Lpxc inhibitor and methods of making

Abstract

Provided herein is an LpxC inhibitor compound, as well as methods of making and pharmaceutical compositions comprising said compound, and methods of use thereof in the treatment of disease that would benefit from treatment with an LpxC inhibitor, including gram-negative bacterial infections such as urinary tract infections and the like.

1 .- 51 . (canceled) 
     
     
         52 . A process for the preparation of a compound of Formula 4: 
       
         
           
           
               
               
           
         
         wherein PG is a suitable protecting group; and 
         R is C 1 -C 10  alkyl; 
         comprising: 
         (1) contacting the compound of Formula 3: 
       
       
         
           
           
               
               
           
         
         
           wherein PG is a suitable protecting group; and 
           R is C 1 -C 10  alkyl; 
         
         with formamidine acetate and a suitable base in a suitable solvent to provide the compound of Formula 4. 
       
     
     
         53 . The process of  claim 52 , wherein:
 the suitable base of step (1) is sodium hydride, sodium methoxide, sodium ethoxide, lithium methoxide, lithium ethoxide, n-butyl lithium, lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), or lithium tetramethylpiperidide (LiTMP); and   the suitable solvent of step (1b) is methanol, ethanol, isopropyl alcohol, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, cyclopropyl methyl ether, or a combination thereof.   
     
     
         54 . The process of  claim 52 , wherein:
 the suitable base of step (1) is sodium ethoxide;   the suitable solvent of step (1) is ethanol; and   step (1) is performed at a temperature of about 0° C. to 10° C.   
     
     
         55 . (canceled) 
     
     
         56 . The process of  claim 52 , further comprising:
 (2) contacting the compound of Formula 4 with a halogenating agent and a suitable base in a suitable solvent to provide the compound of Formula 5:   
       
         
           
           
               
               
           
         
         
           wherein PG is a suitable protecting group; and 
           R is C 1 -C 10  alkyl; and 
           X′ is Cl or Br. 
         
       
     
     
         57 . The process of  claim 56 , wherein:
 the halogenating agent of step (2) is POCl 3 , POBr 3 , or SOCl 2 ;   the suitable base of step (2) is triethylamine, diisopropylethylamine, sec-butylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and   the suitable solvent of step (2) is acetonitrile, dichloromethane, chloroform, dichloroethane, toluene, or a combination thereof.   
     
     
         58 . The process of  claim 56 , wherein:
 the suitable halogenating agent of step (2) is POCl 3 ;   the suitable base of step (2) is triethylamine; and   the suitable solvent of step (2) is toluene; and   step (2) is performed at a temperature of about 85° C. to 95° C.   
     
     
         59 . (canceled) 
     
     
         60 . The process of  claim 56 , further comprising:
 (3) contacting the compound of Formula 5 with benzyl alcohol in the presence of a suitable base, and in a suitable solvent to provide a compound of Formula 6-I or Formula 7-I, or a combination thereof:   
       
         
           
           
               
               
           
         
         
           wherein PG is a suitable protecting group; and 
           R is C 1 -C 10  alkyl. 
         
       
     
     
         61 . The process of  claim 60 , wherein:
 the suitable base of step (3) is triethylamine, diisopropylethylamine, sec-butylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and   the suitable solvent of step (3) is acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, water, or a combination thereof.   
     
     
         62 . The process of  claim 60 , wherein:
 the suitable base of step (3) is DBU;   the suitable solvent of step (3) is acetonitrile; and   step (3) is performed at a temperature of about 20° C. to 25° C.   
     
     
         63 . (canceled) 
     
     
         64 . The process of  claim 60 , further comprising:
 (4) contacting the compound of Formula 6-I or Formula 7-I, or combination thereof, with a suitable reducing agent in a suitable solvent to provide a compound of Formula 8-I:   
       
         
           
           
               
               
           
         
         
           wherein PG is a suitable protecting group. 
         
       
     
     
         65 . The process of  claim 64 , wherein:
 the reducing agent of step (4) is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or lithium cyanoborohydride; and   the suitable solvent of step (4) is acetonitrile, dimethylformamide, diethyl ether, methanol, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, water, or a combination thereof.   
     
     
         66 . The process of  claim 64 , wherein:
 the reducing agent of step (4) is sodium borohydride; and   the suitable solvent of step (4) is a mixture of isopropyl alcohol and methanol.   
     
     
         67 . (canceled) 
     
     
         68 . The process of  claim 64 , further comprising:
 (5) contacting the compound of Formula 8-I with a suitable reagent in a suitable solvent to provide the compound of Formula 9-I:   
       
         
           
           
               
               
           
         
         
           wherein PG is a suitable protecting group; and 
           LG is a suitable leaving group. 
         
       
     
     
         69 . The process of  claim 68 , wherein:
 the suitable reagent of step (5) is a halogenating agent, a sulfonating agent, or a sulfonyl chloride; and   LG is a halogen.   
     
     
         70 . (canceled) 
     
     
         71 . The process of  claim 68 , wherein:
 the suitable reagent of step (5) is SOCl 2 , PBr 3 , or PCl 3 ; and   the suitable solvent is acetonitrile, dimethylformamide, diethyl ether, ethanol, tetrahydrofuran, isopropyl alcohol, 1,4-dioxane, toluene, water, or a combination thereof.   
     
     
         72 . (canceled) 
     
     
         73 . The process of  claim 68 , wherein:
 step (5) further comprises a suitable base, selected from pyridine, N-methylmorpholine, triethylamine, diisopropylethylamine, sec-butylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).   
     
     
         74 . (canceled) 
     
     
         75 . The process of  claim 52 , wherein:
 R is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, pentyl, iso-amyl, hexyl, heptyl, octyl, or nonyl.   
     
     
         76 . (canceled) 
     
     
         77 . (canceled) 
     
     
         78 . The process of  claim 52 , wherein:
 PG is benzyl, p-methoxybenzyl, methoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, triisopropylsilyl, or tert-butyldimethylsilyl.   
     
     
         79 . (canceled) 
     
     
         80 . The process of  claim 56 , wherein:
 R is ethyl;   PG is benzyl; and   X′ is Cl.   
     
     
         81 .- 109 . (canceled) 
     
     
         110 . A compound selected from: 
       
         
           
           
               
               
           
         
       
       or a salt thereof.