# US 10,308,667 B2 · Oxadiazolopyridine derivatives for use as ghrelin O-acyl transferase (GOAT) inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,308,667 B2
- Document ID: US10308667B2
- Status: Granted
- Kind: B2
- Application number: 15/974,882
- Filed: 2018-05-09
- Published: 2018-09-06
- Granted: 2019-06-04
- Earliest claimed: 2016-08-05
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Cédrickx Godbout; Thomas Trieselmann; Viktor Vintonyak
- Web page: https://patentgrep.com/patent/US10308667B2

## CPC

- 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 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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 relates to compounds of general formula I, wherein the groups R1, R2 and n are defined as in claim 1, which have valuable pharmacological properties, in particular bind to ghrelin O-acyl transferase (GOAT) and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular obesity.

## Claims

### Claim 1

A method for treating obesity, type 2 diabetes mellitus, and/or insulin resistance, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula (I)
wherein
X is CH or N;
R1 is selected from the group consisting of CH3—CH2OH and Cl;
R2 is independently of each other selected from the group consisting of H, F, Cl, Br, I, CN, C1-6-alkyl, C3-7-cycloalkyl, OH, —O—(C1-6-alkyl), —O—(C3-7-cycloalkyl), —O—(C1-3-alkyl)-(C3-7-cyclo alkyl), —O-heterocyclyl, —O—(C1-3-alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl, —S—(C1-3-alkyl), —SO—(C1-3-alkyl), —SO21-3-alkyl), —NH2, —NH—(C1-6-alkyl), —NH—(C3-6-cycloalkyl), —NH—(C1-3-alkyl)-heterocyclyl, —NH—(C1-6-alkyl-C(═O)—NH2—C(═O)—NH2—C(═O)—NH—(C1-3-alkyl), —C(═O)—N(C1-3-alkyl)2, —C(═O)OH, —C(═O)—(C1-4-alkyl), alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and
wherein each heterocyclyl group is selected from the group consisting of a mono- or spirocyclic 4-7-membered cycloalkyl group, in which 1, 2 or 3 CH2-groups are independently of each other replaced by O, S, NH or C═O, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently of each other selected from the group consisting of F, OH and C1-3-alkyl,
wherein each aryl group is selected from the group consisting of phenyl and naphthyl, and
wherein each heteroaryl group is selected from the group consisting of 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and
wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, CN and C1-3-alkyl, which is optionally substituted with one or more F;
or, if two groups R2 are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a O—CH2—O—, —O—CH2—CH2—O— or —O—CH2—CH2—CH2—O— bridge, in which 1 or 2H atoms may be replaced with F or C1-3-alkyl; and
n is 1, 2 or 3;
wherein each of the above-mentioned alkyl groups may be substituted with one or more F;
or a pharmaceutically acceptable salt thereof.

### Claim 2

A method for treating a disease or condition which is mediated by inhibiting the activity of the ghrelin O-acyl transferase (GOAT), the method comprising administering a compound of formula
wherein
X is CH or N;
R1 is selected from the group consisting of CH3—CH2OH and Cl;
R2 is independently of each other selected from the group consisting of H, F, Cl, Br, I, CN, C1-6-alkyl, C3-7-cycloalkyl, OH, —O—(C1-6-alkyl), —O—(C3-7-cycloalkyl), —O—(C1-3-alkyl)-(C3-7-cycloalkyl), —O-heterocyclyl, —O—(C1-3-alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl, —S—(C1-3-alkyl), —SO—(C1-3-alkyl), —SO21-3-alkyl), —NH2, —NH—(C1-6-alkyl), —NH—(C3-6-cycloalkyl), —NH—(C1-3-alkyl)-heterocyclyl, —NH—(C1-6-alkyl)-C(═O)—NH2, —C(═O)—NH2, —C(═O)—NH—(C1-3-alkyl), —C(═O)—N(C1-3-alkyl)2, —C(═O)OH, —C(═O)—O—(C1-4-alkyl), —C(═O)—(C1-4-alkyl), alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and
wherein each heterocyclyl group is selected from the group consisting of a mono- or spirocyclic 4-7-membered cycloalkyl group, in which 1, 2 or 3 CH2-groups are independently of each other replaced by O, S, NH or C═O, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently of each other selected from the group consisting of F, OH and C1-3-alkyl,
wherein each aryl group is selected from the group consisting of phenyl and naphthyl, and
wherein each heteroaryl group is selected from the group consisting of 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and
wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, CN and C1-3-alkyl, which is optionally substituted with one or more F;
or, if two groups R2 are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a O—CH2—O—, —O—CH2—CH2—O— or —O—CH2—CH2—CH2—O— bridge, in which 1 or 2H atoms may be replaced with F or C1-3-alkyl; and
n is 1, 2 or 3;
wherein each of the above-mentioned alkyl groups may be substituted with one or more F;
or a pharmaceutically acceptable salt thereof,
to a patient in need thereof.

### Claim 3 (depends on 1)

The method according to claim 1, wherein
R1 is —CH3; and
n is 1 or 2.

