Abstract:
Alkoxy indolinone based acid and amide derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.

Description:
FIELD OF INVENTION 
     The invention relates to protein kinase inhibitors and to their use in treating disorders related to abnormal protein kinase activities such as cancer and inflammation. More particularly, the invention relates to alkoxy indolinone based derivatives and their pharmaceutically acceptable salts employable as protein kinase inhibitors. 
     BACKGROUND 
     Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins. Many aspects of cell life (for example, cell growth, differentiation, proliferation, cell cycle and survival) depend on protein kinase activities. Furthermore, abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, considerable effort has been directed to identifying ways to modulate protein kinase activities. In particular, many attempts have been made to identify small molecules that act as protein kinase inhibitors. 
     Several pyrrolyl-indolinone derivatives have demonstrated excellent activity as inhibitors of protein kinases (Larid et al. FASEB J. 16, 681, 2002; Smolich et al. Blood, 97, 1413, 2001; Mendel et al. Clinical Cancer Res. 9, 327, 2003; Sun et al. J. Med. Chem. 46, 1116, 2003). The clinical utility of these compounds has been promising, but has been partially compromised due to the relatively poor aqueous solubility and/or other drug properties. What is needed is a class of modified pyrrolyl-indolinone derivatives having both inhibitory activity and enhanced drug properties. 
     SUMMARY 
     The invention is directed to alkoxy indolinone based derivatives and to their use as inhibitors of protein kinases. It is disclosed herein that alkoxy indolinone based derivatives have enhanced and unexpected drug properties that advantageously distinguish this class of compounds over known pyrrolyl-indolinone derivatives having protein kinase inhibition activity. It is also disclosed herein that alkoxy indolinone based derivatives are useful in treating disorders related to abnormal protein kinase activities such as cancer. 
     One aspect of the invention is directed to a compound represented by Formula (I): 
                                
In Formula (I), R 1  is selected from the group consisting of hydrogen, halo, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, hydroxy, (C1-C6) alkoxy, amino, (C1-C6) alkylamino, amide, sulfonamide, cyano, substituted or unsubstituted (C6-C10) aryl; R 2  is selected from the group consisting of hydrogen, halo, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C1-C6) haloalkyl, hydroxy, (C1-C6) alkoxy, (C2-C8) alkoxyalkyl, amino, (C1-C6) alkylamino, (C6-C10) arylamino; R 3  is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C6-C10) aryl, (C5-C10) heteroaryl, and amide; R 4 , R 5 , R 6  and R 8  are independently selected from the group consisting of hydrogen and (C1-C6) alkyl; R 7  is (C1-C6) alkyl; R 9  is selected from the group consisting of hydroxy, (C1-C6) O-alkyl, (C3-C8) O-cycloalkyl, and NR 10 R 11 ; where R 10  and R 11  are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C2-C6) dihydroxyalkyl, (C1-C6) alkoxy, (C1-C6) alkyl carboxylic acid, (C1-C6) alkyl phosphonic acid, (C1-C6) alkyl sulfonic acid, (C1-C6) hydroxyalkyl carboxylic acid, (C1-C6) alkyl amide, (C3-C8) cycloalkyl, (C5-C8) heterocycloalkyl, (C6-C8) aryl, (C5-C8) heteroaryl, (C3-C8) cycloalkyl carboxylic acid, or R 10  and R 11  together with N forms a (C5-C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids; n is 1, 2, or 3; and m is 0, 1, or 2. Alternatively, this aspect of the invention also is directed to a pharmaceutically acceptable salt, its tautomer, a pharmaceutically acceptable salt of its tautomer, or a prodrug of Formula (I).
 
     A first preferred subgenus of this first aspect of the invention is directed to the compound, salt, tautomer, or prodrug represented by Formula (II): 
                                
In Formula (II), R 12  is selected from the group consisting of hydrogen, (C1-C6) alkyl, and (C3-C8) cycloalkyl. Other groups are as defined in Formula (I). In preferred embodiments, R 1  and R 2  are independently selected from the group consisting of hydrogen and fluoro; R 3  and R 4  are methyl; R 5 , R 6 , R 8 , and R 12  are hydrogen; R 7  is (C1-C6) alkyl; n is 1 or 2; and m is 0 or 1. Preferred species include the following compounds:
 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     A second preferred subgenus of this first aspect of the invention is directed to a compound, salt, tautomer, or prodrug represented by Formula (III): 
                                
In Formula (III), the various R groups are the same as Formula (I). In preferred embodiments, R 1  and R 2  are independently selected from the group consisting of hydrogen, halo, cyano; R 3  is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C6-C10) aryl, (C5-C10) heteroaryl, and amide; R 4 , R 5 , R 6  and R 8  are independently selected from the group consisting of hydrogen and (C1-C6) )alkyl; R 7  is (C1-C6) alkyl; n is 1 or 2; m is 0 or 1; and R 10  and R 11  are selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C2-C6) dihydroxyalkyl, (C1-C6) alkoxy, (C2-C6) alkyl carboxylic acid, (C1-C6) alkyl phosphonic acid, (C1-C6) alkyl sulfonic acid, (C2-C6) hydroxyalkyl carboxylic acid, (C1-C6) alkyl amide, (C3-C8) cycloalkyl, (C5-C8) heterocycloalkyl, (C6-C8) aryl, (C5-C8) heteroaryl, (C4-C8) cycloalkyl carboxylic acid, or R 10  and R 11  together with N forms a (C5-C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids.
 
     In a first subgroup of this second subgenus, m is 0. Preferred species of this first subgroup are represented by the following structures: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     In a second subgroup of this second subgenus, m is 1. Preferred species of this second subgroup are represented by the following structures: 
     
       
                 
         
             
             
         
      
     
     Further species of the second aspect of the invention are represented by the following structures: 
                                
wherein: R 9  is selected from the group consisting of radicals represented by the following structures:
 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Another aspect of the invention is directed to a method for the modulation of the catalytic activity of a protein kinase with a compound or salt of any one of the compounds of Formulas (I-III). In a preferred mode, the protein kinase is selected from the group consisting of VEGF receptors and PDGF receptors. 
    
