Arginase Inhibitors and Methods of Use

Abstract

or a pharmaceutically acceptable salt thereof, compositions containing these compounds, and methods of their use for the treatment and diagnosis of conditions characterized by upregulation of arginase, abnormally high arginase activity, or by abnormally low nitric oxide synthase activity.

1 .- 67 . (canceled) 
     
     
         68 . A method of treating a pulmonary inflammatory disease in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula IA: 
       
         
           
           
               
               
           
         
         or a stereoisomer, lactone prodrug, or pharmaceutically-acceptable salt thereof, wherein:
 said dashed line represents an optional double bond; 
 
         Z is 
       
       
         
           
           
               
               
           
         
         X 1  is —(CH 2 )—; 
         X 2  is —(CH 2 )—; 
         X 3  is —(CH 2 )—; 
         X 4  is —(CH 2 )—; 
         R 1  is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxy(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl, (C 4 -C 10 )heteroaryl(C 1 -C 4 )alkyl, (C 2 -C 10 )heterocycloalkyl(C 1 -C 4 )alkyl, (C 6 -C 10 )aryloxy(C 1 -C 4 )alkyl, (C 4 -C 10 )heteroaryloxy(C 1 -C 4 )alkyl, —R x —C(═O)—R y , —R x —O—R z , —R x —O—R x —NR 3 R 5 , —R x —NR 3 R 5  or (C 1 -C 4 )alkyl-B—(OH) 2 ; each R x  is independently (C 1 -C 4 )alkylenyl; 
         R y  is (C 1 -C 4 )alkyl, hydroxyl, (C 1 -C 6 )alkoxy or (C 6 -C 10 )aryl; 
         R 2  is (C 1 -C 4 )alkyl; 
         R 3  is H; 
         R 4  is (C 1 -C 4 )alkyl or H; and 
         R 5  is —C(═O)—(C 1 -C 4 )alkyl, —C(═O)—(C 6 -C 10 )aryl, —SO 2 —(C 6 -C 10 )aryl, —C(═O)NR 3 R 4  or —C(═O)—NR 4 (C 6- C 10 )aryl. 
       
     
     
         69 . The method according to  claim 68 , wherein the compound of formula IA has the structure of a compound of formula Ia: 
       
         
           
           
               
               
           
         
       
     
     
         70 . The method according to  claim 68 , wherein,
 R 1  is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxy(C 1 -C 3 )alkyl, (C 3 -C 4 )alkenyl, (C 6 )aryl(C 1 -C 4 )alkyl, (C 5 )heteroaryl(C 1 )alkyl, (C 4 -C 5 )heterocycloalkyl(C 3 )alkyl, (C 6 )aryloxy(C 2 -C 3 )alkyl, (C 6 )heteroaryloxy(C 3 )alkyl, —R x —C(═O)—R y , —R x —O—R z , —R x —O—R x —NR 3 R 5 , —R x —NR 3 R 5  or (C 4 )alkyl-B—(OH) 2 ;   each R x  is independently (C 1 -C 4 )alkylenyl;   R is (C 2 )alkyl, hydroxyl, (C 1 )alkoxy or (C 6 )aryl;   R z  is (C 2 )alkyl;   R 3  is H;   R 4  is (C 1 )alkyl or H; and   R 5  is —C(═O)—(C 1 )alkyl, —C(═O)—(C 6 )aryl, —SO 2 —(C 6 )aryl, —C(═O)NR 3 R 4  or —C(═O)—NR 4 (C 6 )aryl.   
     
     
         71 . The method according to  claim 70 , wherein R 1  is ethyl. 
     
     
         72 . The method according to  claim 70 , wherein R′ is n-butyl, isobutyl, sec-butyl or tert-butyl. 
     
     
         73 . The method according to  claim 70 , wherein R 1  is (C 3 )alkenyl. 
     
     
         74 . The method according to  claim 70 , wherein R 1  is (C 4 )alkenyl. 
     
     
         75 . The method according to  claim 70 , wherein R 1  is hydroxy(C 1 )alkyl. 
     
     
         76 . The method according to  claim 70 , wherein R 1  is hydroxy(C 3 )alkyl. 
     
     
         77 . The method according to  claim 70 , wherein R 1  is (C 6 )aryl(C 1 )alkyl. 
     
     
         78 . The method according to  claim 70 , wherein R 1  is (C 6 )aryl(C 4 )alkyl. 
     
     
         79 . The method according to  claim 70 , wherein R 1  is (C 4 )heterocycloalkyl(C 3 )alkyl. 
     
     
         80 . The method according to  claim 70 , wherein R 1  is (C 5 )heterocycloalkyl(C 3 )alkyl. 
     
     
         81 . The method according to  claim 70 , wherein R 1  is (C 6 )aryloxy(C 2 )alkyl. 
     
     
         82 . The method according to  claim 70 , wherein R 1  is (C 6 )aryloxy(C 3 )alkyl. 
     
     
         83 . The method according to  claim 70 , wherein each R x  is independently (C 1 )alkylenyl. 
     
     
         84 . The method according to  claim 70 , wherein each R x  is independently (C 2 )alkylenyl. 
     
     
         85 . The method according to  claim 70 , wherein each R x  is independently (C 4 )alkylenyl. 
     
