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  
       [0001]     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  
       [0002]     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.  
         [0003]     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  
       [0004]     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.  
         [0005]     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). 
 
         [0006]     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:  
                         
                         
 
         [0007]     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. 
 
         [0008]     In a first subgroup of this second subgenus, m is 0. Preferred species of this first subgroup are represented by the following structures:  
                         
                         
 
         [0009]     In a second subgroup of this second subgenus, m is 1. Preferred species of this second subgroup are represented by the following structures:  
                         
 
         [0010]     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:  
                         
                         
 
         [0011]     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  
       [0012]      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.  
         [0013]      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.  
         [0014]      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  
       [0015]     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  
       [0016]      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 2h (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  
       [0017]     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  
       [0018]     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 2h, 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  
       [0019]     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  
       [0020]     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  
       [0021]     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  
       [0022]     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  
       [0023]     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  
       [0024]     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  
       [0025]     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  
       [0026]     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 2h (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  
       [0027]     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  
       [0028]     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 2h, 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  
       [0029]     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  
       [0030]     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  
       [0031]     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  
       [0032]     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  
       [0033]     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  
       [0034]     Still further amide examples are shown in the following table:  
                                                                                                                                                                                                                                                                                                                                                                                        Ex#   Core   R   Ex#   Core   R   Ex#   Core   R                                                            31   I   p   81   II   p   131   III   p       32   I   q   82   II   q   132   III   q       33   I   r   83   II   r   133   III   r       34   I   s   84   II   s   134   III   s       35   I   t   85   II   t   135   III   t       36   I   u   86   II   u   136   III   u       37   I   v   87   II   v   137   III   v       38   I   w   88   II   w   138   III   w       39   I   x   89   II   x   139   III   x       40   I   y   90   II   y   140   III   y       41   I   z   91   II   z   141   III   z       42   I   aa   92   II   aa   142   III   aa       43   I   ab   93   II   ab   143   III   ab       44   I   ac   94   II   ac   144   III   ac       45   I   ad   95   II   ad   145   III   ad       46   I   ae   96   II   ae   146   III   ae       47   I   af   97   II   af   147   III   af       48   I   ag   98   II   ag   148   III   ag       49   I   ah   99   II   ah   149   III   ah       50   I   ai   100   II   ai   150   III   ai       51   I   aj   101   II   aj   151   III   aj       52   I   ak   102   II   ak   152   III   ak       53   I   al   103   II   at   153   III   al       54   I   am   104   II   am   154   III   am       55   I   an   105   II   an   155   III   an       56   I   ao   106   II   ao   156   III   ao       57   I   ap   107   II   ap   157   III   ap       58   I   aq   108   II   aq   158   III   aq       59   I   ar   109   II   ar   159   III   ar       60   I   as   110   II   as   160   III   as       61   I   at   111   II   at   161   III   at       62   I   au   112   II   au   162   III   au       63   I   av   113   II   av   163   III   av       64   I   aw   114   II   aw   164   III   aw       65   I   ax   115   II   ax   165   III   ax       166   IV   a   216   V   a   266   VI   a       167   IV   b   217   V   b   267   VI   b       168   IV   c   218   V   c   268   VI   c       169   IV   d   219   V   d   269   VI   d       170   IV   e   220   V   e   270   VI   e       171   IV   f   221   V   f   271   VI   f       172   IV   g   222   V   g   272   VI   g       173   IV   h   223   V   h   273   VI   h       174   IV   i   224   V   i   274   VI   i       175   IV   j   225   V   j   275   VI   j       176   IV   k   226   V   k   276   VI   k       177   IV   l   227   V   l   277   VI   l       178   IV   m   228   V   m   278   VI   m       179   IV   n   229   V   n   279   VI   n       180   IV   o   230   V   o   280   VI   o       181   IV   p   231   V   p   281   VI   p       182   IV   q   232   V   q   282   VI   q       183   IV   r   233   V   r   283   VI   r       184   IV   s   234   V   s   284   VI   s       185   IV   t   235   V   t   285   VI   t       186   IV   u   236   V   u   286   VI   u       187   IV   v   237   V   v   287   VI   v       188   IV   w   238   V   w   288   VI   w       189   IV   x   239   V   x   289   VI   x       190   IV   y   240   V   y   290   VI   y       191   IV   z   241   V   z   291   VI   z       192   IV   aa   242   V   aa   292   VI   aa       193   IV   ab   243   V   ab   293   VI   ab       194   IV   ac   244   V   ac   294   VI   ac       195   IV   ad   245   V   ad   295   VI   ad       196   IV   ae   246   V   ae   296   VI   ae       197   IV   af   247   V   af   297   VI   af       198   IV   ag   248   V   ag   298   VI   ag       199   IV   ah   249   V   ah   299   VI   ah       200   IV   ai   250   V   ai   300   VI   ai       201   IV   aj   251   V   aj   301   VI   aj       202   IV   ak   252   V   ak   302   VI   ak       203   IV   al   253   V   al   303   VI   al       204   IV   am   254   V   am   304   VI   am       205   IV   an   255   V   an   305   VI   an       206   IV   ao   256   V   ao   306   VI   ao       207   IV   ap   257   V   ap   307   VI   ap       208   IV   aq   258   V   aq   308   VI   aq       209   IV   ar   259   V   ar   309   VI   ar       210   IV   as   260   V   as   310   VI   as       211   IV   at   261   V   at   311   VI   at       212   IV   au   262   V   au   312   VI   au       213   IV   av   263   V   av   313   VI   av       214   IV   aw   264   V   aw   314   VI   aw       215   IV   ax   265   V   ax   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  
       [0035]     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  
       [0036]     (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 1h, 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 2h (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  
       [0037]     (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  
       [0038]     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 2h, 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  
       [0039]     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  
       [0040]     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 O5: 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  
       [0041]     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). 
 
         [0042]     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.  
         [0000]     VEGFR Biochemical Assay  
         [0043]     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.  
         [0044]     Compounds of the present invention were tested in this assay and exhibited IC 50  between 1-5,000 nM.  
         [0000]     PDGFR Phosphorylation Assay  
         [0045]     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.  
         [0046]     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 4h 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.  
         [0047]     Most of the compounds in this invention showed IC 50  of less than 1 μM in this assay.  
         [0000]     VEGFR Phosphorylation Assay  
         [0048]     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.  
         [0049]     High binding microplates are incubated overnight at room temperature with VEGFR antibody in 50 pL 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.  
         [0050]     Most of the compounds in this invention showed IC 50  of less than 1 μM in this assay.  
         [0000]     Cellular Assay: HUVEC: VEGF Induced Proliferation  
         [0051]     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  
       [0052]      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.  
         [0053]      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.  
         [0054]      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.