    
     
       BRIEF DESCRIPTION OF FIGURES 
         FIG. 1  illustrates a scheme that is used for the synthesis of the 3-alkoxy-4-acylaminoamide derivatives starting from methyl 3-hydroxy-4-aminobutanoate hydrochlorides and the activated acylating agent 1-3. 
         FIG. 2  illustrates a scheme that is used for the synthesis of the 2-alkoxy-3-acylaminoamide derivatives starting from methyl 2-hydroxy-3-aminopropionate hydrochlorides and the activated acylating agent 1-3. 
         FIG. 3  illustrates a scheme that is used for the synthesis of the (2S)-2-alkoxy-4-acylamino-amide derivatives starting from methyl (2S)-2-hydroxy-4-aminobutanoate hydrochloride and the activated acylating agent 1-3. 
     
    
    
     DETAILED DESCRIPTION 
     Examples 1-8 
     The synthesis of acids (1-4) and amides (1-5) is shown in  FIG. 1 . Variations from this general synthetic procedure can be understood and carried out by those skilled in the art. Thus, the compounds of the present invention can be synthesized by those skilled in the art. 
     Example 1 
     4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-3-methoxy-butyric acid 
     
       
                 
         
             
             
         
      
     
     To a suspension of methyl 4-amino-3-hydroxybutyrate (1.0 equiv, which was prepared by refluxing the free amino acid in dry methanol with 1.2 equiv HCl) and DIEA (5 equiv) in DCM, Mmt-Cl (1.1 equiv) was added portion-wise at 25° C. After stirring overnight, the DCM was removed under reduced pressure. The residue was suspended in ethyl acetate, washed with brine (3×), dried over anhydrous Na 2 SO 4 . The ethyl acetate was then removed, and the residue was dried overnight under high vacuum, and subjected to flash chromatography to give compound 1-1. To a solution of compound 1-1 in dry DMF, NaH (1.5 equiv) was added under argon. After stirring at 25° C. for 1 h, Mel (5 equiv) was added to the solution, and the resulting suspension was gently shaken at 25° C. overnight. The DMF was removed under vacuum; the residue was suspended in ethyl acetate, washed with brine (3×), and dried over anhydrous Na 2 SO 4 . After the ethyl acetate was removed via evaporation the resulting residue was treated with 1% TFA in DCE/DCM for 30 min. The organic solvents were then removed under reduced pressure, and the resulting residue was triturated with hexane (3×) to obtain the free amino acid 1-2. This amino acid was used directly in the next step without any purification and characterization. Thus, to a solution of 1-2 (2 equiv) and DIEA (5 equiv) in DMF, compound 1-3 (1 equiv) was added at 25° C. After stirring for 30 min (LC-MS show the complete consumption of 1-3), KOH (5 equiv) in water was added, and the solution was stirred for another 2 h (LC-MS demonstrated a complete hydrolysis). The solvents were removed under reduced pressure, and HCl (1N, excess) was added to give a precipitate. This precipitate was collected and washed (by water) by filtration, dried under high vacuum to give the title compound (95% based on compound 1-3). LC-MS: single peak at 254 nm, MH +  calcd. for C 21 H 22 FN 3 O 5 : 416, obtained: 416.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.67 (s, 1H), 12.18 (b, 1H), 10.90 (s, 1H), 7.75 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.71 (s, 1H), 7.64 (t, J=6.0 Hz, 1H), 6.92 (m, 1H) 6.83 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 3.73 (m, 1H), 3.43-3.31 (m, 2H), 3.22 (s, 3H), 2.52-2.35 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H). 
     Example 2 
     3-Ethoxy-4-({5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-butyric acid 
     
       
                 
         
             
             
         
      
     
