Patent Publication Number: US-2012046306-A1

Title: Substituted Heteroaryl Spiropyrrolidine MDM2 Antagonists

Description:
PRIORITY TO RELATED APPLICATION(S) 
     This application claims the benefit of U.S. Provisional Application No. 61/494,553, filed Jun. 8, 2011, and U.S. Provisional Application No. 61/61/374,725, filed Aug. 18, 2010. The entire contents of the above-identified applications are hereby incorporated by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to heteroaryl spiropyrrolidine derivatives which act as inhibitors of MDM2-p53 interactions and are useful in the amelioration or treatment of cancer. 
     BACKGROUND OF THE INVENTION 
     p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation. 
     The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p16INK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells. 
     SUMMARY OF THE INVENTION 
     The present invention relates to heteroaryl spiropyrrolidine I which act as antagonists of mdm2 interactions and hence are useful as potent and selective anticancer agents. The present compounds are of the general formula 
     
       
         
         
             
             
         
       
     
     wherein A, B, V, W, R 1 , R 2 , R 3 , R 3 , and R 4 , are as described herein and enantiomers and pharmaceutically acceptable salts thereof. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     There are provided compounds of the formula 
     
       
         
         
             
             
         
       
     
     wherein 
     
       
         
         
             
             
         
       
     
     is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
     wherein in the case of (f) A is a bond; 
     R 5  is selected from the group consisting of H, F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
 
R 6  is selected from the group consisting of H, F, Cl, methyl;
 
R 7  is selected from the group consisting of H, F, Cl, methyl;
 
R 8  is selected from the group consisting of H, F, Cl, methyl;
 
R 1  and R 2  are independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
 
R 3  and R 4  are selected from the group consisting of (CH 2 ) n —R′, (CH 2 ) n —NR′R″, (CH 2 ) n —NR′COR″, (CH 2 ) n —NR′SO 2 R″, (CH 2 ) n —COOH, (CH 2 ) n —COOR′, (CH 2 ) n —CONR′R″, (CH 2 ) n —OR′, (CH 2 ) n —SR′, (CH 2 ) n —SOR′, (CH 2 ) n —SO 2 R′, (CH 2 ) n —COR′, (CH 2 ) n —SO 3 H, (CH 2 ) n —SONR′R″, (CH 2 ) n —SO 2 NR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —R′, (CH 2 CH 2 O) m —(CH 2 ) n —OH, (CH 2 CH 2 O) m —(CH 2 ) n —OR′, (CH 2 CH 2 O) m —(CH 2 ) n —NR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —NR′COR″, (CH 2 CH 2 O) m —(CH 2 ) n —NR′SO 2 R″, (CH 2 CH 2 O) m —(CH 2 ) n —COOH, (CH 2 CH 2 O) m —(CH 2 ) n —COOR′, (CH 2 CH 2 O) m —(CH 2 ) n —CONR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —SO 2 R′, (CH 2 CH 2 O) m —(CH 2 ) n —COR′, (CH 2 CH 2 O) m —(CH 2 ) n —SONR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —SO 2 NR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —R′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —OH, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —OR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —NR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —NR′COR″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —NR′SO 2 R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —COOH, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —COOR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —CONR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —SO 2 R′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —COR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —SONR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —SO 2 NR′R″, —COR′, —SOR′ and SO 2 R′
 
wherein R′ and R″ are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, hetereoaryl, substituted hetereoaryl, hetereocycle or substituted hetereocycle or R′ and R″ may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle;
 
m, n and p are independently 0 to 6
 
or a pharmaceutically acceptable salt thereof.
 
     Another embodiment of the invention relates to compounds of formula I having a stereochemical structure shown as formula II 
     
       
         
         
             
             
         
       
     
     wherein 
     
       
         
         
             
             
         
       
     
     is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
     wherein in the case of (f) A is a bond; 
     R 5  is selected from the group consisting of H, F, Cl, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
 
R 6  is selected from the group consisting of H, F, Cl and methyl;
 
R 7  is selected from the group consisting of H, F, Cl and methyl;
 
R 8  is selected from the group consisting of H, F, Cl and methyl;
 
R 1  and R 2  are independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
 
R 3  and R 4  are selected from the group consisting of (CH 2 ) n —R′, (CH 2 ) n —NR′R″, (CH 2 ) n —NR′COR″, (CH 2 ) n —NR′SO 2 R″, (CH 2 ) n —COOH, (CH 2 ) n —COOR′, (CH 2 ) n —CONR′R″, (CH 2 ) n —OR′, (CH 2 ) n —SR′, (CH 2 ) n —SOR′, (CH 2 ) n —SO 2 R′, (CH 2 ) n —COR′, (CH 2 ) n —SO 3 H, (CH 2 ) n —SONR′R″, (CH 2 ) n —SO 2 NR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —R′, (CH 2 CH 2 O) m —(CH 2 ) n —OH, (CH 2 CH 2 O) m —(CH 2 ) n —OR′, (CH 2 CH 2 O) m —(CH 2 ) n —NR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —NR′COR″, (CH 2 CH 2 O) m —(CH 2 ) n —NR′SO 2 R″, (CH 2 CH 2 O) m —(CH 2 ) n —COOH, (CH 2 CH 2 O) m —(CH 2 ) n —COOR′, (CH 2 CH 2 O) m —(CH 2 ) n —CONR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —SO 2 R′, (CH 2 CH 2 O) m —(CH 2 ) n —COR′, (CH 2 CH 2 O) m —(CH 2 ) n —SONR′R″, (CH 2 CH 2 O) m —(CH 2 ) n —SO 2 NR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —R′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —OH, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —OR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —NR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —NR′COR″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —NR′SO 2 R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —COOH, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —COOR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —CONR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —SO 2 R′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —COR′, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —SONR′R″, (CH 2 ) p —(CH 2 CH 2 O) m —(CH 2 ) n —SO 2 NR′R″, —COR′, —SOR′ and SO 2 R′
 
wherein R′ and R″ are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, hetereoaryl, substituted hetereoaryl, hetereocycle or substituted hetereocycle or R′ and R″ may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle;
 
m, n and p are independently 0 to 6
 
or a pharmaceutically acceptable salt thereof.
 
     Preferred are compounds of Formula I, including compounds of Formula II, or a pharmaceutically acceptable salt thereof wherein R 5  is F, Cl or Br. 
     Preferred are compounds of Formula I, including compounds of Formula II, or a pharmaceutically acceptable salt thereof wherein R 6 , R 7 , R 8  are all hydrogen. 
     Preferred are compounds of Formula I, including compounds of Formula II, or a pharmaceutically acceptable salt thereof wherein R 2  is selected from the group consisting of aryl, aryl substitued with Cl, F or Brand heteroaryl optionally substituted with H, F, Cl or Br. 
     Preferred are compounds of Formula I, including compounds of Formula II, or a pharmaceutically acceptable salt thereof wherein R 1  is a substituted lower alkyl of the formula 
     
       
         
         
             
             
         
       
     
     where R 9  and R 10  are both methyl, or alternatively, R 9  and R 10  together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl; 
     R 11  is (CH 2 ) q —R 12 , where q is 0, 1 or 2 and 
     R 12  is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle. 
     Preferred are compounds of Formula I, including compounds of Formula II or a pharmaceutically acceptable salt thereof wherein one of R 3  and R 4  is hydrogen, and the other is (CH 2 ) n —R′, n is 0 or 1 and R′ is aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle. 
     Preferred are compounds of Formula I, including compounds of Formula II, or a pharmaceutically acceptable salt thereof wherein 
     R 5  is selected from F, Cl or Br;
 
R 6 , R 7 , R 8  are hydrogen;
 
R 2  is selected from the group consisting of aryl, aryl substitued with Cl or F or Br, and heteroaryl optionally substituted with H, F, Cl or Br;
 
R 1  is a substituted lower alkyl of the formula
 
     
       
         
         
             
             
         
       
     
     where R 9  and R 10  are both methyl, or alternatively, R 9  and R 10  together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl;
 
R 11  is (CH 2 ) q —R 12 , where q is 0, 1 or 2;
 
R 12  is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle;
 
one of R 3  and R 4  is hydrogen, and the other is (CH 2 ) n —R′;
 
n is 0 or 1 and
 
R′ is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
 
     Further preferred are compounds of Formula II 
     
       
         
         
             
             
         
       
     
     wherein 
     
       
         
         
             
             
         
       
     
     is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
     R 5  is selected from F, Cl or Br;
 
R 6 , R 7 , R 8  are hydrogen;
 
R 2  is selected from the group consisting of
 
     
       
         
         
             
             
         
       
     
     wherein 
     R 13  is F, Cl or Br; 
     R 14  is H or F; 
     R 1  is a substituted lower alkyl of the formula 
     
       
         
         
             
             
         
       
     
     where R 9  and R 10  are both methyl, or alternatively, R 9  and R 10  together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl;
 
R 11  is (CH 2 ) q —R 12 , where q is 0, 1 or 2;
 
R 12  is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle;
 
one of R 3  and R 4  is hydrogen, and the other is (CH 2 ) n —R′;
 
n is 0 or 1;
 
R′ is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle
 
or a pharmaceutically acceptable salt thereof.
 
     Especially preferred are compounds of the formula
     methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide;   methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate;   rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid;   rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide;   methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate;   rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoic acid;   methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate;   rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid;   rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-carboxamide;   methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide;   methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;   rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoic acid;   methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoate;   rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoic acid;   methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   chiral(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide;   methyl rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   methyl rac-4-((2S,3S,4S,5R)-5′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3S,4S,5R)-5′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   chiral methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   chiral methyl 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   chiral 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   chiral(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide;   chiral 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   chiral(2R,3S,4R,5S)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide;   chiral 4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   chiral 4-((2R,3R,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   chiral methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;   chiral methyl 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;   methyl rac-4-{(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate;   rac-4-{(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid;   rac-(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   methyl rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate;   methyl rac-4-{(2S,3R,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate;   rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid;   rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-2-(4-((2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate;   rac-(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   chiral(2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   methyl rac-4-((2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   rac-(2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3S,4S,5R)-6′-bromo-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid;   rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2-methoxyphenyl]-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide;   rac-(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2-methoxyphenyl]-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxamide;   methyl rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate;   methyl rac-4-{(2S,3S,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate;   rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoic acid;   rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxamide;   methyl rac-4-((2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate;   methyl rac-4-((2S,3S,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate;   rac-4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid;   chiral 4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid;   rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide;   chiral(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide;   rac-(2S,3S,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide;   rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide;   rac-(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide,   chiral(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide,   methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate,   rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid,   methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-hydroxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate,   rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-hydroxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid,   rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide,   rac-2-(4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate,   rac-(2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide,   methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate,   rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid,   rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide,   methyl rac-4-((2S,3S,4S,5R)-7′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate,   rac-4-((2S,3S,4S,5R)-7′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid and   rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-carboxamide.   

