# US 11,078,182 B2 · Heteroaromatic compounds as Vanin inhibitors

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- Number: US 11,078,182 B2
- Document ID: US11078182B2
- Status: Granted
- Kind: B2
- Application number: 16/699,799
- Filed: 2019-12-02
- Published: 2020-06-04
- Granted: 2021-08-03
- Earliest claimed: 2018-12-03
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Martin Thomas Fleck; Cedrickx Godbout; Hannes Fiepko Koolman
- Web page: https://patentgrep.com/patent/US11078182B2

## CPC

- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention encompasses compounds of the formula I which are suitable for the treatment of diseases related to Vanin, and processes for making these compounds, pharmaceutical preparations containing these compounds, and their methods of use.

## Claims

### Claim 1

A compound of the formula I, or a pharmaceutically acceptable salt thereof,
wherein
n denotes 1 or 2;
R1, R2 and R3 are independently from each other selected from the group consisting of C1-4-alkyl optionally substituted by hydroxy, CH3—O—, CH3—SO2—, Phenyl-CH2— optionally substituted by 1 to 3 halogen atoms and 5-6 membered heteroaryl-C1-2-alkyl-;
or
R2 and R3 together form a 3-6 membered carbocycle or 4-6 membered heterocyclyl containing one heteroatom selected from the group consisting of N and O;
or
R1, R2 and R3 together may form or a bicyclic 5-8 membered carbocycle or a bicyclic 6-8 membered heterocyclyl containing one heteroatom selected from the group consisting of N and O;
wherein in the definition of R1, R2 and R3 mentioned alkyl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted by 1 to 3 halogen atoms;
R4 denotes R4.1R4.2N—, 5-6 membered heteroaryl, NC— or 5-6 membered heterocyclyl;
or
R4 denotes a group of formula R4.a or R4.b
wherein
X denotes CH2, —NRX or O;
wherein RX denotes H or C1-3-alkyl;
R4.a and R4.b independently from each other are optionally substituted by methyl;
R4.1 is selected from the group consisting of C1-4-alkyl-CO— optionally substituted by 1-3 F-atoms, C3-4-cycloalkyl or C1-2-alkoxy, C3-5-cycloalkyl-CO— substituted with R4.1.1 and R4.1.2, 4-6 membered heterocyclyl-CO— substituted with R4.1.3 and R4.1.4, 4-6 membered heterocyclyl-CH2—CO—, 5-6 membered heteroaryl-CO— optionally substituted by 1 halogen atom, H3C—O— or 1 to 2 methyl, phenyl-CO— substituted with R4.1.5 and R4.1.6, (C1-3-alkyl)(C1-3-alkyl)N—CO— and 5-6 membered heteroaryl;
wherein
R4.1.1, R4.1.2 independently from each other are selected from the group consisting of H, —CH3, F, CF3 and CN;
R4.1.3, R4.1.6 independently from each other are selected from the group consisting of H, —CH3, F, CF3 and —CN;
R4.1.5, R4.1.6 independently from each other are selected from the group consisting of H, —CH3, F, CF3 and —CN;
R4.2 is selected from the group consisting of H, C1-4-alkyl, C3-4-cycloalkyl, C3-4-cycloalkyl-C1-2-alkyl- and phenyl-C1-2-alkyl-;
wherein in the definition of R42 mentioned alkyl, cycloalkyl and phenyl are optionally substituted by 1-3 F-atoms or one C1-2-alkyl-O—;
R5 denotes H or C1-2-alkyl;
or
R4 and R5 together form 4-6 membered heterocyclyl containing 1 heteroatom selected from the group consisting of N and O;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1,
wherein
n denotes 1,
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound according to claim 1,
wherein
n denotes 2,
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein
R1 denotes methyl,
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein
R2 denotes methyl,
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein
R3 denotes C1-3-alkyl optionally substituted by hydroxy
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein
R2 and R3 together form a 4-6 membered carbocycle or 6-membered heterocyclyl
containing one oxygen atom,
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein
R4 is selected from the group consisting of R4.1R4.2N—, pyridinyl and NC—;
or
R4 denotes a group of formula R4.a or R4.b
wherein
X denotes CH2 or O;
R4.a and R4.b independently from each other are optionally substituted by methyl,
R4.1 is selected from the group consisting of C1-4-alkyl-CO—, C3-4-cycloalkyl-CO— substituted with R4.1.1 and R4.1.2, 5-6 membered heteroaryl-CO— substituted with R4.1.3 and R4.1.4, 6 membered heterocyclyl-CH2—CO—, 5 membered heteroaryl-CO— optionally substituted by 1 halogen atom, phenyl-CO— substituted with R4.1.5 and R4.1.6 and 6 membered heteroaryl;
wherein
R4.1.1, R4.1.2 independently from each other are selected from the group consisting of H, —CH3, F, CF3 and —CN;
R4.1.3, R4.1.4 independently from each other are selected from the group consisting of H, —CH3, F, CF3 and —CN;
R4.1.5, R4.1.6 independently from each other are selected from the group consisting of H, —CH3, F, CF3 and —CN;
R4.2 denotes methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein
R5 denotes H or methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein
n denotes 1 or 2;
R1 denotes methyl;
R2 denotes methyl;
R3 denotes C1-3-alkyl optionally substituted by hydroxyl;
or
R2 and R3 together form a 4-6 membered carbocycle or a 6-membered heterocyclyl containing one oxygen atom;
R4 is selected from the group consisting of R4.1R4.2N—, pyridinyl and NC—;
or
R4 denotes a group of formula R4.a or R4.b;
wherein
X denotes CH2 or O;
R4.a and R4.b independently from each other are optionally substituted by methyl,
R4.1 is selected from the group consisting of C1-4-alkyl-CO—, C3-5-cycloalkyl-CO— substituted with R4.1.1 and R4.1.2, 4-6 membered heterocyclyl-CO— substituted with R4.1.3 and R4.1.4, 6 membered heterocyclyl-CH2—CO—, 5-6 membered heteroaryl-CO— optionally substituted by 1 halogen atom, phenyl-CO— substituted with R4.1.5 and R4.1.6 and 6 membered heteroaryl containing 1 or 2 N-atoms;
wherein
R4.1.1, R4.1.2 independently from each other are selected from the group consisting of H, F and —CN;
R4.1.3, R4.1.4 independently from each other are selected from the group consisting of H, —CH3 and CF3;
R4.1.5, R4.1.6 independently from each other are selected from the group consisting of H and F;
R4.2 denotes methyl;
R5 denotes H or methyl;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of formula I according to claim 1 selected from the group consisting of examples 1.2, 1.3, 1.5, 1.6, 1.8, 1.9, 1.11, 3.2, 5.1 and 7.1;
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A compound of formula IB according to claim 1,
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

