Indolinone combinatorial libraries and related products and methods for the treatment of disease

Abstract

The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting protein kinase signal transduction. Such compounds are useful for the treatment of diseases related to unregulated protein kinase signal transduction, including cell proliferative diseases such as cancer, atherosclerosis, arthritis and restenosis and metabolic diseases such as diabetes. The present invention features indolinone compounds that potently inhibit protein kinases and related products and methods. Inhibitors specific to the FLK protein kinase can be obtained by adding chemical substituents to the 3-[(indole-3-yl)methylene]-2-indolinone, in particular at the 1′ position of the indole ring. Indolinone compounds that specifically inhibit the FLK and platelet derived growth factor protein kinases can harbor a tetrahydroindole or cyclopentano-b-pyrrol moiety. Indolinone compounds that are modified with substituents, particularly at the 5 position of the oxindole ring, can effectively activate protein kinases. This invention also features novel hydrosoluble indolinone compounds that are tyrosine kinase inhibitors and related products and methods.

1 . A combinatorial library of indolinone compounds, comprising at least ten indolinones that can be formed by reacting oxindoles with aldehydes.  
     
     
         2 . The combinatorial library of  claim 1  wherein said oxindoles are type A oxindoles.  
     
     
         3 . The combinatorial library of  claim 1  wherein said aldehydes are type B aldehydes.  
     
     
         4 . A method of making an indolinone comprising the steps of 
 (a) creating a combinatorial library of indolinones by reacting a series of oxindoles with a series of aldehydes,    (b) testing said indolinones in biological assays,    (c) selecting one or more indolinones with favorable activity, and    (d) synthesizing one or more of said indolinones selected in step (c).    
     
     
         5 . A 3-[(indole-3-yl)methylene]-2-indolinone compound having a substituent at the 1′ position of the indole, where the substituent at the 1′ position is selected from the group consisting of, 
 (a) alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, aldehyde, or trihalomethyl substituents;  
 (b) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (c) an aldehyde or ketone of formula —CO—R 12 , where R 12  is selected from the group consisting of hydrogen, alkyl, and a five or six membered heterocyclic ring;  
 (d) a carboxylic acid of formula —(R 13 )n—COOH or ester of formula —(R 14 )m—COO—R 15 , where R 13 , R 14 , and R 15  are independently selected from the group consisting of alkyl and a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (e) a sulfone of formula —(SO2)—R 16 , where R 16  is selected from the group consisting of alkyl and a five or six membered heterocyclic ring, where the ring is optionally substituted with an alkyl moiety;  
 (f) —(R 17 ) n -(indole-1-yl) or —(R 18 )m—CHOH—(R 19 )p-(indole-1-yl), where the indol moiety is optionally substituted with an aldehyde and R 17 , R 18 , and R 19  are alkyl and m, n, and p are independently 0 or 1; and  
 (g) taken together with a 2′ substituent of the indole ring forms a tricyclic moiety, where each ring in the tricyclic moiety is a five or six membered heterocyclic ring.  
 
     
     
         6 . The compound, salt, isomer, metabolite, ester, amide, or prodrug of  claim 5 , wherein said compound has the formula,  
       
         
           
           
               
               
           
         
         where (a) R 1  is selected from the group consisting of, 
 (i) alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, aldehyde, or trihalomethyl substituents;  
 (ii) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iii) an aldehyde or ketone of formula —CO—R 2 , where R 11  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (iv) a carboxylic acid of formula —(R 13 ) n —COOH or ester of formula —(R 14 )m—COO—R 15 , where R 13 , R 14 , and R 15  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and n and m are independently 0 or 1;  
 (v) a sulfone of formula —(SO 2 )—R 16 , where R 16  is selected from the group consisting of alkyl or a five or six membered heterocyclic ring, where the ring is optionally substituted with an alkyl moiety;  
 (vi) —(R 17 ) n -(indole-1-yl) or —(R 18 )m—CHOH—(R 19 )p-(indole-1-yl), where the indol moiety is optionally substituted with an aldehyde and R 17 , R 18 , and R 19  are alkyl and n, m, and p are independently 0 or 1;  
 (vii) taken together with a 2′ substituent of the indole ring forms a tricyclic moiety, where each ring in the tricyclic moiety is a five or six membered heterocyclic ring;  
 