     In the specification where indicated the various groups may be substituted by 1-5 or, preferably, 1-3 substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF 3 , NH 2 , N(H, lower-alkyl), N(lower-alkyl) 2 , aminocarbonyl, carboxy, NO 2 , lower-alkoxy, thio-lower-alkoxy, lower-alkylsulfonyl, aminosulfonyl, lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower-alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower-alkoxy, hydroxy-lower-alkoxy, NH 2 -lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower-alkyl) 2 -lower-alkoxy, lower-alkyl-1-oxiranyl-lower-alkoxy-lower-alkyl, 2-oxo-pyrrolidin-1-yl, (1,1-dioxo)-2-isothiazolidine, 3-lower-alkyl sulfinyl, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heteroaryl ring, trifluoro-lower-alkylsulfonylamino-aryl, lower-alkyl sulfonylaminocarbonyl, lower-alkyl sulfonylaminocarbonyl-aryl, hydroxycarbamoyl-phenyl, benzyloxy-lower-alkoxy, mono- or di-lower alkyl substituted amino-sulfonyl and lower-alkyl which can optionally be substituted with halogen, hydroxy, NH 2 , N(H, lower-alkyl) or N(lower-alkyl) 2 . Preferred substituents for the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl, hydroxycarbonyl, carboxy, carboxy lower alkoxy, oxo and CN. Preferred substituents for alkyl are alkoxy and N(lower alkyl) 2 . 
     DEFINITIONS 
     As used herein, the following terms shall have the following definitions. 
     The term “alkyl” refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 12 carbon atoms, including groups having from 1 to about 7 carbon atoms. In certain embodiments, alkyl substituents may be lower alkyl substituents. The term “lower alkyl” refers to alkyl groups having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. 
     The term “alkenyl” as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing at least one double bond and having 2 to 6, preferably 2 to 4 carbon atoms. Examples of such “alkenyl group” are vinyl, ethenyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. 
     “Alkoxy, alkoxyl or lower alkoxy” refers to any of the above lower alkyl groups which is attached to the remainder of the molecule by an oxygen atom (RO—). Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like. 
     The term “alkynyl” as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms. Examples of such “alkynyl group” are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. 
     Amino means the group —NH 2 . 
     “Aryl” means a monovalent, monocyclic or bicyclic, aromatic carboxylic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. 
     The term “cycloalkyl” as used herein means any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated, and the term “cycloalkenyl” is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl. 
     The term “halogen” as used herein means fluorine, chlorine, bromine, or iodine, preferably fluorine and chlorine. 
     “Heteroaryl” means an aromatic heterocyclic ring system containing up to two rings. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole substituted or unsubstituted triazolyl and substituted or unsubstituted tetrazolyl. 
     In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted. 
     “Hetero atom” means an atom selected from N, O and S. 
     “Heterocycle” or “heterocyclic ring” means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Examples include pyrrolidin-2-yl; pyrrolidin-3-yl; piperidinyl; morpholin-4-yl and the like which in turn can be substituted. 
     Hydroxy or hydroxyl is a prefix indicating the presence of a monovalent —OH group. 
     “IC50” refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC 50  can be measured, inter alia, as is described subsequently in the Example providing biological data. 
     “Lower” as in “lower alkenyl” means a group having 1 to 6 carbon atoms. 
     “Nitro” means —NO 2 . 
     Oxo means the group ═O. 
     “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered. 
     “Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (I.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (1995) at pgs. 456-457. 
     “Substituted,” as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options. The term “optionally substituted” refers to the fact that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but does not necessarily have to be, substituted with another substituent. 
     Synthetic Methods 
     The present invention provides novel methods for the synthesis of heteroaryl spiropyrrolidines of formula I or II. Compounds of this invention can be synthesized according to the following general schemes. Suitable processes for synthesizing these compounds are provided in the examples. 
     An intermediate III can be made from a base-catalyzed condensation reaction of appropriately selected substituted 4- or 5- or 6- or 7-aza-2-oxindole I and appropriate substituted aldehyde II in methanol (Scheme 1). The choice of bases includes but is not limited to pyrrolidine or piperidine. The reaction generates III as a mixture of Z- and E-isomers with E-isomer as the major product. 
     
       
         
         
             
             
         
       
     
     Similarly, intermediates V or VII can be made from a acid-catalyzed condensation reaction of appropriately selected substituted 5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one IV or 4,6-dihydro-thieno[3,2-b]pyrrol-5-one VI and aldehyde II in hydrochloric and acetic acid (M. Cheung et al,  Tetrahedron Lett.  2001, 42, 999) (Scheme 2). 
     
       
         
         
             
             
         
       
     
     Preparation of starting material VIa is described in Scheme 3 to exemplify the synthesis of intermediate VI in Scheme 2. 2,5-dichlorothiophene can be treated with sodium nitrate in concentrated sulfuric acid to give 2,5-dichlorothiphene-3-nitrothiophene. Nucleophilic substitution of 5-chloro group with tert-butyl ethyl malonate mono-sodium salt and treatment with trifluoroacetic acid lead to methyl 2-(5-chloro-3-nitrothiophen-2-yl)acetate (WO2008132139). Reduction of nitro group with Zinc and ammonium chloride and cyclizing reaction to form amide promoted by trimathylaluminum afford intermediate VIa (S. Hu, et al,  J. Heterocyclic. Chem.  2005, 42, 661). 
     
       
         
         
             
             
         
       
     
     Racemic synthesis of compounds in formula I and II can be achieved as outlined in Scheme 4. Amine NHR 3 R 4  can be reacted with N-protected glycine like N-Boc glycine by using a coupling reagent like EDCI or HATU to give intermediate VIII. Intermediate VIII can be treated with trifluoroacetic acid or HCl at room temperature to remove protective Boc group and give intermediate IX. Appropriately selected aldehyde R 1 CHO can react with IX to give the imine X. The cycloaddition reaction between intermediates X and intermediate III or V or VII mediated by LiOH or LiCl/DABCO gives a racemic and diastereomeric mixture of compounds XI in formula I together with other isomers. Compounds XI can be purified by flash chromatography followed by chiral separation by chiral Super Fluid Chromatography (SFC) or chiral HPLC to give optically pure or enriched chiral compounds XII in formula II. 
     
       
         
         
             
             
         
       
     
     Similarly, compounds in formula I and II can be prepared as outlined in Scheme 5. Intermediate III or V or VII can be protected with Boc group to give intermediate XIII. The cycloaddition reaction between intermediates X and XIII mediated by LiOH or LiCl/DABCO follow by reaction to remove Boc group by trifluoroacetic acid give compounds XI in formula I. Compounds XI can be subsequently separated into optically pure or enriched chiral compounds XII in formula II. 
     
       
         
         
             
             
         
       
     
     Alternative synthesis of compounds XIIa in formula II can be achieved. As illustrated in Scheme 6, selected aldehyde R 1 CHO can be reacted with glycine tert-butyl ester to generate imine XIV. The racemic mixture of intermediate XV and XV′ can be made from intermediates XIV and VII by LiOH mediated cyclization reaction. The mixture of XVI and XVI′ can be subsequently converted to a racemic mixture of acid XVII and XVII′ by using trifluoroacetic acid. Amide formation with various amine NHR 3 R 4  by using diphenylphsphinic chloride as the coupling reagent can lead to the racemic mixture of compounds XIIa and XIIa′ in formula II. Finally chiral separation by chiral Super Fluid Chromatography (SFC) or chiral HPLC gives optically pure or enriched chiral compounds XIIa in formula II. 
     
       
         
         
             
             
         
       
     
     EXAMPLES 
     The compounds of the present invention may be synthesized according to novel techniques. The following examples and references are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims. 
     Example 1 
     Preparation of intermediate (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)benzoate 
     
       
         
         
             
             
         
       
     
     Step a: A mixture of methyl 4-aminobenzoate (Aldrich, 5.00 g, 32.4 mmol), tert-butoxycarbonylamino-acetic acid (9.44 g, 53.4 mmol, Aldrich) and 1-(3-dimetgylaminopropyl)-3-ethylcarbodiimide hydrochloride (Chem-Impex, 10.16 g, 53.1 mmol) in CH 2 Cl 2  (60 mL) was stirred vigorously at rt for 2 h. The reaction mixture was then concentrated in vacuum and the residue was dissolved in EtOAc (150 mL), washed successively with water (120 mL), sat. NH 4 Cl (20 mL), sat. NaHCO 3  (50 mL), water (50 mL) and brine (20 mL), dried over Na 2 SO 4  and concentrated in vacuum. The white solid was further dried in vacuum overnight to give methyl 4-(2-(tert-butoxycarbonylamino)acetamido)-benzoate (11.28 g). 
     Step b: A solution of methyl 4-(2-(tert-butoxycarbonylamino)acetamido)-benzoate (5.25 g, 17.0 mmol) in CH 2 Cl 2  (40 mL) at 0 C. was treated with TFA (20 mL) and the mixture was stirred at rt for 4 h. The solvent was then removed under reduced pressure. The residue was further dried in vacuum overnight to give methyl 4-(2-aminoacetamido)benzoate as a TFA salt (5.82 g, 99%). 
     Step c: To a suspension of the above methyl 4-(2-aminoacetamido)benzoate TFA salt (4.95 g, 15.4 mmol) in t-butyl methyl ether (160 mL) at rt was added TRIETHYLAMINE (1.74 g, 2.40 ml, 17.2 mmol) and the mixture was stirred for 30 min. 3,3-Dimethylbutanal (1.69 g, 16.9 mmol) in t-butyl methyl ether (5 mL) was added and the reaction mixture was allowed to stir at rt overnight. t-Butyl methyl ether (100 mL) was added and stirred for 20 min. The solid was filtrated off and the filtrate was washed with water, brine, dried over Na 2 SO 4  and concentrated to give (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-benzoate as a white solid (3.25 g, 72%). MS (ES + ) m/z [(M+H) + ]: 291 
     Example 2 
     Preparation of intermediate 4-{2-[3,3-Dimethyl-but-(E)-ylideneamino]-acetylamino}-2-methoxybenzoic acid methyl ester 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl 4-(2-aminoacetamido)-2-methoxybenzoate hydrochloride (prepared in a similar manner as described in Example 1 (0.50 g, 1.82 mmol) in t-butyl methyl ether (8 mL) at rt, was added triethylamine (203 mg, 2.01 mmol) and the mixture was stirred for 30 min. 3,3-Dimethylbutanal (0.24 g, 0.30 mL, 2.27 mmol, Aldrich) in t-butyl methyl ether (2 mL) was added and the reaction mixture was allowed to stir at rt overnight. t-Butyl methyl ether (50 mL) was added and stirred for 20 min. The solid was filtrated off and the filtrate was washed with water, brine, dried over Na 2 SO 4  and concentrated to give 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-2-methoxybenzoic acid methyl ester as a white solid (353 mg, 60%). MS (ES + ) m/z [(M+H) + ]: 320 
     Example 3 
     Preparation of intermediate (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate was prepared in a manner similar to the method described in Example 1. MS (ES + ) m/z [(M+H) + ]: 320 
     Example 4 
     Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2c]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a suspension of 1H-pyrrolo[3,2-c]pyridin-2(3H)-one (1.00 g, 7.46 mmol, prepared according to the method described in J. Org. Chem., 1991, 56, 4805-4808) in MeOH (55 mL) in a 100-mL round-bottomed flask, was added 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 3.55 g, 22.40 mmol), giving a clear solution. Piperidine (Lancaster, 2.66 g, 31.20 mmol) was added slowly. After stirred for 10 min, the reaction mixture was heated at 50° C. for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light yellow crystalline solid (1.38 g, 67%). MS (ES + ) m/z [(M+H) + ]: 275 
     Example 5 
     Preparation of intermediate rac-(2S,3S,4S,5R)-tert-butyl 4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxylate 
     
       
         
         
             
             
         
       
     
