# US 2019/0375712 A1 · Benzyloxypyridylcyclopropanecarboxylic acids, pharmaceutical compositions and uses thereof

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- Number: US 2019/0375712 A1
- Document ID: US20190375712A1
- Status: Published application
- Kind: A1
- Application number: 16/479,225
- Filed: 2018-01-22
- Published: 2019-12-12
- Earliest claimed: 2017-01-26
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Matthias ECKHARDT; Holger WAGNER
- Web page: https://patentgrep.com/patent/US20190375712A1

## CPC

- C07D 213/79: Acids; Esters
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4427: containing further heterocyclic ring systems
- A61K 31/443: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/4433: containing a six-membered ring with oxygen as a ring hetero atom
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 407/10: linked by a carbon chain containing aromatic rings
- 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 R, R1, R2, R3, m and n are defined herein, which have valuable pharmacological properties, in particular bind to the GPR40 receptor 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 diabetes type 2.

## Claims

### Claim 1

A compound of formula (I)
wherein
R is selected from the group consisting of
H, F, Cl, Br, I, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, NC—, HNRN—C(═O)—, C1-4-alkyl-NRN—C(═O)—, C3-6-cycloalkyl-NRN—C(═O)—, heterocyclyl-NRN—C(═O)—, heteroaryl-NRN—C(═O)—, HOOC—, C1-4-alkyl-O—C(═O)—, O2N—, HRNN—, C1-4-alkyl-RNN—, C1-4-alkyl-C(═O)NRN—, C3-6-cycloalkyl-C(═O)NRN—, heterocyclyl-C(═O)NRN—, heteroaryl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, C3-6-cycloalkyl-S(═O)2NRN—, heterocyclyl-S(═O)2NRN—, heteroaryl-S(═O)2NRN—, HO—, C1-6-alkyl-O—, HOOC—C1-3-alkyl-O—, C3-6-cycloalkyl-C1-3-alkyl-O—, heterocyclyl-C1-3-alkyl-O—, phenyl-C1-3-alkyl-O—, C3-6-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—, C1-4-alkyl-S—, C3-6-cycloalkyl-S—, heterocyclyl-S—, C1-4-alkyl-S(═O)—, C3-6-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—, C1-4-alkyl-S(═O)2—, C3-6-cycloalkyl-S(═O)2—, heterocyclyl-S(═O)2—, phenyl-S(═O)2—, heteroaryl-S(═O)2—, HNRN—S(═O)2—, C1-4-alkyl-NRN—S(═O)2—, heterocyclyl, phenyl, and heteroaryl,
wherein each alkyl, cycloalkyl, and heterocyclyl group or sub-group within the groups forming R is optionally substituted with 1 or more F atoms and optionally substituted with 1 to 3 groups independently selected from Cl, C1-3-alkyl, NC—, (RN)2N—, HO—, C1-3-alkyl-O—, and C1-3-alkyl-S(═O)2—; and
wherein each phenyl and heteroaryl group or sub-group within the groups forming R is optionally substituted with 1 to 5 substituents independently selected from F, Cl, C1-3-alkyl, HF2C—, F3C—, NC—, (RN)2N—, HO—, C1-3-alkyl-O—, F3C—O—, and C1-3-alkyl-S(═O)2—;
wherein each heterocyclyl group or sub-group within the groups forming R is selected from
a cyclobutyl group wherein 1 CH2 group is replaced by —NRN— or —O—;
a C5-6-cycloalkyl group wherein 1 CH2 group is replaced by —C(═O)—, —NRN—, —O—, —S— or —S(═O)2— and/or 1 CH group is replaced by N;
a C5-6-cycloalkyl group wherein 1 CH2 group is replaced by —NRN— or —O—, a second CH2 group is replaced by —NRN—, —C(═O)— or —S(═O)2— and/or 1 CH group is replaced by N; and
a C5-6-cycloalkyl group wherein 2 CH2 groups are replaced by —NRN— or 1 CH2 group by —NRN— and the other by —O— and a third CH2 group is replaced by —C(═O)— or —S(═O)2— and/or 1 CH group is replaced by N;
wherein each heteroaryl group or sub-group within the groups forming R is selected from tetrazolyl and a 5- or 6-membered heteroaromatic ring which contains 1, 2, or 3 heteroatoms independently of each other selected from ═N—, —NRN—, —O—, and —S—, wherein in heteroaromatic groups containing a —HC═N— unit this group is optionally replaced by —NRN—C(═O)—;