         (b) R 2 , R 3 l R 4 , R 5 , and R 6  are selected from the group consisting of, 
 (i) hydrogen or alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, aldehyde, or trihalomethyl substituents;  
 (ii) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iii) an aldehyde or ketone of formula —CO—R 20 , where R 20  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (iv) a carboxylic acid of formula —(R 21 )n—COOH or ester of formula —(R 22 )—COO—R 23 , where R 21 , R 22 , and R 23  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (v) halogen or an alcohol of formula (R24)m—OH or an ether of formula —(R 24 )n—O—R 25 , where R 24  and R25 are independently selected from the group consisting of alkyl and a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (vi) —NR 26 R 27 , where R 26  and R 27  are independently selected from the group consisting of hydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring; or —NHCOR 28 , where R 28  is selected from the group consisting of hydroxyl, alkyl, and a five or six membered heterocyclic ring, where the ring is optionally substituted with alkyl, halogen, carboxylate, or ester;  
 (vii) —SO2NR 29 R 30 , where R 29  and R 30  are selected from the group consisting of hydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring;  
 (viii) any two of R 3 , R 4 , R 5 , or R 6  taken together form a bicyclic or tricyclic hetercyclic moiety fused to the six membered ring of the indole, where each ring in the multicyclic moiety is a five or six membered heterocyclic ring;  
 
         (c) R 7 , R 8 , R 9 , and R 10  are independently selected from the group consisting of, 
 (i) hydrogen or alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, aldehyde, or trihalomethyl substituents;  
 (ii) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iii) an aldehyde or ketone of formula —CO—R 31 , where R 31  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (iv) a carboxylic acid of formula —(R 32 )n—COOH or ester of formula —(R 33 )m—COO—R 34 , where R 32 , R 33 , and R34 and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and n and m are independently 0 or 1;  
 (v) halogen or an alcohol of formula (R 35 )m—OH or an ether of formula —(R 35 )n—O—R 36 , where R 35  and R 36  are independently chosen from the group consisting of alkyl or a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (vi) —NR 37 R 38 , where R 37  and R 38  are independently selected from the group consisting of hydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring; or —NHCOR 39 , where R 39  is selected from the group consisting of hydroxyl, alkyl, and a five or six membered heterocyclic ring, where the ring is optionally substituted with alkyl, halogen, carboxylate, or ester;  
 (vii) —SO2NR 40 R 41 , where R 40  and R 41  are selected from the group consisting of hydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring;  
 (viii) any two of R 7 , R 8 , R 9 , or R 10  taken together form a bicyclic or tricyclic hetercyclic moiety fused to the six membered ring of the indole, where each ring in the multicyclic moiety is a five or six membered heterocyclic ring; and  
 
         (d) R 1  is hydrogen or alkyl; provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , or R 10  is alkyl or provided that at least four of R 1 , R 2 , R3, R 4 , R 5 , or R 6  are not hydrogen.  
       
     
     
         7 . An optionally substituted 3-[(tetrahydroindole-2-yl) methylene]-2-indolinone or 3-[(cyclopentano-b-pyrrol-2-yl)methylene]-2-indolinone compound.  
     
     
         8 . The indolinone compound of  claim 7  of formula XIX or XX,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, isomer, metabolite, ester, amide, or prodrug thereof 
 where (a) R 1  is selected from the group consisting of,  
 (i) alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, or trihalomethyl substituents; 
 (ii) five, six, eight, nine, or ten membered nmonocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iii) ketone of formula —CO—R 12 , where R 11  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (iv) a carboxylic acid of formula —(R 13 ) n —COOH or ester of formula —(R 14 ) m —COO—R 15 , where R 13 , R 14 , and R 15  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and n and m are independently 0 or 1;  
 (v) a sulfone of formula —(SO 2 )—R 16 , where R 16  is selected from the group consisting of alkyl or a five or six membered heterocyclic ring, where the ring is optionally substituted with an alkyl moiety;  
 (vi) —(R 17 ) n -(indole-1-yl) or —(R 18 ) m —CHOH—(R 19 )p-(indole-1-yl), where the indolemoiety is optionally substituted with an aldehyde and R 17 , R 18 , and R 19  are alkyl and n, m, and p are independently 0 or 1;  
 (vii) taken together with a 2′ substituent of the indole ring forms a tricyclic moiety, where each ring in the tricyclic moiety is a five or six membered heterocyclic ring;  
 