     Step a: To a solution of tert-butyl 2-aminoacetate (Aldrich, 1.00 g, 7.62 mmol) in CH 2 Cl 2  (30 mL) was added 3,3-dimethylbutanal (Aldrich, 1.00 g, 9.98 mmol). The mixture was stirred at rt for 4 h. Water added and organic layer separated. The aqueous layer was extracted with CH 2 Cl 2 . The combined organic extracts were washed with water and concentrated to give (E)-tert-butyl 2-(3,3-dimethylbutylideneamino)acetate as a colorless oil (1.52 g, 93%). 
     Step b: A suspension of 3-(3-chloro-2-fluorobenzylidene)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (60 mg, 0.218 mmol, Example 4) in CH 2 Cl 2  (8 mL) was treated with triethylamine (133 mg, 1.31 mmol). (E)-tert-butyl 2-(3,3-dimethylbutylideneamino)acetate (69 mg, 0.325 mmol) was added followed by silver(I) fluoride (Aldrich, 47 mg, 0.370 mmol) and the mixture was stirred at rt for 24 h. The reaction mixture was partition between EtOAc and water, washed with brine and dried over Na 2 SO 4  and concentrated to dryness. The residue was dissolved in t-BuOH (8 mL) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) (Aldrich, 266 mg, 1.75 mmol) and heated at 120 C. for 2 h. The reaction mixture was then cooled to rt and partitioned between EtOAc and water, washed with water, brine and concentrated. The crude material was purified by flash chromatography (EtOAc/CH 2 Cl 2 : 5/95 to 40/60) to give rac-(2S,3S,4S,5R)-tert-butyl 4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxylate (10.2 mg, 8.6%) as a white solid. MS (ES + ) m/z [(M+H) + ]: 488 
     Example 6 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a suspension of 3-(3-chloro-2-fluorobenzylidene)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (450 mg, 1.64 mmol, Example 4) in anhydrous THF (25 mL) at 40° C., was added anhydrous LiOH (19 mg, 0.82 mmol) and the suspension was stirred at 40° C. for 10 min before (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)-acetamido)-3-methoxybenzoate (551 mg, 1.72 mmol, Example 3) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 23 h. The mixture was diluted with EtOAc (100 mL), washed with water (2×20 mL) and concentrated to a small volume. MeOH was added slowly (˜15 mL) and the mixture was stirred in cold bath for 20 min. The resulting precipitate was filtered, washed with cold MeOH and dried in vacuum overnight to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white powder (556 mg, 56%). MS (ES + ) m/z [(M+H) + ]: 595 
     Example 7 
     Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (151 mg, 0.254 mmol, Example 6) in THF (8 mL) was added a solution of LiOH hydrate (63 mg, 1.50 mmol) in water (4 mL). The reaction mixture was stirred at rt for 20 h before it was treated with 1N HCl to slightly acidic. The mixture was partitioned between CH 2 Cl 2  (30 mL) and water (10 mL), extracted with CH 2 Cl 2  (3×30 mL). The combined organic extracts were washed with water, dried over Na 2 SO 4 , concentrated and lyophized to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white powder (145 mg, 95%). MS (ES + ) m/z [(M+H) + ]: 581 
     Example 8 
     Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     A mixture of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (51 mg, 0.087 mmol, Example 7) and 1,1′-carbonyldiimidazole (Aldrich, 28 mg, 0.174 mmol) in THF (3 mL) was stirred at rt for 17 h. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHCO 3  (10 mL), water (10 mL) then sat. NH 4 Cl (10 mL). The organic layer was dried over Na 2 SO 4  and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH 2 Cl 2 , 0.5/99.5 to 3/97) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (25 mg, 50%). MS (ES + ) m/z [(M+H) + ]: 580 
     Example 9 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-(E)-3-(3-chloro-2-fluorobenzylidene)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (173 mg, 0.63 mmol, Example 4) in anhydrous THF (12 mL) was added anhydrous LiOH (11 mg, 0.43 mmol) and the mixture was stirred at 40° C. for 10 min. (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-2-methoxybenzoate (220 mg, 0.68 mmol, Example 2) was added in one portion. The reaction mixture was allowed to stir at 40° C. overnight, giving a clear reaction mixture. This mixture was diluted with EtOAc and washed with water, brine and dried over Na 2 SO 4  and concentrated. The crude product was purified on flash chromatography (EtOAc/CH 2 Cl 2 , 3/97 to 60/40) to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate as a white solid (119 mg, 32%). MS (ES + ) m/z [(M+H) + ]: 595 
     Example 10 
     Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate (107 mg, 0.181 mmol, Example 9) in THF (10 mL) was added a solution of LiOH hydrate (61 mg, 1.47 mmol) in water (5 mL). The reaction mixture was stirred at rt overnight until the reaction was complete. The reaction mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na 2 SO 4  and concentrated to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid as a white solid (89 mg, 85%). MS (ES + ) m/z [(M+H) + ]: 581 
     Example 11 
     Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     A mixture of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid (30 mg, 0.052 mmol, Example 10) and 1,1′-carbonyldiimidazole (Aldrich, 37 mg, 0.22 mmol) in THF (3 mL) was stirred at rt for 17 hr. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHCO 3  (10 mL), water (10 mL) then sat. NH 4 Cl (10 mL). The organic layer was dried over Na 2 SO 4  and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH 2 Cl 2 , 0.5/99.5 to 3/97) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (27 mg, 89%). MS (ES + ) m/z [(M+H) + ]: 580 
     Example 12 
     Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a suspension of 1H-pyrrolo[2,3-b]pyridin-2(3H)-one (Chemgenx, 926 mg, 6.91 mmol) in MeOH (55 mL), was added 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 3.29 g, 20.70 mmol). Piperidine (Lancaster, 2.41 g, 2.8 mL, 28.30 mmol) was added slowly. After stirring a few minutes, the reaction mixture was heated at 50° C. for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a light yellow crystalline solid (1.18 g, 62%). MS (ES + ) m/z [(M+H) + ]: 275 
     Example 13 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a suspension of E/Z-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (401 mg, 1.46 mmol, Example 12) in anhydrous THF (25 mL) at 40° C. was added anhydrous LiOH (17 mg, 0.73 mmol) and the suspension was stirred at 40° C. for 10 min before (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (490 mg, 1.53 mmol, Example 3) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 23 h. The mixture was diluted with EtOAc, washed with water and concentrated to a small volume. MeOH was added slowly (˜15 mL) and the mixture was stirred in cold bath for ˜20 min. The resulting precipitate was filtered, washed with cold MeOH and dried overnight in vacuum to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (543 mg, 62%). MS (ES + ) m/z [(M+H) + ]: 595 
     Example 14 
     Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (154 mg, 0.26 mmol, Example 13) in THF (8 mL) was added a solution of LiOH hydrate (77 mg, 1.84 mmol) in water (4 mL). The reaction mixture was stirred at rt for 20 h before it was treated with 1N HCl to slightly acidic. The mixture was partitioned between CH 2 Cl 2  (30 mL) and water (10 ml), extracted with CH 2 Cl 2 . The combined organic extracts were washed with water, dried over Na 2 SO 4 , concentrated and lyophized to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (150 mg, 97%). MS (ES + ) m/z [(M+H) + ]: 581 
     Example 15 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate 
     
       
         
         
             
             
         
       
     
     To a suspension of 3-(3-chloro-2-fluorobenzylidene)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (102 mg, 0.372 mmol, Example 12) in anhydrous THF (25 mL) at 40° C. was added hydrous LiOH (5 mg, 0.21 mmol) and the suspension was stirred at 40° C. for 10 min before (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)benzoate (114 mg, 0.391 mmol, Example 1) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 23 h. The mixture was diluted with EtOAc (100 mL) and washed with water (2×20 mL), concentrated to a small volume (˜5 mL). MeOH was added (2 mL) and the solution was stirred in cold bath until precipitate started to form. The precipitate was filtered and washed with cold MeOH, dried overnight in vacuum to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate as (47.6 mg, 23%) a white powder. MS (ES + ) m/z [(M+H) + ]: 565. 
     Example 16 
     Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate (45 mg, 0.079 mmol, Example 15) in THF (4 mL) was added a solution of LiOH hydrate (23 mg, 0.55 mmol) in water (2 mL). The reaction mixture was stirred at rt for 24 hrs before it was treated with 1N HCl to slightly acidic. The mixture was partitioned between water (10 mL) and CH 2 Cl 2  (30 mL), extracted with CH 2 Cl 2 . The combined organic extracts were washed with water, dried over Na 2 SO 4 , concentrated and lyophized to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoic acid as a white solid (25 mg, 59%). MS (ES + ) m/z [(M+H) + ]: 551 
     Example 17 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-3-(3-chloro-2-fluorobenzylidene)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (99 mg, 0.36 mmol, Example 12) in anhydrous THF (9 mL) was added anhydrous LiOH (6 mg, 0.26 mmol) and the mixture was stirred at 40° C. for 10 min. (E)-Methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-2-methoxybenzoate (123 mg, 0.385 mmol, Example 2) was added in one portion. The reaction mixture was allowed to stir at 40° C. overnight, giving a clear reaction mixture. This mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na 2 SO 4  and concentrated. The crude product was purified by flash chromatography (EtOAc/CH 2 Cl 2 , 3/97 to 60/40) to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate as a white solid (128 mg, 60%). MS (ES + ) m/z [(M+H) + ]: 595 
     Example 18 
     Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate (116 mg, 0.196 mmol, Example 17) in THF (10 mL) was added a solution of LiOH hydrate (66 mg, 1.57 mmol) in water (5 mL). The reaction mixture was stirred at rt overnight and was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na 2 SO 4  and concentrated to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid as a white solid (103 mg, 91%). MS (ES + ) m/z [(M+H) + ]: 581 
     Example 19 
     Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     A mixture of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid (29 mg, 0.051 mmol, Example 18) and 1,1′-carbonyldiimidazole (Aldrich, 35 mg, 0.217 mmol) in THF (3 mL) was stirred at rt for 17 h. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHCO 3  (10 mL), water (10 mL) then sat. NH 4 Cl (10 mL). The organic layer was dried over Na 2 SO 4  and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH 2 Cl 2 , 0.5/99.5 to 5/95) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-carboxamide as a white solid (23 mg, 78%). MS (ES + ) m/z [(M+H) + ]: 580 
     Example 20 
     Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a suspension of 1H-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova. 933 mg, 6.96 mmol) in MeOH (35 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 3.58 g, 22.6 mmol) giving a clear solution. Piperidine (Lancaster, 2.58 g, 30.30 mmol) was added slowly. After stirred for a few minutes, the reaction mixture was heated at 50° C. for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light yellow crystalline solid (1.22 g, 64%). MS (ES + ) m/z [(M+H) + ]: 275 
     Example 21 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 20, 301 mg, 1.10 mmol) in anhydrous THF (22 mL) at 40° C. was added anhydrous LiOH (13 mg, 0.54 mmol) and the mixture was stirred at 40° C. for 10 min before (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)-acetamido)-3-methoxybenzoate (Example 3, 367 mg, 1.15 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 20 h, giving a white precipitate. The resulting precipitate was filtered, washed with cold MeOH and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (242 mg, 37%). MS (ES + ) m/z [(M+H) + ]: 595 
     Example 22 
     Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 21, 124 mg, 0.21 mmol) in THF (8 mL) was added a solution of LiOH hydrate (69 mg, 1.66 mmol) in water (4 mL). The reaction mixture was stirred at 40° C. for 24 h until the reaction was complete. The reaction mixture was treated with 1N HCl to slightly acidic and the precipitate was filtered and washed with cold MeOH and dried overnight to give rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (114 mg, 94%). MS (ES + ) m/z [(M+H) + ]: 581 
     Example 23 
     Preparation of intermediate E/Z-6-Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a suspension of 6-chloro-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (Sinova, 689 mg, 4.09 mmol) in MeOH (50 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 1.89 g, 11.9 mmol). Piperidine (1.46 g, 17.2 mmol) was added slowly, giving a clear brown solution. After stirred for a few minutes, the reaction mixture was heated at 50° C. for 5 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light brown solid (1.07 g, 85%). MS (ES + ) m/z [(M+H) + ]: 309 
     Example 24 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     A suspension of E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (Example 23, 240 mg, 0.78 mmol) in anhydrous THF (25 mL) was mildly warmed to a clear solution and then cooled down to 40° C. Anhydrous LiOH (8.7 mg, 0.367 mmol) was added and the mixture was stirred at 40° C. for 10 min. (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)-acetamido)-3-methoxybenzoate (Example 3, 235 mg, 0.733 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 20 h, giving a clear reaction mixture. This mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na 2 SO 4  and concentrated. The crude product was purified on flash chromatography (THF/hexane, 5/95 to 50/50) to give methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (210 mg, 45%). MS (ES + ) m/z [(M+H) + ]: 629 
     Example 25 
     Preparation of rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 24, 48 mg, 0.076 mmol) in THF (4 mL) was added a solution of liOH hydrate (25 mg, 0.60 mmol) in water (2 mL) and the reaction mixture was stirred at rt overnight. The mixture was treated with 1N HCl to slightly acidic, diluted with ethyl acetate (200 mL), washed with water (15 mL), dried with Na 2 SO 4  and concentrated to give rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (38 mg, 82%). MS (ES + ) m/z [(M+H) + ]: 615 
     Example 26 
     Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     A mixture of rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 25, 19 mg, 0.031 mmol), N,N-diisopropylethylamine (30 mg, 0.23 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU (Chem-Impex, 22 mg, 0.057 mmol) in DMF (4 mL) was stirred for 2 min before a solution of ammonia in isopropanol (Aldrich, 2 M, 0.08 mL, 0.16 mmol) was added. The mixture was stirred for 0.5 h and poured into EtOAc (70 mL), washed with water (10 mL), brine (15 mL) and concentrated. The crude product was purified by flash chromatography (EtOH/CH 2 Cl 2 , 0.5/99.5 to 5/95) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (7.6 mg, 37%). MS (ES + ) m/z [(M+H) + ]: 614 
     Example 27 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate 
     
       
         
         
             
             
         
       
     