### Claim 14 (depends on 1)

A method of using the compound according to claim 1 for treating a patient suffering from Crohn's disease, ulcerative colitis, atopic dermatitis, systemic sclerosis, Non-Alcoholic Steatohepathitis (NASH), psoriasis, chronic kidney disease, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, rheumatoid arthritis, scleroderma, asthma, allergic rhinitis, allergic eczema, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, graft versus host disease, psoriatic arthritis, Hyperlipidemia, colorectal cancer or pancreatic cancer related new onset diabetes.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising additionally to a compound of formula I according to claim 1, a pharmaceutically active compound selected from the group consisting of an immunomodulatory agent, anti-inflammatory agent or a chemotherapeutic agent.

### Claim 16

A compound of formula:

### Claim 17

A compound of formula:

### Claim 18

A compound of formula:

### Claim 19

A compound of formula:

### Claim 20

A compound of formula:

### Claim 21

A compound of formula:

### Claim 22

A compound of formula:

### Claim 23

A compound of formula:

### Claim 24

A compound formula:

### Claim 25

A compound of formula:

### Claim 26

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 27

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 28

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 29

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 30

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 31

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 32

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 33

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 34

A compound of formula:
or a pharmaceutically acceptable salt thereof.

### Claim 35

A compound of formula:
or a pharmaceutically acceptable salt thereof.