     
         86 . The method according to  claim 68 , wherein the compound is selected from the group consisting of
 2-amino-2-benzyl-6-boronohexanoic acid;   2-allyl-2-amino-6-boronohexanoic acid;   2-amino-2-(4-boronobutyl)succinic acid;   2-amino-6-(borono-2-(3-phenoxypropyl)hexanoic acid;   2-amino-6-borono-2-(4-phenylbutyl)hexanoic acid;   2-amino-6-borono-2-(3-(4-chlorophenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(4-methoxyphenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(4-fluorophenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(4-nitrophenoxy)propyl)hexanoic acid;   2-amino-2-(3-(benzo[d][1,3]dioxol-5-yloxy)propyl)-6-boronohexanoic acid;   2-amino-6-borono-2-(3-(4-(trifluoromethyl)phenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(3-methoxyphenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(3-phenoxyphenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(3-isopropylphenoxy)propyl)hexanoic acid;   2-amino-2-(3-(biphenyl-4-yloxy)propyl)-6-boronohexanoic acid;   2-amino-2-(3-(biphenyl-3-yloxy)propyl)-6-boronohexanoic acid;   2-amino-6-borono-2-(3-(3-(trifluoromethyl)phenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(4-(trifluoromethylthio)phenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(2,6-difluorophenoxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(o-tolyloxy)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(p-tolyloxy)propyl)hexanoic acid;   2-amino-2-(3-(4-aminophenoxypropyl)-6-boronohexanoic acid;   2-amino-6-(borono-2-(pyridin-3-ylmethyl)hexanoic acid;   2-amino-2-(benzyloxyethyl)-6-boronohexanoic acid;   2-amino-6-borono-2-(2-methoxyethyl)hexanoic acid;   2-amino-6-borono-2-(2-(p-tolyoxy)ethyl)hexanoic acid;   2-amino-6-borono-2-(2-(3-chlorophenoxy)ethyl)hexanoic acid;   2-amino-6-borono-2-(2-(3-methoxyphenoxy)ethyl)hexanoic acid;   2-amino-6-borono-2-(2-(3-nitrophenoxy)ethyl)hexanoic acid;   2-amino-6-borono-2-(2-(3-(morpholinosulfonyl)phenoxy)ethyl)hexanoic acid;   2-amino-2-(2-(3-aminophenoxy)ethyl)-6-boronohexanoic acid;   2-amino-6-borono-2-(3-hydroxypropyl)hexanoic acid;   2-amino-6-borono-2-(4-boronobutyl)hexanoic acid;   2-amino-2-(4-boronobutyl)hex-4-enoic acid;   2-amino-6-borono-2-(2-(2-methoxyethoxy)ethyl)hexanoic acid;   2-amino-6-borono-2-isobutylhexanoic acid;   2-amino-6-borono-2-(hydroxymethyl)hexanoic acid;   (R)-2-amino-6-borono-2-(hydroxymethyl)hexanoic acid;   (S)-2-amino-6-borono-2-(hydroxymethyl)hexanoic acid;   2-amino-2-(2-(benzyloxy)-2-oxoethyl)-6-boronohexanoic acid;   2-amino-6-borono-2-(2-methoxy-2-oxoethyl)hexanoic acid;   2-amino-6-borono-2-(cyanomethyl)hexanoic acid;   2-amino-6-borono-2-(2-oxobutyl)hexanoic acid;   2-amino-6-borono-2-(2-oxo-2-phenylethyl)hexanoic acid;   2-amino-2-(2-(2-aminoethoxy)ethyl)-6-boronohexanoic acid;   2-amino-6-borono-2-(3-(piperidin-4-yl)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(piperazine-1-yl)propylhexanoic acid;   2,6-diamino-2-(4-boronobutyl)hexanoic acid;   2-amino-6-borono-2-(2-(2-(4-cyanobenzamid)ethoxy)ethyl)hexanoic acid;   2-(2-(2-acetamidoethoxy)ethyl)-2-amino-6-boronohexanoic acid;   2-amino-6-borono-2-(2-(2-(3-(3-methoxyphenyl)ureido)ethoxy)ethyl)hexanoic acid;   2-(3-(1-acetylpiperidin-4-yl)propyl)-2-amino-6-boronohexanoic acid;   2-(3-(4-acetylpiperazin-1-yl)propyl)-2-amino-6-boronohexanoic acid;   2-amino-6-borono-2-(3-(4-(4-cyanobenzoyl)piperazine-1-yl)propyl)hexanoic acid;   2-amino-6-borono-2-(3-(4-(3-methoxyphenylcarbamoyl)piperazin-1-yl)propyl)hexanoic acid;   2-amino-6-borono-2-(4-(4-methylphenylsulfonamido)butyl)hexanoic acid;   2-amino-6-borono-2-(4-(3,5-difluorobenzamido)butyl)hexanoic acid;   6-acetamido-2-amino-2-(4-boronobutyl)hexanoic acid;   2-amino-6-borono-2-(4-(3-(3-methoxyphenyl)ureido)butyl)hexanoic acid; and   pharmaceutically acceptable salts thereof.   
     
     
         87 . The method according to  claim 86 , wherein the pharmaceutically acceptable salts comprise a hydrochloric acid and trifluoroacetic acid addition salt of the compound. 
     
     
         88 . The method according to  claim 68 , wherein the pulmonary inflammatory disease is asthma, chemically-induced lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or a combination thereof. 
     
     
         89 . The method according to  claim 88 , wherein the pulmonary inflammatory disease is asthma. 
     
     
         90 . The method according to  claim 88 , wherein the pulmonary inflammatory disease is chemically-induced lung fibrosis. 
     
     
         91 . The method according to  claim 88 , wherein the pulmonary inflammatory disease is idiopathic pulmonary fibrosis. 
     
     
         92 . The method according to  claim 88 , wherein the pulmonary inflammatory disease is cystic fibrosis. 
     
     
         93 . The method according to  claim 88 , wherein the pulmonary inflammatory disease is chronic obstructive pulmonary disease (COPD).