### Claim 4 (depends on 1)

The method according to claim 1, wherein
R2 is independently of each other selected from the group consisting of H, F, Cl, Br, CN, C1-6-alkyl, C3-7-cycloalkyl, OH, —O—(C1-6-alkyl), —O—(C1-3-alkyl)-(C3-7-cycloalkyl), —O— heterocyclyl, —O—(C1-3-alkyl)-heterocyclyl, —O-aryl, —O-heteroaryl, —S—(C1-3-alkyl), —SO2—(C1-3-alkyl), —NH2, —NH—(C1-6-alkyl), —NH—(C3-6-cycloalkyl), —NH—(C1-3-alkyl)-heterocyclyl, —NH—(C1-6-alkyl)-C(═O)—NH2, —C(═O)—NH2, —C(═O)—NH—(C1-3-alkyl), —C(═O)—(C1-4-alkyl), —C1-3-alkyl-C(═O)—O—(C1-4-alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one or more substituents selected from the group consisting of F, CN and OH, and
wherein each heterocyclyl group is selected from the group consisting of a mono- or spirocyclic 4-7-membered cycloalkyl group, in which 1, 2 or 3 CH2-groups are independently of each other replaced by O, S, NH or C═O, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently of each other selected from the group consisting of F, OH and C1-3-alkyl,
wherein each aryl group is selected from the group consisting of phenyl and naphthyl, and
wherein each heteroaryl group is selected from the group consisting of 5-membered aromatic cycle containing 1 or 2 heteroatoms independently selected from the group consisting of N, O and S or from a 6-membered aromatic cycle containing 1 or 2 N, and
wherein each aryl or heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F and C1-3-alkyl, which is optionally substituted with one or more F;
or, if two groups R2 are attached to adjacent C atoms of the pyridine or pyrimidine group, they may be linked with each other and together form a —O—CH2—O—, —O—CH2—CH2—O— or —O —CH2—CH2—CH2—O— bridge.

### Claim 5 (depends on 4)

The method according to claim 4, wherein
R2 is independently of each other selected from the group consisting of F, Cl, Br, CN, C1-3-alkyl, C3-6-cycloalkyl, —O—(C1-4-alkyl), —O—CH2-cyclopropyl, —O—CH2-heterocyclyl, —O-phenyl, —O-heteroaryl, —S—CH3, —NH2, —NH—(C1-4-alkyl), —NH—(C3-5-cycloalkyl), —NH—(CH2-heterocyclyl), —NH—(C1-4-alkyl)-C(═O)—NH2, —C(═O)—NH—(C1-3-alkyl), —C(═O)—(C1-4-alkyl), heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one to three F atoms or with one CN or one OH, and
wherein each heterocyclyl group is selected from the group consisting of oxetanyl, tetrahydrofuranyl, azetidinyl, pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently of each other selected from the group consisting of F, OH and CH3,
wherein each heteroaryl group is selected from the group consisting of furanyl, isoxazolyl, thiazolyl and pyrazolyl, and
wherein each heteroaryl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, CH3 and CF3.

### Claim 6 (depends on 5)

The method according to claim 5, wherein
R2 is independently of each other selected from the group consisting of F, Cl, Br, CN, CH3, C3-5-cycloalkyl, —O—(C1-4-alkyl), —O—CH2-heterocyclyl, —O-phenyl, —S—CH3, —NH2, —NH—(C1-4-alkyl), —NH—(C3-5-cycloalkyl), —NH—(CH2-heterocyclyl), —NH—(C1-4-alkyl)-C(═O)—NH2, heterocyclyl, heteroaryl and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl,
wherein each alkyl or cycloalkyl group is optionally independently substituted with one to three F atoms or with one CN or one OH, and
wherein each heterocyclyl group is selected from the group consisting of oxetanyl, azetidinyl, pyrrolidinyl, morpholinyl and 1,4-diazepan-5-one, and
wherein each heterocyclyl group is optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, OH and CH3, and
wherein each heteroaryl group is selected from the group consisting of furanyl and thiazolyl.

### Claim 7 (depends on 6)

The method according to claim 6, wherein
R2 is independently selected from the group consisting of:
F, Cl, Br, —CN, —CF3,
—O—CH3, —O—CHF2, —O—CH2—CH2—F, —O—CH2—CHF2, —O—CH2—CF3, —O—CH2—CH2—CH2—F, —O—CH2—CF2—CH3,
—S—CH3, —NH2, —NH—CH2—CH2—CH2—F, —NH—CH2—CH2—CHF2,

### Claim 8 (depends on 1)

The method according to claim 1, where X is CH.

### Claim 9 (depends on 1)

The method according to claim 1, where X is N.

### Claim 10 (depends on 1)

The method according to claim 1, where the compound of formula (I) is of formula I.2
wherein
R1 is CH3;
R2a and R2b are each independently selected from the group consisting of:
H, F, Cl, Br, —CN, —CF3,
—O—CH3, —O—CHF2, —O—CH2—CH2—F, —O—CH2—CHF2, —O—CH2—CF3, —O—CH2—CH2—CH2—F, —O—CH2—CF2—CH3,
—S—CH3, —NH2, —NH—CH2—CH2—CH2—F, —NH—CH2—CH2—CHF2,
wherein at least one R2a and R2b is not H;
or a salt thereof.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the compound of formula I is selected from the group consisting of:
or a salt thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein obesity patient is suffering from Prader-Willi syndrome.