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 . A compound of formula IA or formula IB: 
       
         
           
           
               
               
           
         
         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 )— or, when said double bond is present between X 1  and X 2  , X 1  is —(CH)—; 
         X 2  is —(CH 2 )— or —(NR 2 )—, or, when said double bond is present between X 1  and X 2  or between X 2  and X 3 , X 2  is —(CH)— or N; 
         X 3  is —(CH 2 )—, a heteroatom moiety selected from the group consisting of —S—, —O— and —(NR 2 )— or, when said double bond is present between X 2  and X 3  or between X 3  and X 4 , X 3  is —(CH)— or N; 
         X 4  is —(CH 2 )— or, when said double bond is present between X 3  and X 4  , X 4  is —(CH)— and is in the trans configuration; 
         provided that not more than one of X 2  and X 3  is said —(NR 2 )— or said heteroatom moiety; 
         provided that X 3  is —(NR 2 )— when Z is 
       
       
         
           
           
               
               
           
         
         provided that there are no more than two double bonds between X 1 , X 2 , X 3 , and X 4  and no two double bonds share a common carbon atom; 
         R 1  is a monovalent moiety other than H; or R 1  and said α-carboxylate, when taken together, form a lactone; and 
         R 2  is, independently, H, methyl, or ethyl. 
       
     
     
         2 . The compound according to  claim 1 ,
 wherein said compound of formula IA has the structure of a compound of formula Ia:   
       
         
           
           
               
               
           
         
       
       and
 wherein said compound of formula IB has the structure of a compound of formula Ib: 
 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein:
 R 1  is (C 1 -C 20 )alkyl, hydroxy(C 1 -C 20 )alkyl, hydroxy(C 2 -C 20 )alkenyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryl(C 1 -C 20 )alkyl, (C 2 -C 50 )heterocycloalkyl(C 1 -C 20 )alkyl, (C 5 -C 50 )aryloxy(C 1 -C 20 )alkyl, (C 5 -C 50 )arylthio(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryloxy(C 1 -C 20 )alkyl, (C 5 -C 50 )arylamino(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroarylamino(C 1 -C 20 )alkyl, amino(C 1 -C 20 )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 , -R x —O—C(═O)—R y , (C 1 -C 6 )alkyl-B-(OH) 2 , -L-Y, or labeled derivative thereof; or R 1  and said a-carboxylate, when taken together, form a lactone having 4 to 7 ring atoms;   each R x  is independently (C 1 -C 20 )alkylenyl;   R y  is (C 1 -C 6 )alkyl, (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, (C 5 -C 50 )aryloxy(C 1 -C 6 )alkyl, hydroxyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, N(R 3 ) 2 , (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; heterocyclyl, (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, or (C 3 -C 50 )heteroaryl(C 1 -C 6 )alkyl;   R z  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —R x —O—(C 1 -C 6 )alkyl, (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, or (C 3 -C 50 )heteroaryl(C 1 -C 6 )alkyl;   R 3  is, independently, H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl-N(R 4 ) 2 ;   R 4  is, independently, H or (C 1 -C 6 )alkyl;   R 5  is —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 5 -C 50 )aryl, —SO 2 (C 5 -C 50 )aryl, —C(═O)NR 3 R 4 , —C(═O)—NR 4 (C 5 -C 50 )aryl, or —C(═O)-heterocycle;   or R 3  and R 5  together form a (C 2 -C 10 )heterocycloalkyl;   L is an aliphatic or aromatic linkage; Y is a residue of an imageable moiety, peptide, peptidomimetic, or carbohydrate.   
     
     
         4 . The compound according to  claim 3 , wherein said L aliphatic linkage is divalent alkylenyl group, and said aromatic linkage is a divalent aryl group. 
     
     
         5 . The compound according to  claim 1 , wherein:
 R 1  is (C 1 -C 20 )alkyl, hydroxy(C 1 -C 20 )alkyl, hydroxy(C 2 -C 20 )alkenyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, halo, (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryl(C 1 -C 20 )alkyl, (C 5 -C 50 )aryloxy(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryloxy(C 1 -C 20 )alkyl, (C 5 -C 50 )arylamino(C 1 -C 20 )alkyl, heteroarylamino(C 1 -C 20 )alkyl, amino(C 1 -C 20 )alkyl, —R x —C(═O)—R y , —R x —C(═O)—O—R y , —R x —O—R z , —R x —O—R x —NR 3 R 5 , -L-Y, or labeled derivative thereof; or R 1  and said α-carboxylate, when taken together, form a lactone having 4 to 7 ring atoms;   each R x  is independently (C 1 -C 6 )alkylenyl;   R y  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, N(R 3 ) 2 , (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, or (C 3 -C 50 )heteroaryl(C 1 -C 6 )alkyl;   R z  is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 5 -C 50 )aryl, (C 3 -C 50 )heteroaryl having at least one heteroatom selected from N, O, and S; (C 5 -C 50 )aryl(C 1 -C 6 )alkyl, or (C 3 -C 50 )heteroaryl(C 1 -C 6 )alkyl;   R 3  is, independently, H or (C 1 -C 6 )alkyl;   L is an aliphatic or aromatic linkage;   Y is a residue of an imageable moiety, peptide, peptidomimetic, or carbohydrate.   
     