wherein in heteroaryl and heterocyclyl rings with one or more NH groups, each of said NH groups is replaced by NRN;
R1 is selected from the group consisting of H, F, Cl, C1-4-alkyl, C3-6-cycloalkyl-, HO—C1-4-alkyl, C1-4-alkyl-O—C1-4-alkyl, NC—, HO—, C1-4-alkyl-O—, C3-6-cycloalkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(O)—, and C1-4-alkyl-S(O)2—,
wherein any alkyl and cycloalkyl group or sub-group within the groups forming R1 is optionally substituted with 1 or more F atoms, and wherein multiple R1 may be identical or different if m is 2, 3 or 4;
m is an integer selected from 1, 2, 3, and 4;
R2 is selected from the group consisting of H, F, Cl, C1-4-alkyl, NC—, and C1-4-alkyloxy,
wherein any alkyl group or sub-group within the groups forming R2 is optionally substituted with 1 or more F atoms, and wherein multiple R2 may be identical or different if n is 2 or 3;
R3 is selected from the group consisting of H, F, Cl, C1-4-alkyl, NC—, and C1-4-alkyl-O—,
wherein each alkyl group or sub-group within the groups forming R3 is optionally substituted with 1 or more F atoms;
n is an integer selected from 1, 2, and 3;
RN is independently of each other selected from the group consisting of H, C1-4-alkyl, HO—C1-4-alkyl-(H2C)—, C1-3-alkyl-O—C1-4-alkyl-, C1-4-alkyl-C(═O)—, C1-4-alkyl-NH—C(═O)—, C1-4-alkyl-N(C1-4-alkyl)-C(═O)—, C1-4-alkyl-O—C(═O)—, and C1-4-alkyl-S(═O)2—,
wherein each alkyl group or sub-group within the groups forming RN is optionally substituted with 1 or more F atoms;
wherein in any definition mentioned hereinbefore, if not specified otherwise, any alkyl group or sub-group may be straight-chained or branched,
or a salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein
R is selected from the group consisting of H, F, Cl, C1-4-alkyl, NC—, H2N—C(═O)—, C1-3-alkyl-NRN—C(═O)—, HOOC—, H2N—, C1-3-alkyl-C(═O)NRN—, C1-4-alkyl-S(═O)2NRN—, HO—, C1-5-alkyl-O—, HOOC—CH2—O—, cyclopropyl-H2C—O—, heterocyclyl-CH2—O—, phenyl-CH2—O—, C3-6-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—, heterocyclyl-S(═O)2—, heterocyclyl, and heteroaryl,
wherein each alkyl, cycloalkyl, and heterocyclyl group or sub-group within the groups forming R is optionally substituted with 1 or more F atoms and optionally substituted with 1 group selected from Cl, H3C—, NC—, RNHN—, HO—, H3C—O—, and H3C—S(═O)2—;
wherein each heteroaryl group or sub-group within the groups forming R is optionally substituted with 1 to 2 substituents independently selected from F, Cl, H3C—, F3C—, NC—, (RN)2N—, HO—, H3C—O—, F3C—O—, and H3C—S(═O)2—;
wherein each heterocyclyl or sub-group within the groups forming R is selected from
a cyclobutyl group wherein 1 CH2 group is replaced by —NRN— or —O—;
a C5-6-cycloalkyl group wherein 1 CH2 group is replaced by —C(═O)—, —NRN—, —O—, —S— or —S(═O)2— and/or 1 CH group is replaced by N;
wherein each heteroaryl group or sub-group within the groups forming R is selected from tetrazolyl, a 5-membered heteroaromatic ring which contains 1, 2 or 3 heteroatoms independently of each other selected from ═N—, —NH—, O and S, and a 6-membered heteroaromatic ring which contains 1 or 2 ═N— atoms, wherein a —HC═N— unit is optionally replaced by —NH—C(═O)—;
and wherein in each heteroaryl and heterocyclyl group or sub-group mentioned before containing one or more NH, said NH group(s) is/are replaced by NRN;
or a salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein
R is selected from the group consisting of H, C1-3-alkyl, Cl, (H3C)2N—C(═O)—, HOOC—;
H3C—O— optionally monosubstituted with C1-4-alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl,