     A similar route as that for the synthesis of Example 1 was used to prepare the title compound. Iodoethane was used instead of iodomethane to obtain the 3-ethoxy compound (9.7% based on compound 1-3). LC-MS: single peak at 254 nm, MH +  calcd. for C 22 H 24 FN 3 O 5 : 430, obtained: 430. 
     Examples 3-8 
     The general procedure for the synthesis of amides (1-5): An amine (2 equiv) was added to a solution of the acid (1-4), HATU (1.05 mmol), and DIEA (5 equiv) in DMF (5 mL). After the solution was stirred at 25° C. for 2 h, aqueous HCl (2 mL, 1N) was added. This solution was subjected to preparative HPLC to obtain the pure amide product, which was subsequently characterized by LC-MS and NMR spectroscopy. 
     Example 3 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-dimethylcarbamoyl-2-ethoxy-propyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 13 mg of the title compound (41%) from 30 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 24 H 29 FN 4 O 4 : 457, obtained: 457.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.72 (s, 1H), 7.60 (t, J=6.0 Hz, 1H), 6.92 (m, 1H) 6.83 (dd, J=4.8 Hz, 8.4 Hz, 1H), 3.89 (m, 1H), 3.58-3.45 (m, 2H), 3.40-3.27 (m, 2H, buried in water signals), 2.97 (s, 3H), 2.82 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 1.07 (t, J=7.2 Hz, 3H). 
     Example 4 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-dimethylcarbamoyl-2-methoxy-propyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 46 mg of the title compound (36%) from 120 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 23 H 27 FN 4 O 4 : 443, obtained: 443.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.71 (s, 1H), 7.63 (t, J=5.6 Hz, 1H), 6.92 (m, 1H), 6.83 (dd, J=4.8 Hz, 8.8 Hz, 1H), 3.78 (m, 1H), 3.42-3.31 (m, 2H), 3.30 (s, 3H), 2.97 (s, 3H), 2.82 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 2.63-2.43 (m, 2H). 
     Example 5 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-methoxy-4-morpholin-4-yl-4-oxo-butyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 48 mg of the title compound (37%) from 110 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 25 H 29 FN 4 O 6 : 485, obtained: 485.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.71 (s, 1H), 7.63 (t, J=5.6 Hz, 1H), 6.92 (m, 1H), 6.83 (dd, J=4.8 Hz, 8.4 Hz, 1H), 3.80 (m, 1H), 3.55 (m, 4H), 3.47 (m, 4H), 3.38 (m, 2H), 3.31 (s, 3H), 2.60 (m, 1H), 2.45 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H). 
     Example 6 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [4-(4-hydroxy-piperidin-1-yl)-2-methoxy-4-oxo-butyl]-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 20 mg of the title compound (33%) from 50 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 26 H 31 FN 4 O 5 : 499, obtained: 499.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, 9.6 Hz, 1H), 7.72 (s, 1H), 7.63 (t, J=5.6 Hz, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.4 Hz, 8.4 Hz, 1H), 3.92 (m, 1H), 3.78 (m, 1H), 3.68 (b, 1H), 3.30 (s, 3H), 3.15 (m, 1H), 3.01 (m, 1H), 2.60 (m, 1H), 2.55 (m, 2H), 2.50 (m, 1H), 2.45 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 1.70 (m, 2H), 1.30 (m, 2H). 
     Example 7 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-methoxy-4-oxo-4-pyrrolidin-1-yl-butyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 40 mg of the title compound (32%) from 110 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 25 H 29 FN 4 O 4 : 469, obtained: 469.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, 9.6 Hz, 1H), 7.71 (s, 1H), 7.63 (t, J=5.6 Hz, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.8 Hz, 8.8 Hz, 1H), 3.82 (m, 1H), 3.50-3.25 (m, 6H), 3.30 (s, 3H), 2.55-2.45 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 1.86 (m, 2H), 1.76 (m, 2H). 
     Example 8 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid[2-methoxy-3-(methoxy-methyl-carbamoyl)-propyl]-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 15 mg of the title compound (15%) from 80 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 23 H 27 FN 4 O 5 : 459, obtained: 459.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.90 (s, 1H), 7.76 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.72 (s, 1H), 7.68 (t, J=6.0 Hz, 1H), 6.93 (m, 1H), 6.84 (dd, J=4.4 Hz, 8.4 Hz, 1H), 3.79 (m, 1H), 3.66 (s, 3H), 3.50-3.35 (m, 2H), 3.31 (s, 3H), 3.13 (s, 3H), 2.55-2.45 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H). 
     Examples 9-15 
     The synthesis of acids (2-3) and amides (2-4) is shown in  FIG. 2 . Variations from this general synthetic procedure can be understood and carried out by those skilled in the art. Thus, the compounds of the present invention can be synthesized by those skilled in the art. 
     Example 9 
     3-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-2-methoxy-propionic acid 
     
       
                 
         
             
             
         
      
     
     To a suspension of methyl 3-amino-2-hydroxypropionate (1.0 equiv, which was prepared by refluxing the free amino acid isoserine in dry methanol with 1.2 equiv HCl) and DIEA (5 equiv) in DCM, Mmt-Cl (1.1 equiv) was added portion-wise at 25° C. After stirring overnight, the DCM was removed under reduced pressure. The residue was suspended in ethyl acetate, washed with brine (3×), dried over anhydrous Na 2 SO 4 . The ethyl acetate was then removed, and the residue was dried overnight under high vacuum, and subjected to flash chromatography to give compound 2-1. To a solution of compound 2-1 in dry DMF, NaH (1.5 equiv) was added under argon. After stirring at 25° C. for 1 h, Mel (5 equiv) was added to the solution, and the resulting suspension was gently stirred at 25° C. overnight. The DMF was removed under vacuum; the residue was suspended in ethyl acetate, washed with brine (3×), and dried over anhydrous Na 2 SO 4 . After the ethyl acetate was removed via evaporation the resulting residue was treated with 1% TFA in DCE/DCM for 30 min. The organic solvents were then removed under reduced pressure, and the resulting residue was triturated with hexane (3×) to obtain the free amino acid 2-2. This amino acid was used directly in the next step without any purification and characterizations. Thus, to a solution of 2-2 (2 equiv) and DIEA (5 equiv) in DMF, compound 1-3 (1 equiv) was added at 25° C. After stirring for 30 min (LC-MS show the complete consumption of 1-3), KOH (5 equiv) in water was added, and the solution was stirred for another 2 h (LC-MS demonstrated a complete hydrolysis). The solvents were removed under reduced pressure, and HCl (1N, excess) was added to give a precipitate. This precipitate was collected by filtration, washed with water and dried under high vacuum to give the title compound (99% based on compound 1-3). LC-MS: single peak at 254 nm, MH +  calcd. for C 20 H 20 FN 3 O 5 : 402, obtained: 402.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.67 (s, 1H), 12.83 (b, 1H), 10.90 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.71 (s, 1H), 7.69 (t, J=6.0 Hz, 1H), 6.92 (m, 1H), 6.82 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 3.90 (m, 1H), 3.55 (m, 1H), 3.41 (m, 1H), 3.32 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H). 
     Example 10 
     2-Ethoxy-3-({5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-propionic acid 
     
       
                 
         
             
             
         
      
     