 (b) R 2 , R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′, R 6 , and R 6 ′ are selected from the group consisting of, 
 (i) hydrogen;  
 (ii) alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, or trihalomethyl substituents;  
 (iii) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iv) ketone of formula —CO—R 20 , where. R 20  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (v) a carboxylic acid of formula —(R 21 ) n —COOH or ester of formula —(R 22 )—COO—R 23 , where R 21 , R 22 , and R 23  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (vi) halogen;  
 (vii) an alcohol of formula (R 24 ) m —OH or an ether of formula —(R 24 ) n —O—R 25 , where R 24  and R 25  are independently selected from the group consisting of alkyl and a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (viii) —NR 26 R 27 , where R 26  and R 27  are independently selected from the group consisting of hydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring;  
 (ix) —NHCOR 28 , where R 28  is selected from the group consisting of hydroxyl, alkyl, and a five or six membered heterocyclic ring, where the ring is optionally substituted with alkyl, halogen, carboxylate, or ester;  
 (x) —SO2NR 29 R 30 , where R 29  and R 30  are selected from the group consisting of hydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring;  
 (xi) any two of R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , or R 6′  taken together form a bicyclic or tricyclic hetercyclic moiety fused to the six membered ring of the indole, where each ring in the multicyclic moiety is a five or six membered heterocyclic ring;  
 
 (c) R 7 , R 8 , R 9 , and R 10  are independently selected from the group consisting of, 
 (i) hydrogen;  
 (ii) alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, or trihalomethyl substituents;  
 (iii) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iv) ketone of formula —CO—R 31 , where R 31  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (v) a carboxylic acid of formula —(R 32 ) n —COOH or ester of formula —(R 33 ) m —COO—R 34 , where R 32 , R 33 , and R 34  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and n and m are independently 0 or 1;  
 (vi) halogen;  
 (vii) an alcohol of formula (R 35 ) m —OH or an ether of formula —(R 35 ) n —O—R 36 , where R 35  and R 36  are independently chosen from the group consisting of alkyl or a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (viii) —NR 37 R 38 , where R 37  and R 38  are independently selected from the group consisting of hydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring;  
 (ix) —NHCOR 39 , where R 39  is selected from the group consisting of hydroxyl, alkyl, and a five or six membered heterocyclic ring, where the ring is optionally substituted with alkyl, halogen, carboxylate, or ester;  
 (x) —SO2NR 40 R 41 , where R 40  and R 41  are selected from the group consisting of hydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring;  
 (xi) any two of R 7 , R 8 , R 9 , or R 10  taken together form a bicyclic or tricyclic hetercyclic moiety fused to the six membered ring of the indole, where each ring in the multicyclic moiety is a five or six membered heterocyclic ring; and  
 
 (d) R 11  is hydrogen or alkyl  
 
     
     
         9 . An indolinone compound having a substituent at the 5 position of the oxindole ring, where the substituent at the 5 position of the oxindole ring is selected from the group consisting of 
 (a) alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, or trihalomethyl substituents;    (b) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;    (c) a ketone of formula —CO—R 10 , where R 10  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;    (d) a carboxylic acid of formula —(R 11 )n—COOH or ester of formula —(R 12 )—COO—R 13 , where R 11 , R 12 , R 13  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and m and n are independently 0 or 1;    (e) halogen;    (f) an alcohol of formula (R 14 )m—OH or an ether of formula —(R 14 )n—O—R 15 , where R 14  and R 15  are independently selected from the group consisting of alkyl and a five or six membered heterocyclic ring and m and n are independently 0 or 1;    (g) —NR 16 R 17 , where R 16  and R 17  are independently selected from the group consisting of hydrogen, alkyl, and a five or six membered heterocyclic ring;    (h) —NHCOR 18 , where R 18  is selected from the group consisting of alkyl, and a five or six membered heterocyclic ring, where the ring is optionally substituted with alkyl, halogen, carboxylate, or ester;    (i) —SO2NR 19 R 20 , where R 19  and R 20  are selected from the group consisting of hydrogen, alkyl, and a five as or six membered heterocyclic ring;    (j) any two of R 4 , R 5 , R 6 , or R 7  taken together form a bicyclic or tricyclic hetercyclic moiety fused to the six membered ring of the oxindole, where each ring in the multicyclic moiety is a five or six membered heterocyclic ring.    
     
