# US 10,479,781 B2 · Peptidyl nitril compounds as dipeptidyl peptidase I inhibitors

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- Number: US 10,479,781 B2
- Document ID: US10479781B2
- Status: Granted
- Kind: B2
- Application number: 15/554,514
- Filed: 2016-03-04
- Published: 2018-02-15
- Granted: 2019-11-19
- Earliest claimed: 2015-03-05
- Assignees: Neuprozyme Therapeutics APS
- Applicants: Prozymex A/S
- Inventors: Conni Lauritzen; John Pedersen
- Web page: https://patentgrep.com/patent/US10479781B2

## CPC

- C07D 405/12: linked by a chain containing hetero atoms as chain links
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/02: Local antiseptics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 33/06: Antimalarials
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 309/14: Nitrogen atoms not forming part of a nitro radical
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention relates to compounds of Formula (I) and their use as selective dipeptidyl peptidase I inhibitors, as well as pharmaceutical compositions comprising said compounds, and methods of treatment involving said compounds.

## Claims

### Claim 1

A compound of the formula (I)
wherein n is 0, 1 or 2 and m is 0, 1 or 2; such that the sum of m and n is 1, 2, 3 or 4;
F is fluoro;
X1 represents
wherein y represents 0, 1, 2, 3, 4, 5, 6, 7 or 8;
wherein Z represents O (oxygen);
when y is 1 or 2, then R1 independently represents deuterium; halogen; hydroxyl; cyano;
oxo (═0); mercapto; or C1-3-alkyl; which C1-3-alkyl is optionally substituted with at least one substituent selected from halogen, hydroxyl, cyano and mercapto;
or when y represents 3, 4, 5, 6, 7 or 8, then R1 represents deuterium;
wherein R2 represents —C3-6-cycloalkyl, —C1-3-alkyl-C3-6-cycloalkyl or —C1-6-alkyl, which —C1-6-alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino; as well as pharmaceutically-acceptable salts, solvates and hydrates thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is:

### Claim 3 (depends on 1)

The compound of claim 1, wherein R2 is —C1-6-alkyl, which —C1-6-alkyl is optionally substituted with at least one substituent selected from hydroxyl, cyano or amino.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R2 is —C1-6-alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein y represents 0, 1, 2, 3 or 4.

### Claim 6 (depends on 1)

The compound of claim 1, wherein m+n=1.

### Claim 7 (depends on 1)

The compound of claim 1, wherein m=2.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising the compound of formula (I) of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically-acceptable adjuvant, carrier or diluent.

### Claim 9 (depends on 1)

The compound of claim 1 for use as a medicament.

### Claim 10 (depends on 1)

The compound of claim 1 for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis.

### Claim 11 (depends on 1)

The compound of claim 1 for treating asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, psoriasis, rheumatoid arthritis or sepsis.

### Claim 12 (depends on 1)

A method for treatment of a medical condition selected from the group consisting of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, acute lung injury, acute respiratory distress syndrome, congestive heart failure, atherosclerosis, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, inflammatory bowel diseases, psoriasis, rheumatoid arthritis, multiple sclerosis, malaria, Alzheimer's disease or sepsis, said method comprising administration of a pharmaceutically effective amount of the compound of claim 1.

### Claim 13 (depends on 12)

The method of claim 12, wherein the medical condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, alpha-1 antitrypsin deficiency, idiopathic pulmonary fibrosis, congestive heart failure, myocardial infarction, reperfusion injury, abdominal aortic aneurysms, diabetic cardiomyopathy, gout, pseudogout, respiratory syncytial virus infection, psoriasis, rheumatoid arthritis or sepsis.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R2 is —C1-3-alkyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R2 is methyl-, ethyl- or propyl-.

### Claim 16 (depends on 1)

The compound of claim 1, wherein y represents 0 or 1.

### Claim 17 (depends on 1)

The compound of claim 1, wherein y represents 0.

### Claim 18 (depends on 1)

The compound of claim 1, wherein m=1.

### Claim 19 (depends on 1)

The compound of claim 1 for treating cystic fibrosis.

### Claim 20 (depends on 12)

The method of claim 12, wherein the medical condition is cystic fibrosis.