     A similar route as that for the synthesis of Example 9 was used to prepare the title compound. Iodoethane was used instead of iodomethane to obtain the 2-ethoxy compound (38% based on compound 1-3). LC-MS: single peak at 254 nm, MH +  calcd. for C 21 H 22 FN 4 O 5 : 416, obtained: 416.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.67 (s, 1H), 12.80 (b, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.2 Hz, 1H), 7.71 (s, 1H), 7.68 (t, J=6.0 Hz, 1H), 6.92 (m, 1H), 6.83 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 4.00 (dd, J=5.2 Hz, J=7.6 Hz, 1H), 3.58 (m, 2H), 3.41 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 1.14 (t, J=6.8 Hz, 3H). 
     Examples 11-15 
     The general procedure for the synthesis of amides (compounds 2-4): A corresponding amine (2 equiv) was added to a solution of the acid (compound 2-3), HATU (1.05 mmol), and DIEA (5 equiv) in DMF (5 mL). After the solution was stirred at 25° C. for 2 h, aqueous HCl (2 mL, 1N) was added. This solution was subjected to preparative HPLC to obtain the pure amide product, which was subsequently characterized by LC-MS and NMR spectroscopy. 
     Example 11 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylcarbamoyl-2-ethoxy-ethyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 46 mg of the title compound (62%) from 70 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 23 H 27 FN 4 O 4 : 443, obtained: 443. 
     Example 12 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-ethoxy-3-morpholin-4-yl-3-oxo-propyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 40 mg of the title compound (49%) from 70 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 25 H 29 FN 4 O 5 : 485, obtained: 485.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.67 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.71 (s, 1H), 7.70 (m, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 4.40 (m, 1H), 3.73-3.35 (m, 12H), 2.43 (s, 3H) 2.41 (s, 3H), 1.12 (t, J=7.2 Hz, 3H). 
     Example 13 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylcarbamoyl-2-methoxy-ethyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 93 mg of the title compound (76%) from 115 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 22 H 25 FN 4 O 4 : 429, obtained: 429.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.90 (s, 1H), 7.75 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.72 (m, 1H), 7.71 (s, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.8 Hz, J=8.8 Hz, 1H), 4.40 (dd, J=4.8 Hz, J=7.2 Hz, 1H), 3.50 (m, 1H), 3.32 (m, 1H), 3.24 (s, 3H), 3.10 (s, 3H), 2.86 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H). 
     Example 14 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-methoxy-3-morpholin-4-yl-3-oxo-propyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 98 mg of the title compound (73%) from 115 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 24 H 27 FN 4 O 5 : 471, obtained: 471.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.67 (s, 1H), 10.89 (s, 1H), 7.75 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.71 (s, 1H), 7.70 (m, 1H), 6.92 (m, 1H), 6.83 (dd, J=4.8 Hz, J=8.8 Hz, 1H), 4.34 (dd, J=4.8 Hz, J=7.2 Hz, 1H), 3.85-3.30 (m, 10H), 3.26 (s, 3H), 2.44 (s, 3H), 2.42 (s, 3H). 
     Example 15 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-methoxy-3-oxo-3-pyrrolidin-1-yl-propyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 86 mg of the title compound (66%) from 115 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 24 H 27 FN 4 O 4 : 455, obtained: 455.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.67 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.70 (m, 1H), 7.71 (s, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.4 Hz, J=8.4 Hz, 1H), 4.20 (dd, J=5.2 Hz, J=7.2 Hz, 1H), 3.60-3.47 (m, 3H), 3.43-3.28 (m, 3H), 3.26 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 1.88 (m, 2H), 1.78 (m, 2H). 
     Examples 16-315 
     Still further amide examples are shown in the following table: 
     
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex# 
                 Core 
                 R 
               
               
                   
               
             
          
           
