# US 10,501,455 B2 · Inhibitors of leukotriene A4 hydrolase

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- Number: US 10,501,455 B2
- Document ID: US10501455B2
- Status: Granted
- Kind: B2
- Application number: 15/840,097
- Filed: 2017-12-13
- Published: 2018-06-14
- Granted: 2019-12-10
- Earliest claimed: 2013-03-14
- Assignees: Celtaxsys, Inc.
- Applicants: Celtaxsys, Inc.
- Inventors: William Guilford
- Web page: https://patentgrep.com/patent/US10501455B2

## CPC

- C07D 451/02: containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/09: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 211/26: with hydrocarbon radicals, substituted by nitrogen atoms
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 471/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to compounds encompassed by the Formula (I), pharmaceutical compositions thereof, methods for inhibiting LTA-4 hydrolase, and methods for the treatment of a disease and disorder which is ameliorated by the inhibition of LTA4-h activity. Non-limiting examples of such diseases and conditions include inflammatory and autoimmune diseases and disorders.

## Claims

### Claim 1

A compound having the Formula (I):
wherein:
R is the group;
r is 0;
q is 1;
R1a, R1b, R1c, R1d and R1e are each independently hydrogen, OR10, C(O)OR10, C(O)R10, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C3-C15 cycloalkyl, optionally substituted C3-C15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted 3- to 18-membered heteroaryl, or optionally substituted 3- to 18-membered heterocyclyl;
R3 is —O—;
R4 is a direct bond;
each R5a and R6a are each independently hydrogen and optionally substituted C1-C6 alkyl;
R7 is —C(R5b)2—R15;
each R5b is independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl:
R15 is selected from the group consisting of C(O)R10, C(O)OR10, C(O)—R13—N(R10)R11, optionally substituted aryl, and optionally substituted 3- to 18-membered heteroaryl;
each R9 is independently —OR10, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, halo, optionally substituted aryl, or optionally substituted heteroaryl;
each R10 and R11 is independently selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C3-C15 cycloalkyl, optionally substituted C3-C15 cycloalkenyl, optionally substituted aryl, optionally substituted 3- to 18-membered heteroaryl, and optionally substituted 3- to 18-membered heterocyclyl;
each R13 is independently a direct bond, an optionally substituted straight or branched C1 to C12 alkylene chain, an optionally substituted straight or branched C2 to C12 alkenylene chain, or an optionally substituted straight or branched C3 to C12 alkynylene chain; and
R14 is an optionally substituted pyrrolidinyl;
wherein each of the optionally substituted moieties is independently optionally substituted by one, two or three substituents independently selected from the group consisting of —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C3-C15 cycloalkyl, —C3-C15 cycloalkenyl, C3-C15 cycloalkynyl, -3 to 18-membered heterocyclic, —F, —Cl, —Br, —I, —OH, —NO2, —N3, —CN, —NH2, oxo, thioxo, —NHRx, —NRxRx, dialkylamino, -diarylamino, -diheteroarylamino, —ORx, —C(O)ORy, —C(O)Ry, —C(O)C(O)Ry, —OCO2Ry, —OC(O)Ry, OC(O)C(O)Ry, —NHC(O)Ry, —NHCO2Ry, —NHC(O)C(O)Ry, —NHC(S)NH2, —NHC(S)NHRx, —NHC(NH)NH2, —NHC(NH)NHRx, —NHC(NH)Rx, —C(NH)NHRx, —NRxC(O)Rx, —NRxCO2Ry, —NRxC(O)C(O)Ry, —NRxC(S)NH2, —NRxC(O)NRxRx, —NRxS(O)2NRxRx, —NRxC(S)NHRx, —NRxC(NH)NH2, —NRxC(NH)NHRx, —NRxC(NH)Rx, —C(NRx)NHRx—S(O)nRy, —NHSO2Rx, —CH2NH2, —CH2SO2CH3, —(C═NRx)Rx; -aryl, -arylalkyl, -3 to 18-membered heteroaryl, -3 to 18-membered heteroarylalkyl, polyalkoxyalkyl, -polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—Rx, and -methylthiomethyl,
Rx is selected from the group consisting of hydrogen, —C1-C12 alkyl, —C2-C12 alkenyl, C2-C12 alkynyl, —C3-C15 cycloalkyl, -aryl, -3 to 18-membered heteroaryl, and -3 to 18-membered heterocyclic;
—Ry is selected from the group consisting of hydrogen, —C1-C12 alkyl, —C2-C12 alkenyl, —C2-C12 alkynyl, —C3-C15 cycloalkyl, -aryl, -3 to 18-membered heteroaryl, -3 to 18-membered heterocyclic, —NH2, —NH—C1-C12 alkyl, —NH—C2-C12 alkenyl, —NH—C2-C12-alkynyl, —NH—C3-C15 cycloalkyl, —NH-aryl, —NH-3 to 18-membered heteroaryl, and —NH-3 to 18-membered heterocyclic, and
n is 0, 1 or 2:
as a single stereoisomer or as a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R15 is C(O)OR10 or optionally substituted phenyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R14 is optionally substituted pyrolidin-2-yl or optionally substituted pyrolidin-3-yl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R14 is selected from:
wherein R16 is selected from the group consisting of hydrogen, and optionally substituted C1-C12 alkyl, C(O)R10, C(O)—R13—N(R10)R11, and C(O)OR10.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R16 is optionally substituted benzyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1a is hydrogen, C(O)OR10, C(O)R10, C(O)—R13—N(R10)R11, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C3-C15 cycloalkyl, optionally substituted C3-C15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted 3- to 18-membered heteroaryl, and optionally substituted 3- to 18-membered heterocyclyl.