     A suspension of E/Z-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (Example 23, 258 mg, 0.83 mmol) in anhydrous THF (20 mL) was warmed to a clear solution and then cooled down to 40° C. Anhydrous LiOH (10 mg, 0.42 mmol) was added and the mixture was stirred at 40° C. for 10 min. (E)-Methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)benzoate (Example 1, 247 mg, 0.85 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 20 h, giving a clear reaction mixture. This mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na 2 SO 4  and concentrated. The crude product was purified on flash chromatography (THF/hexane, 5/95 to 50/50) to give methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate as a white solid (148 mg, 29%). MS (ES + ) m/z [(M+H) + ]: 599 
     Example 28 
     Preparation of rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate (Example 27, 22 mg, 0.036 mmol) in THF (4 mL) was added a solution of LiOH hydrate (25 mg, 0.61 mmol) in water (2 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was treated with 1N HCl to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (15 mL), dried with Na 2 SO 4  and concentrated to give rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoic acid as a white solid (20 mg, 93%). MS (ES + ) m/z [(M+H) + ]: 585 
     Example 29 
     Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a suspension of 6-methyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 500 mg, 3.37 mmol) in MeOH (20 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 1.60 g, 10.1 mmol) giving a clear solution. Piperidine (Lancaster, 1.2 g, 14.1 mmol) was added slowly. After stirred for a few minutes, the reaction mixture was heated at 50° C. for 4 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light yellow crystalline solid (946 mg, 97%). MS (ES + ) m/z [(M+H) + ]: 289 
     Example 30 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a suspension of E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 29, 300 mg, 1.04 mmol) in anhydrous THF (20 mL) at 40° C. was added anhydrous LiOH (13 mg, 0.55 mmol) and the mixture was stirred at 40° C. for 10 min before (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (Example 3, 364 mg, 1.14 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 23 h, giving a white precipitate. The resulting precipitate was filtered, washed with cold THF and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (305 mg, 48%). MS (ES + ) m/z [(M+H) + ]: 609 
     Example 31 
     Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 30, 288.8 mg, 0.474 mmol) in THF (16 mL) was added a solution of LiOH hydrate (159 mg, 3.79 mmol) in water (8 mL). The reaction mixture was heated at 45° C. for 22 h. After cooled to rt, the mixture was treated with 1N HCl to slightly acidic. The resulting precipitate was filtered, washed with cold water and then THF, dried overnight to give rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (265 mg, 94%). MS (ES + ) m/z [(M+H) + ]: 595 
     Example 32 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoate 
     
       
         
         
             
             
         
       
     
     To a suspension of E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 29, 201 mg, 0.69 mmol) in anhydrous THF (15 mL) at 40° C. was added LiOH (9.5 mg, 0.397 mmol) and the mixture was stirred at 40° C. for 10 min before methyl 4-(2-(3,3-dimethylbutylideneamino)-acetamido)benzoate (Example 1, 215 mg, 0.740 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 21 h, giving a white precipitate. The resulting precipitate was filtered, washed with cold THF and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoate as a white solid (135 mg, 33%). MS (ES + ) m/z [(M+H) + ]: 579 
     Example 33 
     Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoate (Example 32, 109 mg, 0.19 mmol) in THF (12 mL) was added a solution of LiOH hydrate (63 mg, 1.51 mmol) in water (6 mL). The suspension was warmed at 45° C. for 20 h. After cooled to rt, the mixture was treated with 1N HCl to slightly acidic. The resulting precipitate was filtered and washed with cold water and then THF, dried overnight to give rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoic acid (110 mg, 90%). MS (ES + ) m/z [(M+H) + ]: 565 
     Example 34 
     Preparation of intermediate E/Z-6-Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a suspension of 6-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Sinova, 501.5 mg, 2.83 mmol) in MeOH (25 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 1.35 g, 8.51 mmol). Piperidine (Aldrich, 1.03 g, 12.0 mmol) was added slowly, giving a clear brown solution. After stirred for a few minutes, the reaction mixture was heated at 50° C. overnight, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a grey solid (457 mg, 52%). MS (ES + ) m/z [(M+H) + ]: 309 
     Example 35 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Example 34, 151 mg, 0.49 mmol) in anhydrous THF (12 mL) was added anhydrous LiOH (9 mg, 0.38 mmol) and the mixture was stirred at 40° C. for 10 min. (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)-acetamido)-3-methoxybenzoate (Example 3, 169 mg, 0.53 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. overnight, giving a clear reaction mixture. This mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na 2 SO 4  and concentrated. The crude product was purified by flash chromatography (EtOAc/CH 2 Cl 2 , 1/99 to 50/50) to give methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (34 mg, 11%). MS (ES + ) m/z [(M+H) + ]: 629 
     Example 36 
     Preparation of rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 35, 29 mg, 0.046 mmol) in THF (2 mL) was added a solution of LiOH hydrate (16 mg, 0.39 mmol) in water (2 mL). The reaction mixture was stirred at rt overnight until the reaction was complete. The reaction mixture was treated with 1N HCl to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na 2 SO 4  and concentrated to give rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (26 mg, 92%). MS (ES + ) m/z [(M+H) + ]: 615 
     Example 37 
     Preparation of chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (A) 
     and chiral methyl 4-((2R,3S,4R,5S)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate(B) 
     
       
         
         
             
             
         
       
     
     Methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate (310 mg, Example 6) was separated by SFC (Waters/Thar Multi-Gram II, Kromasil 5-CelluCoat OD 3×25 cm., 35° C. at 100 bar, eluting with 40% MeOH in carbon dioxide) to give chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate, MS (ES + ) m/z [(M+H) + ]: 595, and chiral methyl 4-((2R,3S,4R,5S)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate. MS (ES + ) m/z [(M+H) + ]: 595 
     Example 38 
     Preparation of chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 37, 83 mg, 0.140 mol) in THF (8 mL) was added a solution of LiOH hydrate (47 mg, 1.14 mmol) in water (4 mL). The reaction mixture was stirred at rt overnight before it was treated with 1N HCl to slightly acidic. The mixture was partitioned between water (10 mL) and EtOAc (100 mL), washed with water, brine and dried over Na 2 SO 4 , concentrated and lyophized to give chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white powder (53 mg, 66%). MS (ES + ) m/z [(M+H) + ]: 581 
     Example 39 
     Preparation of chiral(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     A mixture of chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 38, 40 mg, 0.069 mmol) and 1,1′-carbonyldiimidazole (Aldrich, 27.6 mg, 0.170 mmol) in THF (3 mL) was stirred at rt for 17 h. Ammonium hydroxide (Aldrich, 153 mg, 4.37 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHCO 3  (10 mL), water (10 mL) then sat. NH 4 Cl (10 mL). The organic layer was dried over Na 2 SO 4  and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH 2 Cl 2 , 0.5/99.5 to 3/97) to give chiral(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (37 mg, 92%). MS (ES + ) m/z [(M+H) + ]: 580 
     Example 40 
     Preparation of intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a mixture of 6-chloro-4-aza-2-oxindole (Sinova, 1.5 g, 8.9 mmol) and 3-chloro-2-fluorobenzaldehyde (Oakwood, 1.4 g, 8.9 mmol) in methanol (65 mL) was added piperidine (Aldrich, 0.76 g, 8.9 mmol) dropwise. The reaction mixture was heated at 50° C. and stirred for 3 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (1.8 g, 65%). 
     Example 41 
     Preparation of intermediate rac-(2S,3S,4S,5R)-tert-butyl 6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxylate 
     
       
         
         
             
             
         
       
     
     To a suspension of E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 40, 623 mg, 2.02 mmol) in anhydrous THF (20 mL) were added 1,4-diazabicyclo[2,2,2]octane (249 mg, 2.22 mmol, Aldrich) and anhydrous LiCl (Aldrich, 101 mg, 2.38 mmol) under N 2 . The suspension was warmed at 40° C. for a few minutes before (E)-tert-butyl 2-(3,3-dimethylbutylideneamino)acetate (Example 5, Step a, 522 mg, 2.45 mmol) in CH 2 Cl 2  (5 mL) was added. The reaction mixture was allowed to stir at 40° C. for 19 h. The reaction mixture was partitioned between CH 2 Cl 2  and water. The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2  twice. The combined extracts were washed with water, brine and evaporated. The crude product was purified by flash chromatography (EtOAc/hexane, 20/80 to 50/50) to give rac-(2S,3S,4S,5R)-tert-butyl 6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxylate as a light yellow solid (261 mg, 25%). MS (ES + ) m/z [(M+H) + ]: 522 
     Example 42 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (Example 40, 90 mg, 0.29 mmol) in anhydrous THF (8 mL) was added anhydrous LiOH (5 mg, 0.20 mmol) and the mixture was stirred at 40° C. for 10 min. (E)-Methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (99 mg, 0.31 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. overnight giving a white precipitate. The resulting precipitate was filtered, washed with cold THF and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (33 mg, 18%). MS (ES + ) m/z [(M+H) + ]: 629 
     Example 43 
     Preparation of rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 42, 62 mg, 0.10 mmol) in THF (5 mL) was added a solution of LiOH hydrate (34 mg, 0.82 mmol) in water (2.5 mL). The reaction mixture was stirred at rt overnight until the reaction was complete. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na 2 SO 4  and concentrated to give rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (57 mg, 94%). MS (ES + ) m/z [(M+H) + ]: 
     Example 44 
     Preparation of rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     A mixture of rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 43, 30 mg, 0.050 mmol), N,N-disiopropylethylamine (51.9 mg, 0.402 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorohposphate (HATU) (Chem-Impex, 30 mg, 0.080 mmol) in DMF (4 mL) was stirred for 20 min before NH 4 Cl (7.6 mg, 0.13 mmol) was added. The mixture was stirred for 4 h and poured into EtOAc (120 mL), washed with water (10 mL), sat NH 4 Cl (10 mL), sat NaHCO 3  (10 mL), and brine (15 mL) and concentrated. The crude product was purified by RP-HPLC (40% to 100% MeCN in H 2 O) to give rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a white solid (7 mg, 25%). MS (ES + ) m/z [(M+H) + ]: 614 
     Example 45 
     Preparation of intermediate E/Z-5-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a suspension of 5-chloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 815.5 mg, 4.84 mmol) in MeOH (45 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 2.3 g, 14.5 mmol). Piperidine (Aldrich, 1.63 g, 19.2 mmol) was added slowly. After stirring a few minutes, the mixture was heated at 50° C. for 6 h resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-5-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light brown solid (1.38 g, 92%). MS (ES + ) m/z [(M+H) + ]: 309 
     Example 46 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-5′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     A suspension of E/Z-5-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 45, 331.2 mg, 1.07 mmol) in anhydrous THF (25 mL) was warmed to a clear solution and then cooled down to 40 C. LiOH (18 mg, 0.70 mmol) was added and the mixture was stirred at 40° C. for 10 min. (E)-Methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (Example 3, 360.9 mg, 1.13 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 20 h, giving a clear reaction mixture. The mixture was diluted with EtOAc (100 mL), washed with water (2×20 mL) and concentrated to a small volume. MeOH was added slowly (˜10 mL) and the mixture was stirred in cold bath for −20 min. The resulting precipitate was filtered, washed with cold MeOH and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-5′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (420 mg, 76%). MS (ES + ) m/z [(M+H) + ]: 629 
     Example 47 
     Preparation of rac-4-((2S,3S,4S,5R)-5′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3S,4S,5R)-5′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 46, 111 mg, 0.17 mmol) in THF (10 mL) was added a solution of LiOH hydrate (61 mg, 1.46 mmol) in water (5 mL). The reaction mixture was stirred at rt overnight before it was treated with 1N HCl to slightly acidic, diluted with ethyl acetate (200 mL), washed with water (15 mL), dried with Na 2 SO 4  and concentrated to give rac-4-((2S,3S,4S,5R)-5′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (107 mg, 98%). MS (ES + ) m/z [(M+H) + ]: 615 
     Example 48 
     Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-7-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To a suspension of 7-methyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 818.0 mg, 5.52 mmol) in MeOH (30 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 2.60 g, 16.4 mmol) in MeOH (2 mL) to give a clear solution. Piperidine (Aldrich, 1.89 g, 22.2 mmol) was added slowly and a light yellow precipitation started to form shortly. After stirring a few minutes, the reaction mixture was heated at 50° C. for 12 h. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-7-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light brown solid (939 mg, 58%). MS (ES + ) m/z [(M+H) + ]: 288 
     Example 49 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a suspension of E/Z-3-(3-chloro-2-fluoro-benzylidene)-7-methyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 48, 318 mg, 1.10 mmol) in anhydrous THF (25 mL) was added LiOH (20 mg, 0.85 mmol) and the mixture was stirred at 40° C. for 10 min. (E)-Methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (Example 3, 371 mg, 1.16 mmol) was added in one portion. The reaction mixture was allowed to stir at 40° C. for 20 h. The mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na 2 SO 4  and concentrated. The crude product was purified on flash chromatography (EtOAc/CH 2 Cl 2 , 3/97 to 20/20) to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (171 mg, 26%). MS (ES + ) m/z [(M+H) + ]: 609 
     Example 50 
     Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a suspension of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 49, 150 mg, 0.246 mmol) in THF (14 mL) was added LiOH monohydrate (83 mg, 1.98 mmol) in water (5 mL). The mixture was stirred at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na 2 SO 4  and concentrated to give rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (110 mg, 75%). MS (ES + ) m/z [(M+H) + ]: 595 
     Example 51 
     Preparation of chiral methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-e]pyridine]-5-ylcarboxamido)-3-methoxybenzoate(A) 
     and 
     chiral methyl 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate(B) 
     