               
                 16 
                 I 
                 a 
               
               
                 17 
                 I 
                 b 
               
               
                 18 
                 I 
                 c 
               
               
                 19 
                 I 
                 d 
               
               
                 20 
                 I 
                 e 
               
               
                 21 
                 I 
                 f 
               
               
                 22 
                 I 
                 g 
               
               
                 23 
                 I 
                 h 
               
               
                 24 
                 I 
                 i 
               
               
                 25 
                 I 
                 j 
               
               
                 26 
                 I 
                 k 
               
               
                 27 
                 I 
                 l 
               
               
                 28 
                 I 
                 m 
               
               
                 29 
                 I 
                 n 
               
               
                 30 
                 I 
                 o 
               
               
                 31 
                 I 
                 p 
               
               
                 32 
                 I 
                 q 
               
               
                 33 
                 I 
                 r 
               
               
                 34 
                 I 
                 s 
               
               
                 35 
                 I 
                 t 
               
               
                 36 
                 I 
                 u 
               
               
                 37 
                 I 
                 v 
               
               
                 38 
                 I 
                 w 
               
               
                 39 
                 I 
                 x 
               
               
                 40 
                 I 
                 y 
               
               
                 41 
                 I 
                 z 
               
               
                 42 
                 I 
                 aa 
               
               
                 43 
                 I 
                 ab 
               
               
                 44 
                 I 
                 ac 
               
               
                 45 
                 I 
                 ad 
               
               
                 46 
                 I 
                 ae 
               
               
                 47 
                 I 
                 af 
               
               
                 48 
                 I 
                 ag 
               
               
                 49 
                 I 
                 ah 
               
               
                 50 
                 I 
                 ai 
               
               
                 51 
                 I 
                 aj 
               
               
                 52 
                 I 
                 ak 
               
               
                 53 
                 I 
                 al 
               
               
                 54 
                 I 
                 am 
               
               
                 55 
                 I 
                 an 
               
               
                 56 
                 I 
                 ao 
               
               
                 57 
                 I 
                 ap 
               
               
                 58 
                 I 
                 aq 
               
               
                 59 
                 I 
                 ar 
               
               
                 60 
                 I 
                 as 
               
               
                 61 
                 I 
                 at 
               
               
                 62 
                 I 
                 au 
               
               
                 63 
                 I 
                 av 
               
               
                 64 
                 I 
                 aw 
               
               
                 65 
                 I 
                 ax 
               
               
                 66 
                 II 
                 a 
               
               
                 67 
                 II 
                 b 
               
               
                 68 
                 II 
                 c 
               
               
                 69 
                 II 
                 d 
               
               
                 70 
                 II 
                 e 
               
               
                 71 
                 II 
                 f 
               
               
                 72 
                 II 
                 g 
               
               
                 73 
                 II 
                 h 
               
               
                 74 
                 II 
                 i 
               
               
                 75 
                 II 
                 j 
               
               
                 76 
                 II 
                 k 
               
               
                 77 
                 II 
                 l 
               
               
                 78 
                 II 
                 m 
               
               
                 79 
                 II 
                 n 
               
               
                 80 
                 II 
                 o 
               
               
                 81 
                 II 
                 p 
               
               
                 82 
                 II 
                 q 
               
               
                 83 
                 II 
                 r 
               
               
                 84 
                 II 
                 s 
               
               
                 85 
                 II 
                 t 
               
               
                 86 
                 II 
                 u 
               
               
                 87 
                 II 
                 v 
               
               
                 88 
                 II 
                 w 
               
               
                 89 
                 II 
                 x 
               
               
                 90 
                 II 
                 y 
               
               
                 91 
                 II 
                 z 
               
               
                 92 
                 II 
                 aa 
               
               
                 93 
                 II 
                 ab 
               
               
                 94 
                 II 
                 ac 
               
               
                 95 
                 II 
                 ad 
               
               
                 96 
                 II 
                 ae 
               
               
                 97 
                 II 
                 af 
               
               
                 98 
                 II 
                 ag 
               
               
                 99 
                 II 
                 ah 
               
               
                 100 
                 II 
                 ai 
               
               
                 101 
                 II 
                 aj 
               
               
                 102 
                 II 
                 ak 
               
               
                 103 
                 II 
                 at 
               
               
                 104 
                 II 
                 am 
               
               
                 105 
                 II 
                 an 
               
               
                 106 
                 II 
                 ao 
               
               
                 107 
                 II 
                 ap 
               
               
                 108 
                 II 
                 aq 
               
               
                 109 
                 II 
                 ar 
               
               
                 110 
                 II 
                 as 
               
               
                 111 
                 II 
                 at 
               
               
                 112 
                 II 
                 au 
               
               
                 113 
                 II 
                 av 
               
               
                 114 
                 II 
                 aw 
               
               
                 115 
                 II 
                 ax 
               
               
                 116 
                 III 
                 a 
               
               
                 117 
                 III 
                 b 
               
               
                 118 
                 III 
                 c 
               
               
                 119 
                 III 
                 d 
               
               
                 120 
                 III 
                 e 
               
               
                 121 
                 III 
                 f 
               
               
                 122 
                 III 
                 g 
               
               
                 123 
                 III 
                 h 
               
               
                 124 
                 III 
                 i 
               
               
                 125 
                 III 
                 j 
               
               
                 126 
                 III 
                 k 
               
               
                 127 
                 III 
                 l 
               
               
                 128 
                 III 
                 m 
               
               
                 129 
                 III 
                 n 
               
               
                 130 
                 III 
                 o 
               
               
                 131 
                 III 
                 p 
               
               
                 132 
                 III 
                 q 
               
               
                 133 
                 III 
                 r 
               
               
                 134 
                 III 
                 s 
               
               
                 135 
                 III 
                 t 
               
               
                 136 
                 III 
                 u 
               
               
                 137 
                 III 
                 v 
               
               
                 138 
                 III 
                 w 
               
               
                 139 
                 III 
                 x 
               
               
                 140 
                 III 
                 y 
               
               
                 141 
                 III 
                 z 
               
               
                 142 
                 III 
                 aa 
               
               
                 143 
                 III 
                 ab 
               
               
                 144 
                 III 
                 ac 
               
               
                 145 
                 III 
                 ad 
               
               
                 146 
                 III 
                 ae 
               
               
                 147 
                 III 
                 af 
               
               
                 148 
                 III 
                 ag 
               
               
                 149 
                 III 
                 ah 
               
               
                 150 
                 III 
                 ai 
               
               
                 151 
                 III 
                 aj 
               
               
                 152 
                 III 
                 ak 
               
               
                 153 
                 III 
                 al 
               
               
                 154 
                 III 
                 am 
               
               
                 155 
                 III 
                 an 
               
               
                 156 
                 III 
                 ao 
               
               
                 157 
                 III 
                 ap 
               
               
                 158 
                 III 
                 aq 
               
               
                 159 
                 III 
                 ar 
               
               
                 160 
                 III 
                 as 
               
               
                 161 
                 III 
                 at 
               
               
                 162 
                 III 
                 au 
               
               
                 163 
                 III 
                 av 
               
               
                 164 
                 III 
                 aw 
               
               
                 165 
                 III 
                 ax 
               
               
                 166 
                 IV 
                 a 
               
               
                 167 
                 IV 
                 b 
               
               
                 168 
                 IV 
                 c 
               
               
                 169 
                 IV 
                 d 
               
               
                 170 
                 IV 