     
         6 . The compound according to  claim 1 , wherein:
 X 2  is —S— or —O—.   
     
     
         7 . The compound according to  claim 1 , wherein:
 X 2  is —S—.   
     
     
         8 . The compound according to  claim 1 , wherein:
 X 3  is —(NR 2 )—.   
     
     
         9 . The compound according to  claim 1 , wherein:
 R 2  is H.   
     
     
         10 . The compound according to  claim 1 ,
 wherein Y is a residue of an imageable moiety comprises a functional moiety selected from the group consisting of a gamma ray emitting radioisotope, a positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.   
     
     
         11 . The compound according to  claim 4 ,
 wherein R 1  is a fluorescently-labeled derivative thereof.   
     
     
         12 . The compound according to  claim 4 ,
 R 1  is (C 1 -C 20 )alkyl, hydroxy(C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 5 -Cso)aryl, (C 5 -Cso)aryl(C 1 -C 20 )alkyl, (C 3 -C 50 )heteroaryl(C 1 -C 20 )alkyl, (C 5 -C 50 )aryloxy(C 1 -C 20 )alkyl, amino(C 1 -C 20 )alkyl, —R x —C(═O)—R y , —R x —O—R z , —R x —NR 3 R 5 , —R x —O—C(═O)—R y , (C 1 -C 6 )alkyl-B-(OH) 2 , -L-Y, or labeled derivative thereof; or R 1  and said α-carboxylate, when taken together, form a lactone having 4 to 7 ring atoms.   
     
     
         13 . The compound according to  claim 4 ,
 R x  is (C 1 -C 6 )alkylenyl.   
     
     
         14 . The compound according to  claim 4 ,
 R y  is hydroxyl, (C 1 -C 6 )alkoxy, N(R 3 ) 2 , or heterocyclyl.   
     
     
         15 . The compound according to  claim 4 ,
 R z  is —R x —O—(C 1 -C 6 )alkyl.   
     
     
         16 . The compound according to  claim 4 ,
 R 4  is, independently, H or (C 1 -C 4 )alkyl.   
     
     
         17 . The compound according to  claim 4 ,
 R 5  is —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 5 -C 10 )aryl, —SO 2 -(C 5 -C 10 )aryl, —C(═O)NR 3 R 4 , —C(═O)—N R 4 (C 5 -C 10 )aryl, or —C(═O)-heterocycle.   
     
     
         18 . The compound according to  claim 4 ,
 wherein R 1  is selected from the group consisting of the sidechains illustrated in  FIGS. 19-24  in the attached drawings.   
     
     
         19 . The compound according to  claim 1 , wherein said compound is selected form 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;   4-(4-Amino-8-borono-4 carboxyoctyloxy)benzoic 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-(2,3-dihydrobenzo[b][1,4]dioxin-5-yloxy)ethylhexanoic acid;   2-Amino-6-borono-2-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)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-methylhexanoic 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-Amino-6-borono-2-(3-(1-(3-methoxyphenylcarbamoyl)piperidin-4-yl)propyl)hexanoic 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;   2-Amino-6-(benzyloxycarbonylamino)-2-(4-boronobutyl)hexanoic acid;   6-Acetamido-2-amino-2-(4-boronobutyl)hexanoic acid;   2-amino-6-borono-2-(4-(3-(3-methoxyphenyl)ureido)butyl)hexanoic acid;   2-Amino-4-(2-hydroxyguanidino)-2-methylbutanoic acid; and   pharmaceutically acceptable salts thereof.   
     
     
         20 . (canceled) 
     
     
         21 . A composition, comprising:
 at least one compound of  claim 1  or a pharmaceutically acceptable salt thereof; and   a pharmaceutically-acceptable carrier.   
     
     
         22 - 37 . (canceled) 
     
     
         38 . A method of treating a disease or condition associated with upregulation of arginase in a mammal, comprising the step of:
 administering to said mammal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof;   wherein said disease or condition is a gastrointestinal disease, a pulmonary inflammatory disease, a sexual arousal disorder, a cardiovascular disorder, a hemolytic disorder, an autoimmune disease, wound healing, a disease caused by parasitic protozoa, a disease caused by bacteria, a cancer, pre-term labor, psoriasis, or a combination thereof.   
     
     
         39 . (canceled) 
     
     
         40 . The method according to  claim 38 ,
 wherein said pulmonary inflammatory disease is asthma, chemically-induced lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD) or a combination thereof.   
     
     
         41 - 67 . (canceled)