       
         
         
             
             
         
       
     
     Methyl rac-4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 24) was separated by SFC Chromatography (Waters/Thar Multi-Gram II, Kromasil 5-CelluCoat OD 3×25 cm., 35° C. at 100 bar, eluting with 40% ethanol in carbon dioxide) to give chiral methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, MS (ES + ) m/z [(M+H) + ]: 629, and chiral methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate. MS (ES + ) m/z [(M+H) + ]: 629 
     Example 52 
     Preparation of chiral 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of chiral methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 51, 56 mg, 0.090 mmol) in THF (6 mL) was added a solution of LiOH hydrate (31 mg, 0.74 mmol) in water (3 mL). The reaction mixture was stirred at rt overnight before it was treated with 1N HCl to slightly acidic. The mixture was partitioned between EtOAc (100 mL) and water (10 mL), washed with water, brine and dried over Na 2 SO 4 , concentrated and lyophized to give chiral 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white powder (46 mg, 84%). MS (ES + ) m/z [(M+H) + ]: 615 
     Example 53 
     Preparation of chiral(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     A mixture of chiral 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 52, 26 mg, 0.043 mmol) and 1,1′-carbonyldiimidazole (Aldrich, 26 mg, 0.16 mmol) in THF (3 mL) was stirred at rt for 17 hrs. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHCO 3  (10 mL), water (10 mL) then sat. NH 4 Cl (10 mL). The organic layer was dried over Na 2 SO 4  and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH 2 Cl 2 , 0.5/99.5 to 3/97) to give chiral(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (21 mg, 79%). MS (ES + ) m/z [(M+H) + ]: 614 
     Example 54 
     Preparation of chiral 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of chiral methyl 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (62 mg, 0.099 mmol, Example 51) in THF (6 mL) was added a solution of LiOH hydrate (34 mg, 0.82 mmol) in water (3 mL). The reaction mixture was stirred at rt overnight before it was treated with 1N HCl to slightly acidic. The mixture was partitioned between EtOAc (100 mL) and water (10 mL), washed with water, brine and dried over Na 2 SO 4 , concentrated and lyophized to give chiral 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white powder (50 mg, 81%). MS (ES + ) m/z [(M+H) + ]: 615 
     Example 55 
     Preparation of chiral(2R,3S,4R,5S)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     A mixture of chiral 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 54, 29 mg, 0.047 mmol) and 1,1′-carbonyldiimidazole (Aldrich, 23 mg, 0.14 mmol) in THF (3 mL) was stirred at rt for 17 h. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHCO 3  (10 mL), water (10 mL) then sat. NH 4 Cl (10 mL). The organic layer was dried over Na 2 SO 4  and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH 2 Cl 2 , 0.5/99.5 to 3/97) to give chiral (2R,3S,4R,5S)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (20 mg, 70%). MS (ES + ) m/z [(M+H) + ]: 614 
     Example 56 
     Preparation of chiral 4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid(A) 
     and chiral 4-((2R,3R,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid(B) 
     
       
         
         
             
             
         
       
     
     A rac-4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 43) was separated by SFC Chromatography SFC (Waters/Thar Multi-Gram II, Chiral Technologies, Diacel OD, 3×25 cm., 35° C. at 100 bar, eluting with 35% Ethanol in carbon dioxide) to give chiral 4-((2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid, MS (ES + ) m/z [(M+H) + ]: 615, and chiral 4-((2R,3R,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid. MS (ES + ) m/z [(M+H) + ]: 615 
     Example 57 
     Preparation of chiral methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate(A) 
     and chiral methyl 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate(B) 
     
       
         
         
             
             
         
       
     
     Rac-methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate (Example 27) was separated by SFC (Waters/Thar Multi-Gram II, Chiral Technologies, Diacel IA, 3×25 cm., 35° C. at 100 bar, eluting with 35% ethanol in carbon dioxide) to give chiral methyl 4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate, MS (ES + ) m/z [(M+H) + ]: 599, and chiral methyl 4-((2R,3S,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate. MS (ES + ) m/z [(M+H) + ]: 599 
     Example 58 
     Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To the mixture of 6-chloro-4-aza-2-oxindole (Sinova, 1 g, 5.9 mmol) and 3-chloro-benzaldehyde (Aldrich, 0.83 g, 5.9 mmol) in methanol (50 mL) was added piperidine (Aldrich, 0.5 g, 5.9 mmol) dropwise. The reaction mixture was heated at 80° C. and stirred for 1 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (0-25% EtOAc in dichlormethane) to give the second batch of product. The two batches were combined to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as an orange solid (0.9 g, 52%). 
     Example 59 
     Preparation of methyl rac-4-{(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 58, 0.25 g, 0.86 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (41 mg, 1.72 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester 
     (Example 3, 0.27 g, 0.86 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 2 h. The mixture was cooled to room temperature and filtered. The resulting precipitate was collected, washed with ethyl acetate, and dried to give methyl rac-4-{(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate as an off-white solid (0.15 g, 29%). MS (ES + ) m/z Calcd for C 31 H 32 Cl 2 N 4 O 5 +H [(M+H) + ]: 611. found: 611. 
     Example 60 
     Preparation of rac-4-{(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-{(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate (Example 59, 70 mg, 0.11 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1 N) of NaOH (1.1 mL, 1.1 mmol). The reaction mixture was stirred at room temperature for 5 h. The “pH” of the mixture was adjusted to 5 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-4-{(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid as an off-white solid (58 mg, 85%). MS (ES + ) m/z Calcd for C 30 H 30 Cl 2 N 4 O 5 +H [(M+H) + ]: 597. found: 597. 
     Example 61 
     Preparation of intermediate N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide 
     
       
         
         
             
             
         
       
     
     Step a: A mixture of 3-methoxy-4-nitrobenzoic acid (Acros, 10 g, 51 mmol) in thionyl chloride (36 g) was heated at reflux for 2 h. The mixture was concentrated. To the residue was added a methanolic solution (7 N) of ammonia. The reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The precipitate between the two layers was filtered and collected to give 3-methoxy-4-nitrobenzamide as a light yellow solid (8 g, 81%). 
     Step b: To a solution of 3-methoxy-4-nitrobenzamide (8 g, 41 mmol) in dioxane (300 mL) was added pyridine (32 g, 408 mmol), followed by dropwise addition of trifluoroacetic anhydride (43 g, 204 mmol). The reaction mixture was stirred at room temperature for 5 h. Water was added to quench the reaction. The mixture was concentrated, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, aqueous saturated CuSO 4  solution, brine, dried over MgSO 4 , and concentrated to give 3-methoxy-4-nitrobenzonitrile as a off white solid (6.5 g, 90%) 
     Step c: To the suspension of 3-methoxy-4-nitrobenzonitrile (11.4 g, 64 mmol) in ethyl acetate (60 mL) was added 10% Pd/C (1 g). The reaction mixture was vigorously shaken in a Parr under an atmosphere of hydrogen (50 psi) at room temperature for 45 min. The mixture was filtered through a short pad of celite, and the filtrate was concentrated to give 4-amino-3-methoxy-benzonitrile as a yellow oil, which solidified at stand (9.5 g, 95%) 
     Step d: To a solution of 2-(tert-butoxycarbonylamino)acetic acid (Advanced Chemical, 3.9 g, 22.3 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI) (Aldrich, 4.27 g, 22.3 mmol) in dichloromethane (20 mL) was added 4-amino-3-methoxy-benzonitrile (2 g, 13.5 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous NH 4 Cl solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with saturated aqueous NaHCO 3  solution, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-15% EtOAc in dichlormethane) to give tert-butyl 2-(4-cyano-2-methoxyphenylamino)-2-oxoethylcarbamate as a white solid (3.3 g, 80%). 
     Step e: To a solution of tert-butyl 2-(4-cyano-2-methoxyphenylamino)-2-oxoethylcarbamate (1.5 g, 4.9 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was then triturated with hexanes, concentrated, dried in vacuo to give 2-amino-N-(4-cyano-2-methoxyphenyl)acetamide trifluoroacetic acid as a yellow solid (1.2 g, 77%). 
     Step f: To a mixture of 2-amino-N-(4-cyano-2-methoxyphenyl)acetamide trifluoroacetic acid (1.7 g, 5.4 mmol) in methyl tert-butyl ether (20 mL) was added triethylamine (0.78 mL, 5.7 mmol). The mixture was stirred at room temperature for 30 min. Then 3,3-dimethyl-butyraldehyde (Aldrich, 0.57 g, 5.7 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 h. The mixture was filtered, and the filtrate was concentrated. The residue was partitioned between dichloromethane and water. The organic layer was separated, and aqueous layer was extracted with dichlormethane. The combined organic extract was washed with water, dried over MgSO 4 , and concentrated to give N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (1.2 g, 77%) as a yellow foam which was used in the next step without further purification. 
     Example 62 
     Preparation of rac-(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 58, 0.1 g, 0.34 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (16.5 mg, 0.69 mmol). The mixture was warmed to 40° C. and stirred for 10 min. N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.15 g, 0.52 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 2 h. The mixture was cooled to room temperature and filtered. The resulting precipitate was collected, washed with ethyl acetate, and dried to give rac-(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a white solid (33 mg, 17%). MS (ES + ) m/z Calcd for C 30 H 29 Cl 2 N 5 O 3 +H [(M+H) + ]: 578. found: 578. 
     Example 63 
     Preparation of rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To the solution of rac-(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide (Example 62, 26 mg, 0.045 mmol) in DMSO (0.2 mL) at 0° C. was added an aqueous solution (30%) of H 2 O 2  (Aldrich, 0.076 mg, 0.67 mmol), followed by the addition of aqueous solution (1 N) of NaOH (0.23 mL, 0.23 mmol). The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na 2 SO 3  solution. The organic layer was separated, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as an off-white solid (24 mg, 90%). MS (ES + ) m/z Calcd for C 30 H 31 Cl 2 N 5 O 4 +H [(M+H) + ]: 596. found: 596. 
     Example 64 
     Preparation of intermediate E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To the mixture of 6-chloro-4-aza-2-oxindole (Sinova, 1 g, 5.9 mmol) and 3-bromo-2-fluorobenzaldehyde (Aldrich, 1.6 g, 7.9 mmol) in methanol (30 mL) was added piperidine (Aldrich, 2 g, 24 mmol) dropwise. The reaction mixture was heated at 50° C. and stirred for 3 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (25-50% EtOAc in hexanes) to give the second batch of product. The two batches were combined to give E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (1.6 g, 76%). 
     Example 65 
     Preparation of methyl rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 64, 0.3 g, 0.85 mmol) in tetrahydrofuran (10 mL) was added anhydrous LiOH (41 mg, 1.7 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.27 g, 0.85 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 18 h. The mixture was cooled to room temperature and filtered. The resulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give the second batch of desired product. The two batches were combined to give methyl rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate as a white solid (0.17 g, 30%). MS (ES + ) m/z Calcd for C 31 H 31 BrClFN 4 O 5 +H [(M+H) + ]:673. found: 673. 
     Example 66 
     Preparation of methyl rac-4-{(2S,3R,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     In the preparation of rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate as described in Example 65, methyl rac-4-{(2S,3R,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate was obtained as another product by chromatography (5-10% EtOAc in dichlormethane): 50 mg, 9%, off white solid. MS (ES + ) m/z Calcd for C 31 H 31 BrClFN 4 O 5 +H [(M+H) + ]:673. found: 673. 
     Example 67 
     Preparation of rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate (Example 65, 120 mg, 0.18 mmol) in tetrahydrofuran (8 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol). The reaction mixture was stirred at room temperature for 18 h. The “pH” of the mixture was adjusted to 3 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid as a white solid (80 mg, 68%). MS (ES + ) m/z Calcd for C 30 H 29 BrClFN 4 O 5 +H [(M+H) + ]: 659. found: 659. 
     Example 68 
     Preparation of rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 64, 0.1 g, 0.28 mmol) in tetrahydrofuran (1 mL) was added anhydrous LiOH (13.5 mg, 0.57 mmol). The mixture was warmed to 40° C. and stirred for 10 min. N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.12 g, 0.42 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 1 h. The mixture was cooled to room temperature and filtered. The resulting precipitate was collected, washed with ethyl acetate, and dried to give rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a white solid (40 mg, 22%). MS (ES + ) m/z Calcd for C 30 H 28 BrClFN 5 O 4 +H [(M+H) + ]: 640. found: 640. 
     Example 69 
     Preparation of rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide (Example 68, 32 mg, 0.05 mmol) in DMSO (0.2 mL) at 0° C. was added an aqueous solution (30%) of H 2 O 2  (Aldrich, 0.085 mg, 0.75 mmol), followed by the addition of aqueous solution (1 N) of NaOH (0.25 mL, 0.25 mmol). The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na 2 SO 3  solution. The organic layer was separated, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a off white solid (29 mg, 88%). MS (ES + ) m/z Calcd for C 30 H 30 BrClFN 5 O 4 +H [(M+H) + ]: 658. found: 658. 
     Example 70 
     Preparation of intermediate acetic acid 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester 
     
