Arginase inhibitors and methods of use

1. 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 z 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.

2. The compound according to claim 1 , wherein said compound of formula IA has the structure of a compound of formula Ia:

3. The compound according to claim 1 , 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 y 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.

4. The compound according to claim 3 , wherein R 1 is ethyl.

5. The compound according to claim 3 , wherein R 1 is n-butyl, isobutyl, sec-butyl or tert-butyl.

6. The compound according to claim 3 , wherein R 1 is (C 3 )alkenyl.

7. The compound according to claim 3 , wherein R 1 is (C 4 )alkenyl.

8. The compound according to claim 3 , wherein R 1 is hydroxy(C 1 )alkyl.

9. The compound according to claim 3 , wherein R 1 is hydroxy(C 3 )alkyl.

10. The compound according to claim 3 , wherein R 1 is (C 6 )aryl(C 1 )alkyl.

11. The compound according to claim 3 , wherein R 1 is (C 6 )aryl(C 4 )alkyl.

12. The compound according to claim 3 , wherein R 1 is (C 4 )heterocycloalkyl(C 3 )alkyl.

13. The compound according to claim 3 , wherein R 1 is (C 5 )heterocycloalkyl(C 3 )alkyl.

14. The compound according to claim 3 , wherein R 1 is (C 6 )aryloxy(C 2 )alkyl.

15. The compound according to claim 3 , wherein R 1 is (C 6 )aryloxy(C 3 )alkyl.

16. The compound according to claim 3 , wherein each R x is independently (C 1 )alkylenyl.

17. The compound according to claim 3 , wherein each R x is independently (C 2 )alkylenyl.

18. The compound according to claim 3 , wherein each R x is independently (C 4 )alkylenyl.

19. The compound according to claim 1 , wherein said 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.

20. The compound according to claim 19 , wherein said pharmaceutically acceptable salts comprise at least one hydrochloric acid and trifluoroacetic acid addition salt of said compound.

21. A composition, comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically-acceptable carrier.

22. A method of inhibiting arginase in a mammal, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.