# US 10,118,936 B2 · Arginase inhibitors and methods of use

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- Number: US 10,118,936 B2
- Document ID: US10118936B2
- Status: Granted
- Kind: B2
- Application number: 14/959,765
- Filed: 2015-12-04
- Published: 2016-07-07
- Granted: 2018-11-06
- Earliest claimed: 2009-01-26
- Assignees: The Trustees of the University of Pennsylvania; AstraZeneca AB
- Applicants: Astrazeneca AB; The Trustees of the University of Pennsylvania
- Inventors: David W. Christianson; Bruce Edward Tomczuk; Richard Scott Pottorf; Andrew Vargha Colasanti; Gary Lee Olson
- Web page: https://patentgrep.com/patent/US10118936B2

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- A61K 49/0002: {General or multifunctional contrast agents, e.g. chelated agents}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/10: for impotence
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to arginase inhibitor compounds of formula IA or formula IB: 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.

## Claims

### Claim 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
X1 is —(CH2)—;
X2 is —(CH2)—;
X3 is —(CH2)—;
X4 is —(CH2)—;
R1 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxy(C1-C4)alkyl, (C2-C4)alkenyl, (C6-C10)aryl(C1-C4)alkyl, (C4-C10)heteroaryl(C1-C4)alkyl, (C2-C10)heterocycloalkyl(C1-C4)alkyl, (C6-C10)aryloxy(C1-C4)alkyl, (C4-C10)heteroaryloxy(C1-C4)alkyl, —Rx—C(═O)—Ry, —Rx—O—Rz, —Rx—O—Rx—NR3R5, —Rx—NR3R5 or (C1-C4)alkyl-B—(OH)2;
each Rx is independently (C1-C4)alkylenyl;
Ry is (C1-C4)alkyl, hydroxyl, (C1-C6)alkoxy or (C6-C10)aryl;
Rz is (C1-C4)alkyl;
R3 is H;
R4 is (C1-C4)alkyl or H; and
R5 is —C(═O)—(C1-C4)alkyl, —C(═O)—(C6-C10)aryl, —SO2—(C6-C10)aryl, —C(═O)NR3R4 or —C(═O)—NR4(C6-C10)aryl.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The compound according to claim 1, wherein,
R1 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, hydroxy(C1-C3)alkyl, (C3-C4)alkenyl, (C6)aryl(C1-C4)alkyl, (C5)heteroaryl(C1)alkyl, (C4-C5)heterocycloalkyl(C3)alkyl, (C6)aryloxy(C2-C3)alkyl, (C6)heteroaryloxy(C3)alkyl, —Rx—C(═O)—Ry, —Rx—O—Rz, —Rx—O—Rx—NR3R5, —Rx—NR3R5 or (C4)alkyl-B—(OH)2;
each Rx is independently (C1-C4)alkylenyl;
Ry is (C2)alkyl, hydroxyl, (C1)alkoxy or (C6)aryl;
Rz is (C2)alkyl;
R3 is H;
R4 is (C1)alkyl or H; and
R5 is —C(═O)—(C1)alkyl, —C(═O)—(C6)aryl, —SO2—(C6)aryl, —C(═O)NR3R4 or —C(═O)—NR4(C6)aryl.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein R1 is ethyl.

### Claim 5 (depends on 3)

The compound according to claim 3, wherein R1 is n-butyl, isobutyl, sec-butyl or tert-butyl.

### Claim 6 (depends on 3)

The compound according to claim 3, wherein R1 is (C3)alkenyl.

### Claim 7 (depends on 3)

The compound according to claim 3, wherein R1 is (C4)alkenyl.

### Claim 8 (depends on 3)

The compound according to claim 3, wherein R1 is hydroxy(C1)alkyl.

### Claim 9 (depends on 3)

The compound according to claim 3, wherein R1 is hydroxy(C3)alkyl.

### Claim 10 (depends on 3)

The compound according to claim 3, wherein R1 is (C6)aryl(C1)alkyl.

### Claim 11 (depends on 3)

The compound according to claim 3, wherein R1 is (C6)aryl(C4)alkyl.

### Claim 12 (depends on 3)

The compound according to claim 3, wherein R1 is (C4)heterocycloalkyl(C3)alkyl.

### Claim 13 (depends on 3)

The compound according to claim 3, wherein R1 is (C5)heterocycloalkyl(C3)alkyl.

### Claim 14 (depends on 3)

The compound according to claim 3, wherein R1 is (C6)aryloxy(C2)alkyl.

### Claim 15 (depends on 3)

The compound according to claim 3, wherein R1 is (C6)aryloxy(C3)alkyl.

### Claim 16 (depends on 3)

The compound according to claim 3, wherein each Rx is independently (C1)alkylenyl.

### Claim 17 (depends on 3)

The compound according to claim 3, wherein each Rx is independently (C2)alkylenyl.

### Claim 18 (depends on 3)

The compound according to claim 3, wherein each Rx is independently (C4)alkylenyl.

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 19)

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.

### Claim 21 (depends on 1)

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

### Claim 22 (depends on 1)

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.