       
         
         
             
             
         
       
     
     Step a: To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80° C. for 20 h. The mixture was cooled to room temperature, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%). 
     Step b: To a solution of 3-methoxy-4-nitrophenol (1 g, 5.9 mmol) in anhydrous DMF (25 mL) were added K 2 CO 3  (2.45 g, 17.7 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.7 g, 7.1 mmol) sequentially. The reaction mixture was heated at 70° C. for 20 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-20% EtOAc in hexanes) to give tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane as a light yellow oil (1.0 g, 52%). 
     Step c: To a solution of tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane (4 g, 12.2 mmol) in THF (50 mL) was added an aqueous HCl solution (1 N, 20 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO 3  solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated to give 2-(3-methoxy-4-nitrophenoxy)ethanol as an off white solid (2.1 g, 81%). 
     Step d: To a solution of 2-(3-methoxy-4-nitrophenoxy)ethanol (2.1 g, 9.9 mmol) and pyridine (0.9 g, 11.4 mmol) in THF (50 mL) at 0° C. was acetyl chloride (0.89 g, 11.4 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, saturated aqueous CuSO 4  solution, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-40% EtOAc in dichloromethane) to give 2-(3-methoxy-4-nitrophenoxy)ethyl acetate as a yellow foam (2.4 g, 95%). 
     Step e: A suspension of 2-(3-methoxy-4-nitrophenoxy)ethyl acetate (2.4 g, 9.4 mmol) and Pd/C (Aldrich, 10%, 0.4 g) in ethyl acetate (30 mL) was vigorously shaken in a Parr under atmosphere of H 2  (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give acetic acid 2-(4-amino-3-methoxy-phenoxy)-ethyl ester as a light brown oil (2 g, 94%). 
     Step f: To a solution of 2-(tert-butoxycarbonylamino)acetic acid (Advanced Chemical, 2.57 g, 14.7 mmol) and EDCI (Aldrich, 2.81 g, 14.7 mmol) in dichloromethane (20 mL) was added 2-(4-amino-3-methoxy-phenoxy)-ethyl ester (2 g, 8.9 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated, and the residue was partitioned between dichloromethane and saturated aqueous NH 4 Cl solution. The organic layer was separated, and aqueous layer was extracted with dichloromethane twice. The combined organic extract was washed with saturated aqueous NaHCO 3  solution, brine, dried over MgSO 4 , and concentrated to give 2-(4-(2-(tert-butoxycarbonylamino)acetamido)-3-methoxyphenoxy)ethyl acetate as a light brown oil (3.3 g, 97%). 
     Step g: A solution of 2-(4-(2-(tert-butoxycarbonylamino)acetamido)-3-methoxyphenoxy)ethyl acetate (1 g, 2.6 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was then triturated with hexanes, concentrated, dried in vacuo to give 2-(4-(2-aminoacetamido)-3-methoxyphenoxy)ethyl acetate trifluoroacetic acid as an off white foam (0.8 g, 77%). 
     Step h: To a mixture of 2-(4-(2-aminoacetamido)-3-methoxyphenoxy)ethyl acetate trifluoroacetic acid (1 g, 2.5 mmol) in methyl tert-butyl ether (12 mL) was added triethylamine (0.53 mL, 3.8 mmol). The mixture was stirred at room temperature for 30 min. Then 3,3-dimethyl-butyraldehyde (Aldrich, 0.33 g, 2.7 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was filtered, and the filtrate was concentrated. The residue was partitioned between dichloromethane and water. The organic layer was separated, and aqueous layer was extracted with dichlormethane. The combined organic extract was washed with water, dried over MgSO 4 , and concentrated to give acetic acid 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester as a yellow oil (0.9 g, 98%) which was used in the next step without further purification. 
     Example 71 
     Preparation of rac-2-(4-((2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 58, 0.14 g, 0.48 mmol) in tetrahydrofuran (3 mL) was added anhydrous LiOH (23 mg, 0.96 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.18 g, 0.48 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 2 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by chromatography (0-20% EtOAc in dichloromethane) to give rac-2-(4-((2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate as an off white solid (0.1 g, 32%). 
     Example 72 
     Preparation of rac-(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of rac-2-(4-((2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate (Example 71, 0.1 g, 0.15 mmol) in tetrahydrofuran (2 mL) was added an aqueous solution (1 N) of NaOH (2 mL, 2 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO 3  solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO 4 , and concentrated. The residue was recrystallized in methanol to give rac-(2S,3S,4R,5R)-6′-chloro-4-(3-chlorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a white solid (11 mg, 12%). MS (ES + ) m/z Calcd for C 31 H 34 Cl 2 N 4 O 5 +H [(M+H) + ]: 613. found: 613. 
     Example 73 
     Preparation of rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 64, 0.1 g, 0.28 mmol) in tetrahydrofuran (1 mL) was added anhydrous LiOH (14 mg, 0.57 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.16 g, 0.42 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 3 h. Then an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40° C. for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichloromethane) to give rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a light yellow solid (40 mg, 21%). 
     MS (ES + ) m/z Calcd for C 31 H 33 BrClFN 4 O 5 +H [(M+H) + ]: 675. found: 675. 
     Example 74 
     Preparation of rac-(2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 40, 0.15 g, 0.49 mmol) in tetrahydrofuran (1.5 mL) was added anhydrous LiOH (23 mg, 0.97 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.27 g, 0.73 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 2 h. Then an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40° C. for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichloromethane) to give rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6′-chloro-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a yellow solid (51 mg, 17%). MS (ES + ) m/z Calcd for C 31 H 33 Cl 2 FN 4 O 5 +H [(M+H) + ]: 631. found: 631. 
     Example 75 
     Preparation of chiral(2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     Rac-(2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide (Example 74, 0.11 g) was separated by chiral SFC chromatography to provide chiral(2S,3S,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a off white solid (10 mg, 9%) and chiral(2R,3R,4R,5S)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as an off white solid (12 mg, 11%). 
     MS (ES + ) m/z Calcd for C 31 H 33 Cl 2 FN 4 O 5 +H [(M+H) + ]: 631. found: 631. 
     Example 76 
     Preparation of intermediate E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To the mixture of 6-bromo-4-aza-2-oxindole (Sinova, 0.3 g, 1.4 mmol) and 3-chloro-2-fluorobenzaldehyde (Oakwood, 0.45 g, 2.8 mmol) in methanol (20 mL) was added piperidine (Aldrich, 0.36 g, 4.2 mmol) dropwise. The reaction mixture was heated at 50° C. and stirred for 3 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (25-50% EtOAc in hexanes) to give the second batch of product. The two batches were combined to give E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (0.35 g, 70%). 
     Example 77 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 76, 0.16 g, 0.45 mmol) in tetrahydrofuran (10 mL) was added anhydrous LiOH (11 mg, 0.45 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.15 g, 0.48 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 18 h. The mixture was cooled to room temperature and filtered. The resulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give the second batch of desired product. The two batches were combined to give methyl rac-4-((2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (32 mg, 10%). 
     MS (ES + ) m/z Calcd for C 31 H 31 BrClFN 4 O 5 +H [(M+H) + ]: 673. found: 673. 
     Example 78 
     Preparation of rac-4-((2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-((2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 77, 25 mg, 0.037 mmol) in tetrahydrofuran (6 mL) was added an aqueous solution (1 N) of NaOH (2 mL, 2 mmol). The reaction mixture was stirred at room temperature for 20 h. The “pH” of the mixture was adjusted to 3 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-4-((2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (19 mg, 78%). 
     MS (ES + ) m/z Calcd for C 30 H 29 BrClFN 4 O 5 +H [(M+H) + ]: 659. found: 659. 
     Example 79 
     Preparation of rac-(2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 76, 0.2 g, 0.57 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (27 mg, 1.1 mmol). The mixture was warmed to 40° C. and stirred for 10 min. N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.24 g, 0.85 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 1 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The resulting precipitate was filtered and collected to give rac-(2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a yellow solid (80 mg, 22%). MS (ES + ) m/z Calcd for C 30 H 28 BrClFN 5 O 3 +H [(M+H) + ]: 640. found: 640. 
     Example 80 
     Preparation of rac-(2S,3S,4S,5R)-6′-bromo-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of rac-(2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide (Example 79, 70 mg, 0.11 mmol) in DMSO (0.5 mL) at 0° C. was added an aqueous solution (30%) of H 2 O 2  (Aldrich, 0.19 g, 1.6 mmol), followed by the addition of aqueous solution (1 N) of NaOH (0.54 mL, 0.54 mmol). The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na 2 SO 3  solution. The organic layer was separated, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-(2S,3S,4S,5R)-6′-bromo-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a off white solid (56 mg, 78%). MS (ES + ) m/z Calcd for C 30 H 30 BrClFN 5 O 4 +H [(M+H) + ]: 658. found: 658. 
     Example 81 
     Preparation of rac-(2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 76, 0.2 g, 0.57 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (27 mg, 1.1 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.31 g, 0.85 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 3 h. Then an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40° C. for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichloromethane) to give rac-(2S,3S,4S,5R)-6′-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a light yellow solid (65 mg, 17%). 
     MS (ES + ) m/z Calcd for C 31 H 33 BrClFN 4 O 5 +H [(M+H) + ]: 675. found: 675. 
     Example 82 
     Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     To the mixture of 6-fluoro-4-aza-2-oxindole (Sinova, 1 g, 4.6 mmol) and 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 1.2 g, 7.6 mmol) in methanol (50 mL) was added piperidine (Aldrich, 2 g, 24 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 h. Then the mixture was filtered. The resulting precipitate was collected to give the first batch of desired product. The filtrate was concentrated. The residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desire product. The two batches were combined to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (Yield 1.1 g, 82%). 
     Example 83 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 82, 0.3 g, 1 mmol) in tetrahydrofuran (10 mL) was added anhydrous LiOH (25 mg, 1 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.33 g, 1 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 24 h. The mixture was cooled to room temperature and filtered. The resulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give the second batch of desired product. The two batches were combined to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (0.21 g, 33%). MS (ES + ) m/z Calcd for C 31 H 31 ClF 2 N 4 O 5 +H [(M+H) + ]: 613. found: 613. 
     Example 84 
     Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 83, 0.21 g, 0.34 mmol) in tetrahydrofuran (8 mL) was added an aqueous solution (1 N) of NaOH (2 mL, 2 mmol). The reaction mixture was stirred at 60° C. for 24 h. The “pH” of the mixture was adjusted to 3 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (0.19 g, 93%). MS (ES + ) m/z Calcd for C 30 H 29 ClF 2 N 4 O 5 +H [(M+H) + ]: 599. found: 599. 
     Example 85 
     Preparation of rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 82, 0.18 g, 0.62 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (30 mg, 1.2 mmol). The mixture was warmed to 40° C. and stirred for 10 min. N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.27 g, 0.92 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 1 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The resulting precipitate was filtered and collected to give rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a white solid (40 mg, 11%). MS (ES + ) m/z Calcd for C 30 H 28 ClF 2 N 5 O 3 +H [(M+H) + ]: 580. found: 580. 
     Example 86 
     Preparation of rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide (Example 85, 30 mg, 0.52 mmol) in DMSO (0.3 mL) at 0° C. was added an aqueous solution (30%) of H 2 O 2  (Aldrich, 0.088 g, 0.78 mmol), followed by the addition of aqueous solution (1 N) of NaOH (0.26 mL, 0.26 mmol). The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na 2 SO 3  solution. The organic layer was separated, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as an off white solid (24 mg, 78%). MS (ES + ) m/z Calcd for C 30 H 30 ClF 2 N 5 O 4 +H [(M+H) + ]: 598. found: 598. 
     Example 87 
     Preparation of rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2-methoxyphenyl]-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 82, 0.15 g, 0.51 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (25 mg, 1 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.28 g, 0.77 mmol) prepared in was added in one portion. The reaction mixture was stirred at 40° C. for 3 h. Then an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40° C. for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichloromethane) to give rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2-methoxyphenyl]-6′-fluoro-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-carboxamide as a light yellow solid (55 mg, 17%). MS (ES + ) m/z Calcd for C 31 H 33 ClF 2 N 4 O 5 +H [(M+H) + ]: 615. found: 615. 
     Example 88 
     Preparation of intermediate E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one 
     