                 e 
               
               
                 171 
                 IV 
                 f 
               
               
                 172 
                 IV 
                 g 
               
               
                 173 
                 IV 
                 h 
               
               
                 174 
                 IV 
                 i 
               
               
                 175 
                 IV 
                 j 
               
               
                 176 
                 IV 
                 k 
               
               
                 177 
                 IV 
                 l 
               
               
                 178 
                 IV 
                 m 
               
               
                 179 
                 IV 
                 n 
               
               
                 180 
                 IV 
                 o 
               
               
                 181 
                 IV 
                 p 
               
               
                 182 
                 IV 
                 q 
               
               
                 183 
                 IV 
                 r 
               
               
                 184 
                 IV 
                 s 
               
               
                 185 
                 IV 
                 t 
               
               
                 186 
                 IV 
                 u 
               
               
                 187 
                 IV 
                 v 
               
               
                 188 
                 IV 
                 w 
               
               
                 189 
                 IV 
                 x 
               
               
                 190 
                 IV 
                 y 
               
               
                 191 
                 IV 
                 z 
               
               
                 192 
                 IV 
                 aa 
               
               
                 193 
                 IV 
                 ab 
               
               
                 194 
                 IV 
                 ac 
               
               
                 195 
                 IV 
                 ad 
               
               
                 196 
                 IV 
                 ae 
               
               
                 197 
                 IV 
                 af 
               
               
                 198 
                 IV 
                 ag 
               
               
                 199 
                 IV 
                 ah 
               
               
                 200 
                 IV 
                 ai 
               
               
                 201 
                 IV 
                 aj 
               
               
                 202 
                 IV 
                 ak 
               
               
                 203 
                 IV 
                 al 
               
               
                 204 
                 IV 
                 am 
               
               
                 205 
                 IV 
                 an 
               
               
                 206 
                 IV 
                 ao 
               
               
                 207 
                 IV 
                 ap 
               
               
                 208 
                 IV 
                 aq 
               
               
                 209 
                 IV 
                 ar 
               
               
                 210 
                 IV 
                 as 
               
               
                 211 
                 IV 
                 at 
               
               
                 212 
                 IV 
                 au 
               
               
                 213 
                 IV 
                 av 
               
               
                 214 
                 IV 
                 aw 
               
               
                 215 
                 IV 
                 ax 
               
               
                 216 
                 V 
                 a 
               
               
                 217 
                 V 
                 b 
               
               
                 218 
                 V 
                 c 
               
               
                 219 
                 V 
                 d 
               
               
                 220 
                 V 
                 e 
               
               
                 221 
                 V 
                 f 
               
               
                 222 
                 V 
                 g 
               
               
                 223 
                 V 
                 h 
               
               
                 224 
                 V 
                 i 
               
               
                 225 
                 V 
                 j 
               
               
                 226 
                 V 
                 k 
               
               
                 227 
                 V 
                 l 
               
               
                 228 
                 V 
                 m 
               
               
                 229 
                 V 
                 n 
               
               
                 230 
                 V 
                 o 
               
               
                 231 
                 V 
                 p 
               
               
                 232 
                 V 
                 q 
               
               
                 233 
                 V 
                 r 
               
               
                 234 
                 V 
                 s 
               
               
                 235 
                 V 
                 t 
               
               
                 236 
                 V 
                 u 
               
               
                 237 
                 V 
                 v 
               
               
                 238 
                 V 
                 w 
               
               
                 239 
                 V 
                 x 
               
               
                 240 
                 V 
                 y 
               
               
                 241 
                 V 
                 z 
               
               
                 242 
                 V 
                 aa 
               
               
                 243 
                 V 
                 ab 
               
               
                 244 
                 V 
                 ac 
               
               
                 245 
                 V 
                 ad 
               
               
                 246 
                 V 
                 ae 
               
               
                 247 
                 V 
                 af 
               
               
                 248 
                 V 
                 ag 
               
               
                 249 
                 V 
                 ah 
               
               
                 250 
                 V 
                 ai 
               
               
                 251 
                 V 
                 aj 
               
               
                 252 
                 V 
                 ak 
               
               
                 253 
                 V 
                 al 
               
               
                 254 
                 V 
                 am 
               
               
                 255 
                 V 
                 an 
               
               
                 256 
                 V 
                 ao 
               
               
                 257 
                 V 
                 ap 
               
               
                 258 
                 V 
                 aq 
               
               
                 259 
                 V 
                 ar 
               
               
                 260 
                 V 
                 as 
               
               
                 261 
                 V 
                 at 
               
               
                 262 
                 V 
                 au 
               
               
                 263 
                 V 
                 av 
               
               
                 264 
                 V 
                 aw 
               
               
                 265 
                 V 
                 ax 
               
               
                 266 
                 VI 
                 a 
               
               
                 267 
                 VI 
                 b 
               
               
                 268 
                 VI 
                 c 
               
               
                 269 
                 VI 
                 d 
               
               
                 270 
                 VI 
                 e 
               
               
                 271 
                 VI 
                 f 
               
               
                 272 
                 VI 
                 g 
               
               
                 273 
                 VI 
                 h 
               
               
                 274 
                 VI 
                 i 
               
               
                 275 
                 VI 
                 j 
               
               
                 276 
                 VI 
                 k 
               
               
                 277 
                 VI 
                 l 
               
               
                 278 
                 VI 
                 m 
               
               
                 279 
                 VI 
                 n 
               
               
                 280 
                 VI 
                 o 
               
               
                 281 
                 VI 
                 p 
               
               
                 282 
                 VI 
                 q 
               
               
                 283 
                 VI 
                 r 
               
               
                 284 
                 VI 
                 s 
               
               
                 285 
                 VI 
                 t 
               
               
                 286 
                 VI 
                 u 
               
               
                 287 
                 VI 
                 v 
               
               
                 288 
                 VI 
                 w 
               
               
                 289 
                 VI 
                 x 
               
               
                 290 
                 VI 
                 y 
               
               
                 291 
                 VI 
                 z 
               
               
                 292 
                 VI 
                 aa 
               
               
                 293 
                 VI 
                 ab 
               
               
                 294 
                 VI 
                 ac 
               
               
                 295 
                 VI 
                 ad 
               
               
                 296 
                 VI 
                 ae 
               
               
                 297 
                 VI 
                 af 
               
               
                 298 
                 VI 
                 ag 
               
               
                 299 
                 VI 
                 ah 
               
               
                 300 
                 VI 
                 ai 
               
               
                 301 
                 VI 
                 aj 
               
               
                 302 
                 VI 
                 ak 
               
               
                 303 
                 VI 
                 al 
               
               
                 304 
                 VI 
                 am 
               
               
                 305 
                 VI 
                 an 
               
               
                 306 
                 VI 
                 ao 
               
               
                 307 
                 VI 
                 ap 
               
               
                 308 
                 VI 
                 aq 
               
               
                 309 
                 VI 
                 ar 
               
               
                 310 
                 VI 
                 as 
               
               
                 311 
                 VI 
                 at 
               
               
                 312 
                 VI 
                 au 
               
               
                 313 
                 VI 
                 av 
               
               
                 314 
                 VI 
                 aw 
               
               
                 315 
                 VI 
                 ax 
               
               
                   
               
             
          
         
       
     
     In the above table, R 9  is selected from the following radicals: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     These amide examples 16-315 can be made by those skilled in the art following the above procedure and/or known procedures. 
     Examples 316-320 
     The synthesis of acids (3-3) and amides (3-4) is shown in  FIG. 3 . Variations from this general synthetic procedure can be understood and carried out by those skilled in the art. Thus, the compounds of the present invention can be synthesized by those skilled in the art. 
     Example 316 
     (S)-4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-2-methoxy-butyric acid 
     
       
                 
         
             
             
         
      
     