### Claim 7

A compound selected from the compounds shown in the following Table or a pharmaceutically acceptable salt thereof:
X
Y

### Claim 8 (depends on 1)

The compound of claim 1, wherein each R5b is hydrogen.

### Claim 9 (depends on 2)

The compound of claim 2, wherein R15 is unsubstituted phenyl or phenyl substituted with a substituent selected from the group consisting of C(O)OR10′ and halo, wherein R10′ is hydrogen or C1-C6 alkyl.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R15 is phenyl substituted with C(O)OH or C(O)OCH3.

### Claim 11 (depends on 9)

The compound of claim 9, wherein R15 is phenyl substituted with halo.

### Claim 12 (depends on 4)

The compound of claim 4, wherein R16 is selected from the group consisting of hydrogen, optionally substituted C1-C12 alkyl, and C(O)OR10.

### Claim 13 (depends on 5)

The compound of claim 5, wherein the optionally substituted benzyl is a benzyl optionally substituted with C(O)OH, C(O)OCH3, and halo.

### Claim 14 (depends on 6)

The compound of claim 6, wherein R1a is hydrogen, C(O)OR10, C(O)R10, C(O)—R13—N(R10)R11, optionally substituted alkyl, halo, optionally substituted phenyl, furanyl, thienyl, thiazolyl, or optionally substituted oxazolyl; and wherein R1b, R1c, R1d and R1e are each hydrogen.

### Claim 15 (depends on 14)

The compound of claim 14, wherein R1a is halo.

### Claim 16 (depends on 14)

The compound of claim 14, wherein R1a is oxazolyl or thiazolyl.

### Claim 17 (depends on 7)

The compound of claim 7, wherein the compound is:

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A method of treating an inflammatory disease or autoimmune disorder, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the inflammatory or autoimmune disorder is selected from the group consisting of a pulmonary or respiratory tract inflammation and an inflammatory skin condition.

### Claim 20 (depends on 19)

The method of claim 19, wherein the inflammatory disease or autoimmune disorder is a pulmonary or respiratory tract inflammation.

### Claim 21 (depends on 19)

The method of claim 19, wherein the mammal is a human.

### Claim 22 (depends on 20)

The method of claim 20, wherein the pulmonary or respiratory tract inflammation is selected from the group consisting of asthma, chronic bronchitis, bronchiolitis, bronchiolitis obliterans, allergic inflammation of the respiratory tract, eosinophilic granuloma, pneumonias, pulmonary fibroses, pulmonary manifestations of connective tissue diseases, acute or chronic lung injury, chronic obstructive pulmonary diseases, adult respiratory distress syndrome, and other non-infectious inflammatory disorders of the lung characterized by eosinophil infiltration.

### Claim 23 (depends on 19)

The method of claim 19, wherein the disease or disorder is cystic fibrosis.

### Claim 24 (depends on 19)

The method of claim 19, wherein the disease or disorder is an inflammatory skin condition.