       
         
         
             
             
         
       
     
     To a mixture of 2-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (Molbridge, 0.5 g, 3.0 mmol) in acetic acid (8 mL) and aqueous concentrated HCl solution (37%, 2 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 0.9 g, 5.7 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was neutralized to “pH” 7-8 by aqueous saturated NaHCO 3  solution, then extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated to a small volume. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product. The two batches were combined to give E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as a yellow solid (0.51 g, 56%). 
     Example 89 
     Preparation of rac-(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2-methoxyphenyl]-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (Example 88, 0.3 g, 0.97 mmol) in tetrahydrofuran (3 mL) was added anhydrous LiOH (23 mg, 0.97 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.53 g, 1.5 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 2 h. Then an aqueous solution (1 N) of NaOH (1.5 mL, 1.5 mmol) was added, and the reaction mixture was stirred at 40° C. for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-80% EtOAc in dichloromethane) to give rac-(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2-methoxyphenyl]-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxamide as a yellow solid (25 mg, 4%). MS (ES + ) m/z Calcd for C 30 H 32 Cl 2 FN 5 O 5 +H [(M+H) + ]: 632. found: 632. 
     Example 90 
     Preparation of methyl rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (Example 88, 0.2 g, 0.65 mmol) in tetrahydrofuran (15 mL) was added anhydrous LiOH (15 mg, 0.65 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.22 g, 0.68 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 5 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give methyl rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate as a white solid (0.12 g, 28%). MS (ES + ) m/z Calcd for C 30 H 30 Cl 2 FN 5 O 5 +H [(M+H) + ]: 630. found: 630. 
     Example 91 
     Preparation of methyl rac-4-{(2S,3S,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     In the preparation of methyl rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate as described in Example 90, methyl rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate was obtained as another product by chromatography (5-10% EtOAc in dichlormethane): Yield 45 mg, 11%, a white solid. MS (ES + ) m/z Calcd for C 30 H 30 Cl 2 FN 5 O 5 +H [(M+H) + ]: 630. found: 630. 
     Example 92 
     Preparation of rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate (Example 90, 98 mg, 0.16 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol). The reaction mixture was stirred at 60° C. for 24 h. The “pH” of the mixture was adjusted to 3 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoic acid as a white solid (90 mg, 94%). MS (ES + ) m/z Calcd for C 29 H 28 Cl 2 FN 5 O 5 +H [(M+H) + ]: 616. found: 616. 
     Example 93 
     Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of rac-4-{(2S,3R,4S,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoic acid (Example 92, 90 mg, 0.15 mmol) in anhydrous DMF (2 mL) were added EDCI (56 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol), NH 4 Cl (77 mg, 1.5 mmol), and triethylamine (30 mg, 0.29 mmol) sequentially. The reaction mixture was heated at 68° C. for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (25-100% EtOAc in dichloromethane) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6′-oxo-6′,7′-dihydrospiro[pyrrolidine-3,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxamide as a light yellow solid (67 mg, 75%). MS (ES + ) m/z Calcd for C 29 H 29 Cl 2 FN 6 O 4 +H [(M+H) + ]: 615. found: 615. 
     Example 94 
     Preparation of intermediate 2-chloro-4,6-dihydro-thieno[3,2-b]pyrrol-5-one 
     
       
         
         
             
             
         
       
     
     Step a: To a solution of 2,5-dichlorothiophene (Aldrich, 21 g, 137 mmol) in concentrated H 2 SO 4  (59 mL) at 0° C. was added a fine powder form of NaNO 3  (28 g, 412 mmol) in one portion. The reaction mixture was stirred at 0° C. for 2 min when a brown fume began to appear. The reaction mixture was poured into the mixture of ice-water and ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (1% EtOAc in hexanes) to give 2,5-dichloro-3-nitrothiophene as a yellow oil (17 g, 63%). 
     Step b: To a solution of tert-butyl ethyl malonate (Alfa, 16.2 g, 86 mmol) in anhydrous DMSO (50 mL) were added NaH (Aldrich, 60%, 5.15 g, 129 mmol). The mixture was heated at 100° C. for 1 h, the cooled to room temperature. 2,5-Dichloro-3-nitrothiophene (17 g, 86 mmol) was added in one portion. The reaction mixture was heated at 60° C. for 2 h. The mixture was cooled to room temperature, and water and dilute aqueous HCl solution were slowly added. The mixture was extracted with ethyl acetate twice times. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated. Trifluoroacetic acid (50 mL) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO 3  solution. The organic layer was separated, washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (0-20% EtOAc in hexanes) to give ethyl 2-(5-chloro-3-nitrothiophen-2-yl)acetate as a brown oil (10 g, 61%). 
     Step c: To a solution of ethyl 2-(5-chloro-3-nitrothiophen-2-yl)acetate (10 g, 40 mmol) in methanol (200 mL) was added an aqueous solution (40 mL) of NH 4 Cl (17 g, 320 mmol), followed by activated Zinc (Aldrich, 15.7 g, 240 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through a short pad of celite. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (20-50% EtOAc in hexanes) to give ethyl 2-(3-amino-5-chlorothiophen-2-yl)acetate as a yellow oil (7 g, 80%). 
     Step d: To a flask charged with ethyl 2-(3-amino-5-chlorothiophen-2-yl)acetate (6.7 g, 31 mmol) was added anhydrous toluene (30 mL). The mixture was evaporated to dryness. The process was repeated three times. To the residue was added toluene (300 mL), and the temperature of the solution was lowered to 0° C. A toluene solution (2 N) of trimethylaluminum (38 mL, 76 mmol) was added. The reaction mixture was stirred at 10° C. for 0.5 h, then quenched by methanol (10 mL) slowly. The mixture was poured into saturated aqueous NH 4 Cl solution, and extracted with ethyl acetate twice. The combined organic extract was dried over MgSO 4  and concentrated to give warmed to room temperature and stirred for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, saturated aqueous CuSO 4  solution, brine, dried over MgSO 4 , and concentrated to give crude 2-chloro-4,6-dihydro-thieno[3,2-b]pyrrol-5-one as a black solid (5.4 g, 75%). 
     Example 95 
     Preparation of intermediate E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)-one 
     
       
         
         
             
             
         
       
     
     To a mixture of 2-chloro-4,6-dihydro-thieno[3,2-b]pyrrol-5-one (Example 94, 4.2 g, 24 mmol) in acetic acid (60 mL) and aqueous concentrated HCl solution (37%, 15 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 7.5 g, 47 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered, and the resulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desire product. The filtrate was concentrated, and the residue was neutralized to “pH” 7-8 by aqueous saturated NaHCO 3  solution, then extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product. The two batches were combined to give E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)-one as a brown solid (5.1 g, 69%). 
     Example 96 
     Preparation of methyl rac-4-((2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)-one (Example 95, 0.37 g, 1.2 mmol) in tetrahydrofuran (10 mL) was added anhydrous LiOH (28 mg, 1.2 mmol). The mixture was warmed to 40° C. and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.4 g, 1.3 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 60 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give methyl rac-4-((2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate as a brown solid (90 mg, 12%). MS (ES + ) m/z Calcd for C 30 H 30 Cl 2 FN 3 O 5 S+H [(M+H) + ]: 634. found: 634. 
     Example 97 
     Preparation of methyl rac-4-((2S,3S,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     In the preparation of methyl rac-4-((2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate as described in Example 96, methyl rac-4-((2S,3S,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate was obtained as another product by chromatography (5-10% EtOAc in dichlormethane): Yield 30 mg, 4%, a brown solid. MS (ES + ) m/z Calcd for C 30 H 30 Cl 2 FN 3 O 5 S+H [(M+H) + ]: 634. found: 634. 
     Example 98 
     Preparation of rac-4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     To a solution of methyl rac-4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoate (Example 96, 90 mg, 0.14 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) and methanol (1 mL). The reaction mixture was stirred at room temperature for 18 h. The “pH” of the mixture was adjusted to 3-6 by aqueous HCl solution. The mixture was concentrated to a small volume, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid as a off white solid (75 mg, 85%). MS (ES + ) m/z Calcd for C 29 H 28 Cl 2 FN 3 O 5 S+H [(M+H) + ]: 620. found: 620. 
     Example 99 
     Preparation of chiral 4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     Rac-4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid (Example 98, 0.15 g) was separated by chiral SFC chromatography to provide chiral 4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid as a yellow solid (39 mg, 24%) and chiral 4-{(2R,3S,4S,5S)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid as an off white solid (41 mg, 25%). MS (ES + ) m/z Calcd for C 29 H 28 Cl 2 FN 3 O 5 S+H [(M+H) + ]: 620. found: 620. 
     Example 100 
     Preparation of rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of rac-4-{(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid (220 mg, 0.36 mmol) in anhydrous DMF (2 mL) were added EDCI (Example 98, 136 mg, 0.71 mmol), HOBt (96 mg, 0.71 mmol), NH 4 Cl (188 mg, 3.55 mmol), and triethylamine (72 mg, 0.71 mmol) sequentially. The reaction mixture was heated at 68° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO 4 , and concentrated. The residue was purified by chromatography (25-100% EtOAc in dichloromethane) to give rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide as a light brown solid (170 mg, 77%). MS (ES + ) m/z Calcd for C 29 H 29 Cl 2 FN 4 O 4 S+H [(M+H) + ]: 619. found: 619. 
     Example 101 
     Preparation of chiral(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     Rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide (Example 100, 0.17 g) was separated by chiral SFC chromatography to provide chiral(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide as a light yellow solid (70 mg, 41%) and chiral(2R,3S,4S,5S)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide as a light yellow solid (68 mg, 40%). MS (ES + ) m/z Calcd for C 29 H 29 Cl 2 FN 4 O 4 S+H [(M+H) + ]: 619. found: 619. 
     Example 102 
     Preparation of rac-(2S,3S,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)-one (Example 95, 0.15 g, 0.48 mmol) in tetrahydrofuran (1 mL) was added anhydrous LiOH (23 mg, 0.96 mmol). The mixture was warmed to 40° C. and stirred for 10 min. N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.23 g, 0.79 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 1 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography (0-20% EtOAc in dichlormethane) to give rac-(2S,3S,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide as a purple solid (40 mg, 14%). MS (ES) m/z Calcd for C 29 H 27 Cl 2 FN 4 O 3 S+H [(M+H) + ]: 601. found: 601. 
     Example 103 
     Preparation of rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of rac-(2S,3S,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide (Example 102, 28 mg, 0.47 mmol) in DMSO (0.2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H 2 O 2  (0.079 g, 0.7 mmol), followed by the addition of aqueous solution (1 N) of NaOH (0.23 mL, 0.23 mmol). The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na 2 SO 3  solution. The organic layer was separated, washed with water, brine, dried over MgSO 4 , and concentrated to give rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide as a purple solid (Yield 25 mg, 87%). MS (ES + ) m/z Calcd for C 29 H 29 Cl 2 FN 4 O 4 S+H [(M+H) + ]: 619. found: 619. 
     Example 104 
     Preparation of intermediate rac-(2S,3R,4R,5R)-tert-butyl 2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxylate 
     