wherein the C1-4-alkyl group optionally attached to H3C—O— is optionally monosubstituted with HO— or H3C—S(═O)2—, and
wherein said oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl groups are optionally monosubstituted with H3C—;
tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and
a heteroaryl group selected from pyrazolyl, tetrazolyl, pyridyl, pyridin-2-onyl, pyridazinyl, pyrazinyl, and pyrimidinyl,
wherein each of said heteroaryl groups is optionally monosubstituted with H3C— or H3C—O—, and
wherein each H—N group in said heteroaryl groups is optionally replaced with H3C—N or (H3C)2C(OH)—H2C—N;
or a salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein
R1 is H, F, Cl, H3C—, H3C—H2C—, (H3C)2HC—, F3C—, NC—, or H3C—O—;
m is 2;
R2 is H, F, or F3C—;
n is 1 or 2; and
R3 is H;
or a salt thereof.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R1 is H or H3C—; or a salt thereof.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R is selected from the group consisting of H, C1-3-alkyl, Cl, (H3C)2N—C(═O)—, HOOC—;
H3C—O— optionally monosubstituted with C1-4-alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl,
wherein the C1-4-alkyl group optionally attached to H3C—O— is optionally monosubstituted with HO— or H3C—S(═O)2—, and
wherein said oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl groups are optionally monosubstituted with H3C—;
tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and
a heteroaryl group selected from pyrazolyl, tetrazolyl, pyridyl, pyridin-2-onyl, pyridazinyl, pyrazinyl, and pyrimidinyl,
wherein each of said heteroaryl groups is optionally monosubstituted with H3C— or H3C—O—, and
wherein each H—N group in said heteroaryl groups is optionally replaced with H3C—N or (H3C)2C(OH)—H2C—N;
R1 is selected from the group consisting of H, F, Cl, H3C—, H3C—H2C—, (H3C)2HC—, F3C—, NC—, and H3C—O—;
m is 2;
R2 is H, F, or F3C—;
n is 1 or 2; and
R3 is H;
or a salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R is selected from the group consisting of H, Cl, H3C—H2C—, (H3C)2N—C(═O)—, HOOC—, H3C—O—,
wherein the asterisk (-*) indicates the site/point of attachment;
R1 is H or H3C—;
m is 2;
R2 is H, F, or F3C—;
n is 1 or 2; and
R3 is H;
or a salt thereof.

### Claim 8 (depends on 1)

The compound according to claim 1, with the structure and stereochemistry shown in formulae I.1, I.2, I.3, I.4, I.5, or I.6
or a salt thereof.

### Claim 9 (depends on 1)

A pharmaceutically acceptable salt of a compound according to claim 1.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising one or more compounds according to claim 1 or one or more pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and/or diluents.

### Claim 11 (depends on 1)

A method for treating a disease or condition which can be influenced by the modulation of the function of GPR40, comprising administering to a patient in need thereof, a pharmaceutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 12

(canceled)

### Claim 13 (depends on 11)

The method according to claim 11, wherein the disease or condition is selected from type 2 diabetes mellitus, insulin resistance, obesity, cardiovascular disease and dyslipidemia.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising one or more compounds according to claim 1 or one or more pharmaceutically acceptable salts thereof and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.

### Claim 15 (depends on 14)

The pharmaceutical composition according to claim 14 wherein one or more additional therapeutic agents is selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity and agents for the treatment of high blood pressure, heart failure and atherosclerosis.