     To a suspension of methyl 4-amino-2-hydroxybutyrate (1.0 equiv, which was prepared by refluxing the free amino acid in dry methanol with 1.2 equiv HCl) and DIEA (5 equiv) in DCM, Mmt-Cl (1.1 equiv) was added portion-wise at 25° C. After stirring overnight, the DCM was removed under reduced pressure. The residue was suspended in ethyl acetate, washed with brine (3×), dried over anhydrous Na 2 SO 4 . The ethyl acetate was then removed, and the residue was dried overnight under high vacuum, and subjected to flash chromatography to give compound 3-1. To a solution of compound 3-1 in dry DMF, NaH (1.5 equiv) was added under argon. After stirring at 25° C. for 1 h, Mel (5 equiv) was added to the solution, and the resulting suspension was gently stirred at 25° C. overnight. The DMF was removed under vacuum; the residue was suspended in ethyl acetate, washed with brine (3×), and dried over anhydrous Na 2 SO 4 . After the ethyl acetate was removed via evaporation the resulting residue was treated with 1% TFA in DCE/DCM for 30 min. The organic solvents were then removed under reduced pressure, and the resulting residue was triturated with hexane (3×) to obtain the free amino acid 3-2. This amino acid was used directly in the next step without any purification and characterization. Thus, to a solution of 3-2 (2 equiv) and DIEA (5 equiv) in DMF, compound 1-3 (1 equiv) was added at 25° C. After stirring for 30 min (LC-MS show the complete consumption of 1-3), KOH (5 equiv) in water was added, and the solution was stirred for another 2 h (LC-MS demonstrated a complete hydrolysis). The solvents were removed under reduced pressure, and HCl (1N, excess) was added to give a precipitate. This precipitate was collected and washed (by water) by filtration, dried under high vacuum to give the title compound (97% based on compound 1-3). LC-MS: single peak at 254 nm, MH +  calcd. for C 21 H 22 FN 3 O 5 : 416, obtained: 416.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 12.80 (b, 1H), 10.90 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.71 (s, 1H), 7.65 (t, J=5.6 Hz, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 3.77 (dd, J=4.0 Hz, J=8.8 Hz, 1H), 3.40-3.30 (m, 2H), 3.30 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 1.92 (m, 1H), 1.78 (m, 1H). 
     Example 317 
     (S)-2-Ethoxy-4-({5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-butyric acid 
     
       
                 
         
             
             
         
      
     
     A similar route as that for the synthesis of Example 316 was used to prepare the title compound. Iodoethane was used instead of iodomethane to obtain the 2-ethoxy compound (84% based on compound 1-3). LC-MS: single peak at 254 nm, MH +  calcd. for C 22 H 24 FN 3 O 5 : 430, obtained: 430.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 12.70 (b, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.71 (s, 1H), 7.66 (t, J=5.6 Hz, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 3.85 (dd, J=4.0 Hz, J=8.4 Hz, 1H), 3.58 (m, 1H), 3.40-3.25 (m, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 1.92 (m, 1H), 1.77 (m, 1H), 1.13 (t, J=7.2 Hz, 3H). 
     Example 318-320 
     The general procedure for the synthesis of amides (compounds 3-4): A corresponding amine (2 equiv) was added to a solution of the acid (compound 3-3), HATU (1.05 mmol), and DIEA (5 equiv) in DMF (5 mL). After the solution was stirred at 25° C. for 2 h, aqueous HCl (2 mL, 1N) was added. This solution was subjected to preparative HPLC to obtain the pure amide product, which was subsequently characterized by LC-MS and NMR spectroscopy. 
     Example 318 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-3-dimethylcarbamoyl-3-methoxy-propyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 37 mg of the title compound (58%) from 60 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 23 H 27 FN 4 O 4 : 443, obtained: 443.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.72 (s, 1H), 7.65 (t, J=5.6 Hz, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 4.20 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 3.30 (m, 2H), 3.27 (s, 3H), 3.04 (s, 3H), 2.88 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 1.80 (m, 2H). 
     Example 319 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-3-methoxy-4-morpholin-4-yl-4-oxo-butyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 32 mg of the title compound (46%) from 60 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 25 H 29 FN 4 O 5 : 485, obtained: 485.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.68 (s, 1H), 10.89 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.72 (s, 1H), 7.65 (t, J=5.6 Hz, 1H), 6.93 (m, 1H), 6.83 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 4.19 (dd, J=4.8 Hz, J=8.0 Hz, 1H), 3.57 (m, 6H), 3.47 (m, 2H), 3.28 (m, 2H), 3.23 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H), 1.79 (m, 2H). 
     Example 320 
     5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-3-dimethylcarbamoyl-3-ethoxy-propyl)-amide 
     
       
                 
         
             
             
         
      
     