       
         
         
             
             
         
       
     
     To a solution of E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)-one (Example 95, 0.9 g, 2.9 mmol) in tetrahydrofuran (20 mL) was added anhydrous LiOH (97 mg, 4.1 mmol). The mixture was warmed to 40° C. and stirred for 10 min. [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (Example 5, Step a, 1.8 g, 8.4 mmol) was added in one portion. The reaction mixture was stirred at 40° C. for 66 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography (10-33% EtOAc in dichlormethane) to give rac-(2S,3R,4R,5R)-tert-butyl 2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxylate as a white solid (0.18 g, 12%). 
     Example 105 
     Preparation of intermediate rac-(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxylic acid trifluoroacetic acid 
     
       
         
         
             
             
         
       
     
     A solution of rac-(2S,3R,4R,5R)-tert-butyl 2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxylate (Example 104, 64 mg, 0.12 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 24 h, then concentrated. The residue was then triturated with ethyl ether and hexanes, concentrated, dried in vacuo to give rac-(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxylic acid trifluoroacetic acid as an off white solid (71 mg, 100%). 
     Example 106 
     Preparation of intermediate 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-methoxy-phenylamine 
     
       
         
         
             
             
         
       
     
     A suspension of tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane (Example 70, Step b, 1 g, 3.05 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in ethyl acetate (25 mL) was vigorously shaken in a Parr under atmosphere of H 2  (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-methoxy-phenylamine as a light yellow oil (0.9 g, 99%). 
     Example 107 
     Preparation of rac-(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     To a solution of rac-(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxylic acid trifluoroacetic acid (Example 105, 0.18 g, 0.31 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (0.2 g, 1.5 mmol), diphenylphosphinic chloride (Aldrich, 0.15 g, 0.61 mmol) respectively. The mixture was stirred at room temperature for 8 min, then 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2-methoxyaniline (0.14 g, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and an aqueous solution (1 N) of HCl (1 mL, 1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over Na 2 SO 4 , then concentrated. The residue was purified by chromatography (10-100% of EtOAc in CH 2 Cl 2 ) to give rac-(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide as a yellow solid (0.1 g, 51%). 
     HRMS (ES + ) m/z Calcd for C 30 H 32 Cl 2 FN 3 O 5 S+H [(M+H) + ]: 636. found: 636. 
     Example 108 
     Preparation of chiral(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     Rac-(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide (Example 107, 93 mg) was separated by chiral SFC chromatography to provide chiral(2S,3R,4R,5R)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide as a off white solid (25 mg, 27%) and chiral(2R,3S,4S,5S)-2′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5′-oxo-4′,5′-dihydrospiro[pyrrolidine-3,6′-thieno[3,2-b]pyrrole]-5-carboxamide as an off white solid (33 mg, 36%). MS (ES + ) m/z Calcd for C 30 H 32 Cl 2 FN 3 O 5 S+H [(M+H) + ]: 637. found: 637. 
     Example 109 
     Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methoxy-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 12, 6-methoxy-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (Sinova, 489 mg, 2.98 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 1.42 g, 8.94 mmol) and piperidine (Lancaster, 1.03 g, 1.2 mL, 12.1 mmol) in methanol (20 mL) to give E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methoxy-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light yellow solid (835 mg, 92%). MS (ES + ) m/z [(M+H) + ]: 305 
     Example 110 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 13, E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methoxy-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (300 mg, 0.985 mmol, Example X1) was reacted with anhydrous LiOH (14 mg, 0.585 mmol) and (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (329 mg, 1.03 mmol, Example 3) at 40° C. for 23 h to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (188 mg, 30%). MS (ES + ) m/z [(M+H) + ]: 625 
     Example 111 
     Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 14, methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 110, 86 mg, 0.14 mmole) was reacted with LiOH hydrate (57 mg, 1.36 mmol) in water to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (76 mg, 98%). MS (ES + ) m/z [(M+H) + ]: 611 
     Example 112 
     Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-hydroxy-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 12, 6-hydroxy-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (Sinova, 700 mg, 4.66 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 2.20 g, 13.9 mmol) and piperidine (Lancaster, 1.59 g, 18.7 mmol) to give E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-hydroxy-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light brown solid (683 mg, 50%). MS (ES + ) m/z [(M+H) + ]: 291 
     Example 113 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-hydroxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 13, E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-hydroxy-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (300 mg, 0.985 mmol, Example 112) was reacted with anhydrous LiOH (17.5 mg, 0.73 mmol) and (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (405 mg, 1.26 mmol, Example 3) at 40° C. for 23 h to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-hydroxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (253 mg, 32%). MS (ES + ) m/z [(M+H) + ]: 611 
     Example 114 
     Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-hydroxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 14, methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 113, 99 mg, 0.16 mmole) was reacted with LiOH hydrate (62 mg, 1.49 mmol) in water to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-hydroxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (87 mg, 90%). MS (ES + ) m/z [(M+H) + ]: 597 
     Example 115 
     Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 19, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (40 mg, 0.065 mmol, Example 111) was reacted with 1,1′-carbonyldiimidazole (Aldrich, 52 mg, 0.32 mmol) in THF (3 mL) followed by work-up with ammonium hydroxide (310 mg, 8.84 mmol) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-methoxy-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (11 mg, 26%). MS (ES + ) m/z [(M+H) + ]: 610 
     Example 116 
     Preparation of rac-2-(4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 71, E/Z-6-Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (Example 23, 245 mg, 0.795 mmole) was reacted with 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 316 mg, 0.867 mmol) and anhydrous LiOH (14 mg, 0.60 mmol) to give rac-2-(4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate as an off-white solid. MS (ES + ) m/z [(M+H) + ]: 655 
     Example 117 
     Preparation of rac-(2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 72, rac-2-(4-((2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate was reacted with aqueous NaOH in THF to give rac-(2S,3R,4S,5R)-6′-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid. MS (ES + ) m/z [(M+H) + ]: 631. 
     Example 118 
     Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 12, 6-methyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (Sinova, 750 mg, 5.06 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 2.40 g, 15.1 mmol) and piperidine (Lancaster, 172 g, 20.2 mmol) to give E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light brown solid (623 mg, 41%). MS (ES + ) m/z [(M+H) + ]: 289 
     Example 119 
     Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 13, E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (318 mg, 1.10 mmol, Example 118) was reacted with anhydrous LiOH (19 mg, 0.81 mmol) and (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (393 mg, 1.23 mmol, Example 3) at 40° C. for 23 h to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (146 mg, 21%). MS (ES + ) m/z [(M+H) + ]: 609 
     Example 120 
     Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 14, methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example X11, 136 mg, 0.22 mmole) was reacted with LiOH hydrate (78 mg, 1.87 mmol) in water to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (118 mg, 88%). MS (ES + ) m/z [(M+H) + ]: 595 
     Example 121 
     Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 19, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (21 mg, 0.034 mmol, Example 120) was reacted with 1,1′-carbonyldiimidazole (Aldrich, 27 mg, 0.165 mmol) in THF (3 mL) followed by work-up with ammonium hydroxide (0.18 mL mg, 4.62 mmol) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6′-methyl-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (20 mg, 97%). MS (ES + ) m/z [(M+H) + ]: 594 
     Example 122 
     Preparation of intermediate E/Z-7-Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 12, 7-chloro-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 500 mg, 2.97 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 1.010 g, 8.9 mmol) and piperidine (Lancaster, 1.01 g, 11.9 mmol) to give E/Z-7-Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light brown solid (615 mg, 67%). MS (ES + ) m/z [(M+H) + ]: 309 
     Example 123 
     Preparation of methyl rac-4-((2S,3S,4S,5R)-7′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 13, E/Z-7-Chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (301 mg, 0.974 mmol, Example 122) was reacted with anhydrous LiOH (17 mg, 0.697 mmol) and (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (326 mg, 1.02 mmol, Example 3) at 40° C. for 23 h to give methyl rac-4-((2S,3S,4S,5R)-7′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (38 mg, 6%). MS (ES + ) m/z [(M+H) + ]: 629 
     Example 124 
     Preparation of rac-4-((2S,3S,4S,5R)-7′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 14, methyl rac-4-((2S,3S,4S,5R)-7′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 123, 32 mg, 0.052 mmole) was reacted with LiOH hydrate (17 mg, 0.42 mmol) in water to give rac-4-((2S,3S,4S,5R)-7′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (30 mg, 95%). MS (ES + ) m/z [(M+H) + ]: 615 
     Example 125 
     Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-carboxamide 
     
       
         
         
             
             
         
       
     
     In a manner similar to the method described in Example 19, rac-4-((2S,3S,4S,5R)-7′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (16 mg, 0.026 mmol, Example 124) was reacted with 1,1′-carbonyldiimidazole (Aldrich, 19 mg, 0.115 mmol) in THF (3 mL) followed by work-up with ammonium hydroxide (126 mg, 3.6 mmol) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6′-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2′-oxo-1′,2′-dihydrospiro[pyrrolidine-3,3′-pyrrolo[2,3-b]pyridine]-5-carboxamide as a white solid (11 mg, 65%). MS (ES + ) m/z [(M+H) + ]: 614 
     Example 126 
     In Vitro Activity Assay 
     The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53. Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N-terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti-GST antibody and streptavidin-conjugated Allophycocyanin (APC). 
     Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing: 90 nM biotinylate peptide, 160 ng/ml GST-MDM2, 20 nM streptavidin-APC (PerkinElmerWallac), 2 nM Eu-labeled anti-GST-antibody (PerkinElmerWallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/ml working solution) in reaction buffer to each well. Add 10 uL diluted compounds (1:5 dilution in reaction buffer) to each well, mix by shaking Add 20 uL biotinylated p53 peptide (180 nM working solution) in reaction buffer to each well and mix on shaker. Incubate at 37° C. for 1 h. Add 20 uL streptavidin-APC and Eu-anti-GST antibody mixture (6 nM Eu-anti-GST and 60 nM streptavidin-APC working solution) in TBS buffer with 0.2% BSA, shake at room temperature for 30 minutes and read using a TRF-capable plate reader at 
     665 and 615 nm (Victor 5, Perkin Elmer Wallace). If not specified, the reagents were purchased from Sigma Chemical Co. 
     Activity data for some of the Example compounds expressed as IC 50 : bsa: 0.02% are as follows: 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                 Example 
                   
               
               
                   
                 Number 
                 IC 50 : bsa: 0.02% 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                  6 
                 0.0324 
               
               
                   
                  13 
                 0.0303 
               
               
                   
                  28 
                 0.0105 
               
               
                   
                  35 
                 0.0145 
               
               
                   
                  39 
                 0.0084 
               
               
                   
                  47 
                 0.0345 
               
               
                   
                  52 
                 0.0050 
               
               
                   
                  56A 
                 0.0050 
               
               
                   
                  63 
                 0.0146 
               
               
                   
                  66 
                 1.8332 
               
               
                   
                  69 
                 0.0129 
               
               
                   
                  75 
                 0.0064 
               
               
                   
                  83 
                 0.0195 
               
               
                   
                  86 
                 0.0187 
               
               
                   
                 101 
                 0.0046 
               
               
                   
                  89 
                 0.0117 
               
               
                   
                  91 
                 0.0107 
               
               
                   
                  96 
                 0.0227 
               
               
                   
                  99 
                 0.0054 
               
               
                   
                 110 
                 0.0136 
               
               
                   
                 111 
                 0.007 
               
               
                   
                 113 
                 &gt;10 
               
               
                   
                 114 
                 &gt;10 
               
               
                   
                 115 
                 0.127 
               
               
                   
                 116 
                 0.012 
               
               
                   
                 117 
                 0.014 
               
               
                   
                 119 
                 0.0116 
               
               
                   
                 120 
                 0.012 
               
               
                   
                 121 
                 0.0118 
               
               
                   
                 123 
                 6.253 
               
               
                   
                 124 
                 1.013 
               
               
                   
                 125 
                 0.005