 . The method of  claim 7  wherein the metabolic disorder is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases. 
     
     
         13 . The compound of  claim 1  selected from the group consisting of
 (3E)-6-fluoro-3-{4-[4-({4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-yl}carbonyl)phenyl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 6-Fluoro-3-[4-[4-(3-hydroxy-pyrrolidine-1-carbonyl)-phenyl]-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one, 
 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-N-(2-{2-[2-(2-hydroxyethoxyl)ethoxy]ethoxy}ethyl)benzamide methyl (3E)-3-{5,5-dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylate, 
 methyl (3E)-3-{5,5-dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-6-carboxylate, 
 (3E)-3-{5,5-dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-N-methyl-2-oxoindoline-6-carboxamide, 
 methyl (3E)-3-{5,5-dimethyl-4-[4-(pyrrolidin-1-ylcarbonyl)phenyl]furan-2(5H)-ylidene}-5-fluoro-2-oxoindoline-6-carboxylate, 
 methyl (3E)-3-[4-(4-{[(2,3-dihydroxypropyl)(methyl)amino]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-5-fluoro-2-oxoindoline-6-carboxylate, 
 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-N-(2,3-dihydroxypropyl)-N-methylbenzamide, 
 ethyl (2S)-2-({4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoyl}amino)-4-(methylthio)butanoate, 
 (3E)-6-fluoro-3-[4-(4-{[3-(hydroxymethyl)piperidin-1-yl]carbonyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 ethyl 3-({4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoyl}amino)propanoate, 
 methyl (2S)-2-({4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoyl}amino)-3-hydroxypropanoate, 
 N-(2,3-dihydroxypropyl)-4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-N-methylbenzamide, 
 methyl 1-{4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoyl}piperidine-4-carboxylate, 
 methyl (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-6-carboxylate, 
 (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylic acid, 
 (3E)-3-[4-(4-{[4-(hydroxymethyl)piperidin-1-yl]methyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-2-oxoindoline-5-carboxylic acid, 
 methyl 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylate, 
 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylic acid, 
 (3E)-6-fluoro-3-[4-{4-[(3-hydroxypiperidin-1-yl)methyl]phenyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-(4-{[3-(2-hydroxyethyl)piperidin-1-yl]methyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 methyl 1-{4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}-4-hydroxypyrrolidine-2-carboxylate 
 (3E)-3-[5,5-dimethyl-4-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-5-fluoro-3-[4-(4-{[3-(hydroxymethyl)piperidin-1-yl]methyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-5-fluoro-3-{4-[4-({4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-yl}methyl)phenyl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one, 
 (3E)-3-[4-(4-{[(2,3-dihydroxypropyl)(methyl)amino]methyl}phenyl)-5,5-dimethylfuran-2(5H)-ylidene]-5-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-3-[5,5-dimethyl-4-(4-{[(2S,3R,4S,5R)-3,4,5-trihydroxy-2-methylpiperidin-1-yl]methyl}phenyl)furan-2(5H)-ylidene]-5-fluoro-1,3-dihydro-2H-indol-2-one, 
 1-{4-[(5E)-5-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylic acid, 
 (3E)-3-{5,5-dimethyl-4-[6-(2-morpholin-4-ylethyl)pyridin-3-yl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-(6-{2-[3-(hydroxymethyl)piperidin-1-yl]ethyl}pyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-{6-[2-(4-hydroxypiperidin-1-yl)ethyl]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-(6-{4-[2-(2-hydroxyethoxyl)ethyl]piperazin-1-yl}pyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-{6-[2-(hydroxymethyl)morpholin-4-yl]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-3-[4-{6-[(1,1-dioxidotetrahydro-3-thienyl)(methyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-{6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-{6-[(2-hydroxyethyl)(2-pyridin-4-ylethyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-{6-[4-(2-hydroxyethyl)piperazin-1-yl]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (4-{5-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]pyridin-2-yl}piperazin-1-yl)acetic acid, 
 6-Fluoro-3-[4-{6-[(2-hydroxy-ethyl)-(2-pyridin-4-yl-ethyl)-amino]-pyridin-3-yl}-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one, 
 ethyl (4-{5-[(5E)-5-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]pyridin-2-yl}piperazin-1-yl)acetate, 
 (3E)-3-[4-{6-[(2,3-dihydroxypropyl)(methyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-5-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-5-fluoro-3-[4-{6-[(2-{2-[2-(2-hydroxyethoxyl)ethoxy]ethoxy}ethyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 1-{5-[(5E)-5-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]pyridin-2-yl}piperidine-4-carboxylic acid, 
 (3E)-3-[4-{6-[(2,3-dihydroxypropyl)(methyl)amino]pyridin-3-yl}-5,5-dimethylfuran-2(5H)-ylidene]-5,6-difluoro-1,3-dihydro-2H-indol-2-one, 
 ethyl (2 S)-2-({4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]pyridin-2-yl}amino)-4-(methylthio)butanoate, 
 (3E)-6-fluoro-3-[4-{2-[4-(hydroxymethyl)piperidin-1-yl]pyridin-4-yl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-{2-[(2-hydroxyethyl)(2-pyridin-4-ylethyl)amino]pyridin-4-yl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 methyl [({4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-2-thienyl}methyl)amino]acetate, 
 (3E)-3-{5,5-dimethyl-4-[5-(morpholin-4-ylmethyl)-3-thienyl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-(5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-3-thienyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-3-[4-(5-{[ethyl(2-pyridin-2-ylethyl)amino]methyl}-3-thienyl)-5,5-dimethylfuran-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-3-[4-(5-{[bis(2-methoxyethyl)amino]methyl}-3-thienyl)-5,5-dimethylfuran-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-{4-[4-(2-hydroxyethyl)piperazin-1-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one, 
 (3E)-3-{4-[(2,4-dimethoxybenzyl)amino]-5,5-dimethylfuran-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 N-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-6-[4-(2-hydroxyethyl)piperazin-1-yl]nicotinamide, 
 (3E)-6-(4-methoxyphenyl)-3-[4-(4-methoxyphenyl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one, 
 6-Fluoro-3-(4-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-5H-furan-2-ylidene)-1,3-dihydro-indol-2-one, 
 3-{4-[4-(2-Diethylamino-ethoxy)-phenylamino]-5H-furan-2-ylidene}-6-flu(3E)-3-(3,3′-bifuran-5(2H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-(1H-pyrrol-3-yl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-[4-(3-thienyl)furan-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one oro-1,3-dihydro-indol-2-one, 
 3-{4-[5-(6-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-2,5-dihydro-furan-3-yl]-phenyl}-propionic acid, 
 6-Fluoro-3-{4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-5H-furan-2-ylidene}-1,3-dihydro-indol-2-one, 
 (3E)-3-[5,5-dimethyl-4-(3-thienyl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one, 
 (3E)-6-fluoro-3-{4-[4-(3-hydroxypropyl)phenyl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one, 
 methyl ({4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoyl}amino)acetate, 
 ethyl 3-{4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]phenyl}propanoate, and 
 N-{3-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]phenyl}acetamide.