# US 10,864,201 B2 · Heteroaromatic compounds as Vanin inhibitors

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- Number: US 10,864,201 B2
- Document ID: US10864201B2
- Status: Granted
- Kind: B2
- Application number: 16/550,347
- Filed: 2019-08-26
- Published: 2020-03-05
- Granted: 2020-12-15
- Earliest claimed: 2018-08-28
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Cédrickx Godbout; Martin Thomas Fleck; Hannes Fiepko Koolman
- Web page: https://patentgrep.com/patent/US10864201B2

## CPC

- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 471/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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, 2 or 3;
m denotes 1, 2 or 3;
R1 and R2 are independently from each other selected from the group consisting of H, C1-4-alkyl optionally substituted by 1-3 F-atoms or C1-2-alkoxy, 6-10 membered aryl substituted by R2.1 and 5-6 membered heteroaryl substituted by R2.1,
wherein
R2.1 is selected from the group consisting of H, F, Cl, Br, —CN, NR2.1.1R2.1.2, —SO2R2.1.3 and —OR2.1.4,
wherein
R2.1.1, R2.1.2 independently from each other denote H, C1-4-alkyl or C3-4-cycloalkyl;
or
R2.1.1 and R2.1.2 together with the N-atom to which they are attached form a 4-5 membered heterocyclyl or a 6 membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N and O;
R2.1.3, denotes C1-4-alkyl or NR2.1.1 R2.1.2,
R2.1.4 is selected from the group consisting of H, C1-4-alkyl, C3-5-cycoalkyl, 4-5 membered heterocyclyl containing 1 heteroatom selected from the group consisting of N and O;
wherein in the definition of R2.1.1, R2.1.2, R2.1.3 and R2.1.4 mentioned alkyl, cycloalkyl and heterocyclyl are optionally substituted by 1-3 F-atoms or one C1-2-alkoxy;
or
R1 and R2 together may form a 3-5 membered carbocycle or 4-6 membered heterocyclyl containing one heteroatom selected from the group consisting of N and O;
R3 denotes NR3.1R3.2;
or
R3 denotes a group of formula R3.a or R3.b
wherein
X denotes CH2, NRX or O;
wherein RX denotes H or C1-3-alkyl;
R3.1 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, R3.1.3R3.1.4N—CO—, R3.1.5O—CO—, pyrimidine, pyridine, C3-5-cycloalkyl-CO— substituted with R3.1.1 and R3.1.2, 4-6-membered-heterocyclyl-CO— substituted with R3.1.1 and R3.1.2, —CO-phenyl substituted with R3.1.1 and R3.1.2;
wherein
R3.1.1, R3.1.2 independently from each other are selected from the group consisting of H, CH3, —OR3.1.1.1, F and —CN;
R3.1.3, R3.1.4 independently from each other denote H, C1-4-alkyl or C3-4-cycloalkyl;
or
R3.1.3 and R3.1.4 together with the N-atom to which they are attached form a form a 4-5 membered heterocyclyl or a 6 membered heterocyclyl optionally containing one additional heteroatom selected from the group consisting of N and O;
R3.1.5 is selected from the group consisting of C1-4-alkyl, C3-5-cycloalkyl, 4-5 membered heterocyclyl and C3-4-cycloalkyl-CH2—;
R3.1.1.1 denotes C1-4-alkyl, C3-5-cycloalkyl or 4-5 membered heterocyclyl;
wherein in the definition of R3.1.1, R3.1.2, R3.1.3, R3.1.4, R3.1.5 and R3.1.1.1 mentioned alkyl, cycloalkyl and heterocyclyl are optionally substituted by 1-3 F-atoms or one C1-2-alkoxy;
R3.2 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 R3.2 mentioned alkyl, cycloalkyl and phenyl are optionally substituted by 1-3 F-atoms or one C1-2-alkoxy;
R4 denotes hydrogen or C1-4-alkyl optionally substituted with 1 to 3 F-atoms;
or
R3 and R4 together form a 4-6-membered heterocycle containing one oxygen atom.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

The compound according to claim 1, wherein
R2 denotes methyl, ethyl, pyrimidin or phenyl substituted by R2.1, wherein
R2.1 is selected from the group consisting of H, F, Cl and —CN,
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein
R3 denotes NR3.1R3.2,
or
R3 denotes a group of formula R3.a
wherein
X denotes CH2 or O
R3.1 denotes —COCH3, pyrimidine, C3-4-cycloalkyl-CO— substituted with R3.1.1 and R3.1.2
wherein
R3.1.1, R3.1.2 independently from each other denote H, CH3, F or —CN
R3.2 denotes CH3,
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein
R3 and R4 together form a 6 membered heterocycle containing one oxygen atom, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein
R4 denotes hydrogen,
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein
n denotes 1 or 2;
m denotes 1;
R1 denotes methyl,
R2 denotes methyl or phenyl substituted by R2.1,
wherein
R2.1 is selected from the group consisting of H, F, Cl and —CN;
R3 denotes NR3.1R3.2;
or
R3 denotes a group of formula R3.a,
wherein
X denotes CH2 or O;
R3.1 denotes —COCH3, pyrimidine, C3-4-cycloalkyl-CO— substituted with R3.1.1 and R3.1.2
wherein
R3.1.1, R3.1.2 independently from each other denote H, —CH3, F or —CN;
R3.2 denotes CH3,
R4 denotes hydrogen;
or
R3 and R4 together form a 6 membered heterocycle containing one oxygen atom;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound according to claim 1,
wherein
n denotes 1 or 2;
m denotes 2;
R1 denotes H or methyl;
R2 denotes methyl, ethyl, pyrimidin or phenyl;
R3 denotes NR3.1R3.2;
or
R3 denotes a group of formula R3.a;
wherein
X denotes CH2 or O;
R3.1 denotes —COCH3, pyrimidine C3-4-cycloalkyl-CO— substituted with R3.1.1 and R3.1.2,
wherein
R3.1.1, R3.1.2 independently from each other denote H, CH3, F or —CN;
R3.2 denotes CH3,
R4 denotes hydrogen,
or
R3 and R4 together form a 6 membered heterocycle containing one oxygen atom;
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of formula I according to claim 1 selected from the group consisting of examples 6, 9.1, 8.2, 5.3, 2.1, 7.2, 13.3, 5.2, 13.1, 4.1, 11.10, 4.4, 11.9, 7.4, 4.3, 7.1, 8.3, 11.6, 10 and 9.3;
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 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, comprising administering to the patient the compound according to claim 1.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising additionally to the compound of claim 1, a pharmaceutically active compound selected from the group consisting of an immunomodulatory agent, anti-inflammatory agent and 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 of formula:

### Claim 25

A compound of formula:

### Claim 26

A compound of formula:

### Claim 27

A compound of formula:

### Claim 28

A compound of formula:

### Claim 29

A compound of formula:

### Claim 30

A compound of formula:

### Claim 31

A compound of formula:

### Claim 32

A compound of formula:

### Claim 33

A compound of formula:

### Claim 34

A compound of formula:

### Claim 35

A compound of formula:

### Claim 36

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

### Claim 37

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

### Claim 38

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

### Claim 39

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

### Claim 40

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

### Claim 41

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

### Claim 42

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

### Claim 43

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

### Claim 44

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

### Claim 45

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

### Claim 46

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

### Claim 47

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

### Claim 48

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

### Claim 49

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

### Claim 50

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

### Claim 51

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

### Claim 52

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

### Claim 53

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

### Claim 54

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

### Claim 55

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