     
         10 . The compound of  claim 9  of the following formula,  
       
         
           
           
               
               
           
         
         where (a) R 5  is selected from the group consisting of, 
 (i) alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, or trihalomethyl substituents;  
 (ii) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iii) a ketone of formula —CO—R 10 , where R 10  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (iv) a carboxylic acid of formula —(R 11 )n—COOH or ester of formula —(R 12 )—COO—R 13 , where R 11 , R 12 , and R 13  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (v) halogen;  
 (vi) an alcohol of formula (R 14 )m—OH or an ether of formula —(R 14 )n—O—R 15 , where R 14  and R 15  are independently selected from the group consisting of alkyl and a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (vii) —NR 16 R 17 , where R 16  and R 17  are independently selected-from the group consisting of hydrogen, alkyl, and a five or six membered heterocyclic ring;  
 (viii) —NHCOR 18 , where R 18  is selected from the group consisting of alkyl, and a five or six membered heterocyclic ring, where the ring is optionally to substituted with alkyl, halogen, carboxylate, or ester;  
 (ix) —SO 2 NR 19 R 20 , where R 19  and R 20  are selected from the group consisting of hydrogen, alkyl, and a five or six membered heterocyclic ring;  
 (x) any two of R 4 , R 5 , R 6 , or R 7  taken together form a bicyclic or tricyclic hetercyclic moiety fused to the six membered ring of the oxindole, where each ring in the multicyclic moiety is a five or six membered heterocyclic ring;  
 
         (b) R 1  is selected from the group consisting of a five, six, eight, nine, and ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more substituents selected from the group consisting of 
 (i) hydrogen and alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, or trihalomethyl substituents;  
 (ii) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iii) a ketone of formula —CO—R 21 , where R 21  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (iv) a carboxylic acid of formula —(R 22 )n—COOH or ester of formula —(R 23 )—COOR 24 , where R 22 , R 23 , and R 24  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (v) halogen;  
 (vi) an alcohol of formula (R 25 )m—OH or an ether of formula —(R 25 )n—O—R 26 , where R 25  and R 26  are independently selected from the group consisting of alkyl and a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (vii) —NR 27 R 28 , where R 27  and R 28  are independently selected from the group consisting of hydrogen, alkyl, and a five or six membered heterocyclic ring;  
 (viii) —NHCOR 29 , where R 29  is selected from the group consisting of alkyl, and a five or six membered heterocyclic ring, where the ring is optionally substituted with alkyl, halogen, carboxylate, or ester;  
 (ix) —SO 2 NR 30 R 31 , where R 30  and R 31  are selected from the group consisting of hydrogen, alkyl, and a five or six membered heterocyclic ring;  
 
         (c) R 4 , R 6 , and R 7  are independently selected from the group consisting of, 
 (i) hydrogen and alkyl that is optionally substituted with a monocyclic or bicyclic five, six, eight, nine, or ten membered heterocyclic ring, where the ring is optionally substituted with one or more halogen, or trihalomethyl substituents;  
 (ii) five, six, eight, nine, or ten membered monocyclic or bicyclic heterocyclic ring, where the ring is optionally substituted with one or more halogen or trihalomethyl substituents;  
 (iii) a ketone of formula —CO—R 32 , where R 32  is selected from the group consisting of hydrogen, alkyl, or a five or six membered heterocyclic ring;  
 (iv) a carboxylic acid of formula —(R 33 )n—COOH or ester of formula —(R 34 )—COO—R 35 , where R 33  R 34  and R 35  and are independently selected from the group consisting of alkyl or a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (v) halogen;  
 (vi) an alcohol of formula (R 36 )m—OH or an ether of formula —(R 36 )n—O—R 37 , where R 36  and R 37  are independently selected from the group consisting of alkyl and a five or six membered heterocyclic ring and m and n are independently 0 or 1;  
 (vii) —NR 38 R 39 , where R 38  and R 39  are independently selected from the group consisting of hydrogen, alkyl, and a five or six membered heterocyclic ring;  
 (viii) —NHCOR 40 , where R 40  is selected from the group consisting of alkyl, and a five or six membered heterocyclic ring, where the ring is optionally substituted with alkyl, halogen, carboxylate, or ester;  
 (ix) —SO 2 NR 41 R 42 , where R 41  and R 42  are selected from the group consisting of hydrogen, alkyl, and a five or six membered heterocyclic ring; and  
 
         (d) R 2  is hydrogen or alkyl.  
       
