Arginase Inhibitors and Methods of Use

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)