Arginase Inhibitors and Methods of Use

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).