     
     
         11 . A compound having formula XXI, wherein:  
       
         
           
           
               
               
           
         
         (a) A is a five or six membered ring comprised of atoms selected from the group consisting of oxygen, carbon, sulfer and nitrogen;  
         (b) m is zero, 1, or 2;  
         (c) R 1  is hydrogen,C 1 -C 6  alkyl or C 2 -C 6  alkanoyl;  
         (d) one of R 2  and R 3  independently is hydrogen and the other is a substituent selected from:  
         (1) a C 1 -C 6  alkyl group substituted by 1, 2 or 3 hydroxy groups;  
         (2) SO 3 R 4  in which R 4  is hydrogen or C 1 -C 6  alkyl unsubstituted or substituted by 1, 2 or 3 hydroxy groups;  
         (3) SO 2 NHR 5  in which R 5  is as R 4  defined above or a —(CH 2 ) n —N(C 1 -C 6  alkyl) 2  group in which n is 2 or 3;  
         (4) COOR 6  in which R 6  is C 1 -C 6  alkyl unsubstituted or substituted by phenyl or by 1, 2 or 3 hydroxy groups or phenyl;  
         (5) CONHR 7  in which R 7  is hydrogen, phenyl or C 1 -C 6  alkyl substituted by 1, 2 or 3 hydroxy groups or by phenyl;  
         (6) NHSO 2 R 8  in which R 8  is C 1 -C 6  alkyl or phenyl unsubstituted or substituted by halogen or by C 1 -C 4  alkyl;  
         (7) N(R 9 ) 2 , NHR 9  or OR 9  wherein R 9  is C 2 -C 6  alkyl substituted by 1, 2 or 3 hydroxy groups;  
         (8) NHCOR 10 , OOCR 10  or CH 2 OOCR 10  in which RIO is C 1 -C 6  alkyl substituted by 1, 2 or 3 hydroxy groups;  
         (9) NHCONH 2 ; NH—C(NH 2 )═NH; C(NH 2 )═NH; CH 2 NHC(NH 2 )═NH; CH 2 NH 2 ; OPO(OH) 2 ; CH 2 OPO(OH) 2 ; PO(OH) 2 ; or a  
         
           
             
             
                 
                 
             
           
         
         wherein X is selected from the group consisting of CH 2 , SO 2 , CO, or NHCO(CH 2 ) p  in which p is 1,2, or 3 and Z is CH 2 , O or N—R 11  in which R 11  is hydrogen or is as R 9  defined above.  
       
     
     
         12 . A method of making an indolinone compound of any one of claims  5 - 11  comprising the steps of reaching an appropriate aldehyde and oxindol and separating the indolinone from the aldehyde and oxindol reactants.  
     
     
         13 . A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient and (ii) a compound according to any one of claims  5 - 11 .  
     
     
         14 . A method for treating a disease 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 according to any one of claims  5 - 11 .  
     
     
         15 . A method for regulating tyrosine kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims  5 - 11 .  
     
     
         16 . A method of preventing or treating an abnormal condition in an organism, where the abnormal condition is associated with an aberration in a signal transduction pathway characterized by an interaction between a protein kinase and a natural binding partner, where the method comprises the following steps: 
 (a) administering a compound of any one of claims  5 - 11  to an organism; and    (b) promoting or disrupting the abnormal interaction.    
     
     
         17 . A method of preventing or treating an abnormal condition in an organism, where the abnormal condition is associated with an aberration in a signal transduction pathway characterized by an interaction between a protein kinase and a natural binding partner, where the method comprises the following steps: 
 (a) administering a compound of any one of claims  5 - 11  to an organism; and    (b) promoting or disrupting the abnormal interaction.