     Preparative HPLC gave 67 mg of the title compound (57%) from 120 mg starting material (acid). LC-MS: single peak at 254 nm, MH +  calcd. for C 24 H 29 FN 4 O 4 : 457, obtained: 457.  1 H-NMR (DMSO-d 6 , 400 MHz), δ 13.67 (s, 1H), 10.88 (s, 1H), 7.76 (dd, J=2.4 Hz, J=9.6 Hz, 1H), 7.71 (s, 1H), 7.56 (m, 1H), 6.91 (m, 1H), 6.83 (m, 1H), 4.25 (m, 1H), 3.45-3.25 (m, 4H), 3.03 (s, 3H), 2.83 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H), 1.80 (m, 2H). 
     The compounds described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. 
     VEGFR Biochemical Assay 
     The compounds were assayed for biochemical activity by Upstate Ltd at Dundee, United Kingdom, according to the following procedure. In a final reaction volume of 25 μl, KDR (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/ml myelin basic protein, 10 mM MgAcetate and [γ- 33 P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 μl of a 3% phosphoric acid solution. 10 μl of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. 
     Compounds of the present invention were tested in this assay and exhibited IC 50  between 1-5,000 nM. 
     PDGFR Phosphorylation Assay 
     NIH3T3 cells are plated in a 96 well plate in DMEM+10% FBS. Following cell attachment the cells are serum starved overnight before adding the chemical test compounds to a final concentration of 0.1% DMSO. Following a 1 hour incubation at 37° C. cells are removed from the incubator and allowed to cool to RT for 20 min before stimulation with PDGF-BB for 15 min at RT. Cells are placed on ice for 5 min, the media removed and the cells are lysed with 100 μwell lysis buffer for 1 hour at 4° C. Plates are spun at 2000 rpm for 30 min at 4° C. and solubilized phosphorylated PDGFR is quantitated by ELISA. 
     High binding microplates are incubated overnight at RT with anti-mouse PDGFR-b capture-antibody in PBS, washed with PBS+0.05% Tween20 and blocked for 4 h at RT with PBS+1% BSA and washed again. 100 μL lysate/well is incubated overnight at 4° C. Plates are washed and wells are incubated with 100 μL/well of mouse anti-phosphotyrosine-HRP antibody for 2 h at 37° C. Plates are washed again and colorimetric detection is performed using TMB as substrate. 
     Most of the compounds in this invention showed IC 50  of less than 1 μM in this assay. 
     VEGFR Phosphorylation Assay 
     NIHT3T cells overexpressing mouse VEGFR-2 (FLK-1) are plated in a 96 well plate in DMEM+10% FBS. Following cell attachment for 4 hours the cells are serum starved overnight before adding the chemical test compounds to a final concentration of 0.1% DMSO. Following a 1 hour incubation at 37° C. cells are stimulated for 15 min at 37° C. with VEGF165. Cells are placed on ice for 5 min, the media removed, washed once with ice cold PBS and the cells are lysed with 50 μL/well lysis buffer for 1 hour at 4° C. Plates are spun for 10 min at 2000 rpm at 4° C. and solubilized phosphorylated VEGFR is quantitated by ELISA. 
     High binding microplates are incubated overnight at room temperature with VEGFR antibody in 50 μL PBS, washed with PBS+0.05% Tween20 and blocked for 4 h at RT with PBS+1% BSA and washed again. 50 μL lysate/well is incubated overnight at 4° C. Plates are washed and wells are incubated with 50 μL/well of mouse anti-phosphotyrosine-HRP antibody for 2 h at 37° C. Plates are washed again and colorimetric detection is performed using TMB as substrate. 
     Most of the compounds in this invention showed IC 50  of less than 1 μM in this assay. 
     Cellular Assay: HUVEC: VEGF Induced Proliferation 
     The compounds were assayed for cellular activity in the VEGF induced proliferation of HUVEC cells. HUVEC cells (Cambrex, CC-2517) were maintained in EGM (Cambrex, CC-3124) at 37° C. and 5% CO 2 . HUVEC cells were plated at a density 5000 cells/well (96 well plate) in EGM. Following cell attachment (1 hour) the EGM-medium was replaced by EBM (Cambrex, CC-3129) +0.1% FBS (ATTC, 30-2020) and the cells were incubated for 20 hours at 37° C. The medium was replaced by EBM +1% FBS, the compounds were serial diluted in DMSO and added to the cells to a final concentration of 0-5,000 nM and 1% DMSO. Following a 1 hour pre-incubation at 37° C. cells were stimulated with 10 ng/ml VEGF (Sigma, V7259) and incubated for 45 hours at 37° C. Cell proliferation was measured by BrdU DNA incorporation for 4 hours and BrdU label was quantitated by ELISA (Roche kit, 16472229) using 1M H 2 SO 4  to stop the reaction. Absorbance was measured at 450 nm using a reference wavelength at 690 nm. 
     DETAILED DESCRIPTION OF FIGURES 
       FIG. 1  shows a scheme that is used for the synthesis of the 3-alkoxy-4-acylaminoamide derivatives starting from methyl 3-hydroxy-4-aminobutanoate hydrochlorides and the activated acylating agent 1-3. The amino ester hydrochloride starting material was prepared by refluxing the free amino acid in anhydrous methanol in the presence of 1.2 eq of HCl. The amino group was protected as its monomethoxytrityl derivative in the presence of the secondary hydroxyl group to give the neutral hydroxy ester 1-1. The hydroxyl group was alkylated using methyl- or ethyl iodide to form the protected amino alkoxy ester. The Mmt group was removed in 1% trifluoroacetic acid leaving the amino hydrochloride or trifluoracetate compound 1-2. This compound was quickly acylated with the preformed acylating agent 1-3 and the methyl ester was hydrolyzed by potassium hydroxide in water/DMF to give 1-4. The free acid was then exposed to HATU, amine and diisopropylethyl amine in DMF to give the alkoxy amide 1-5. 
       FIG. 2  shows a scheme that is used for the synthesis of the 2-alkoxy-3-acylaminoamide derivatives starting from methyl 2-hydroxy-3-aminopropionate hydrochlorides and the activated acylating agent 1-3. The amino ester hydrochloride starting material was prepared by refluxing the free amino acid in anhydrous methanol in the presence of 1.2 eq of HCl. The amino group was protected as its monomethoxytrityl derivative in the presence of the secondary hydroxyl group to give 2-1. The hydroxyl group was alkylated using methyl- or ethyl iodide to form the protected amino alkoxy ester. The Mmt group was removed in 1% trifluoroacetic acid leaving the amino hydrochloride or trifluoracetate compound 2-2. This compound was quickly acylated with the preformed acylating agent 1-3 and the methyl ester was hydrolyzed by potassium hydroxide in water/DMF to give 2-4. The free acid was then exposed to HATU, amine and diisopropylethyl amine in DMF to give the alkoxy amide 2-5. 
       FIG. 3  shows a scheme that is used for the synthesis of the (2S)-2-alkoxy-4-acylamino-amide derivatives starting from methyl (2S)-2-hydroxy-4-aminobutanoate hydrochloride and the activated acylating agent 1-3. The amino ester hydrochloride starting material was prepared by refluxing the free amino acid in anhydrous methanol in the presence of 1.2 eq of HCl. The amino group was protected as its monomethoxytrityl derivative in the presence of the secondary hydroxyl group to give the neutral hydroxy ester 3-1. The hydroxyl group was alkylated using methyl- or ethyl iodide to form the protected amino alkoxy ester. The Mmt group was removed in 1% trifluoroacetic acid leaving the amino hydrochloride or trifluoracetate compound 3-2. This compound was quickly acylated with the preformed acylating agent 1-3 and the methyl ester was hydrolyzed by potassium hydroxide in water/DMF to give 3-4. The free acid was then exposed to HATU, amine and diisopropylethyl amine in DMF to give the alkoxy amide 3-5.