# US 2014/0194436 A1 · Heteroarylmethyl amides

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- Number: US 2014/0194436 A1
- Document ID: US20140194436A1
- Status: Published application
- Kind: A1
- Application number: 14/187,723
- Filed: 2014-02-24
- Published: 2014-07-10
- Earliest claimed: 2010-09-09
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Paul Hebeisen; Hugues Matile; Stephan Roever; Matthew Wright; Sannah Zoffmann Jensen
- Web page: https://patentgrep.com/patent/US20140194436A1

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 9/12: Antihypertensives
- C07D 213/82: in position 3
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of the formula wherein A1, A2, A3 and R1 to R8 are defined in the description, and to pharmaceutically acceptable salts thereof, their manufacture, pharmaceutical compositions containing them and their use as medicaments for the treatment and/or prophylaxis of diseases which can be treated with HDL-cholesterol raising agents, such as particularly dyslipidemia, atherosclerosis and cardiovascular diseases.

## Claims

### Claim 1

A compound of formula I,
wherein:
A1 is N;
A2 and A3 are CH;
R1 is selected from the group consisting of:
lower alkyl,
cycloalkyl,
lower cycloalkylalkyl,
lower hydroxyalkyl,
lower alkoxyalkyl,
lower halogenalkyl,
lower carbamoylalkyl,
lower alkylcarbonylaminoalkyl,
lower phenylalkyl,
lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,
lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di-substituted by lower alkyl, and
phenyl which is unsubstituted or mono- or di-substituted by halogen;
R2 and R6 independently from each other are hydrogen or halogen;
R3 and R5 independently from each other are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;
R4 is selected from the group consisting of hydrogen, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;
or R4 and R5 together with the C atoms they are attached to form a five- or six-membered carbocycle or a five- or six-membered heterocycle containing one, two or three heteroatoms selected from the group consisting of N, O and S, said carbocycle or heterocycle being unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;
R7 and R7′ independently from each other are hydrogen or lower alkyl; and
R8 is a five- or six-membered heteroaryl group containing one, two or three heteroatoms selected from the group consisting of N, O and S, said heteroaryl group being unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein
A1 is N;
A2 and A3 are CH;
R1 is selected from the group consisting of:
lower alkyl,
cycloalkyl,
lower cycloalkylalkyl,
lower hydroxyalkyl,
lower alkoxyalkyl,
lower halogenalkyl,
lower carbamoylalkyl,
lower alkylcarbonylaminoalkyl,
lower phenylalkyl,
lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,
lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di-substituted by lower alkyl, and
phenyl which is unsubstituted or mono- or di-substituted by halogen;
R2 and R6 independently from each other are hydrogen or halogen;
R3 and R5 independently from each other are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;
R4 is selected from the group consisting of hydrogen, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;
R7 and R7′ independently from each other are hydrogen or lower alkyl; and
R8 is a five- or six-membered heteroaryl group containing one, two or three heteroatoms selected from the group consisting of N, O and S, said heteroaryl group being unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R1 is lower cycloalkylalkyl or lower halogenalkyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R2 and R6 are hydrogen.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R3 and R5 are hydrogen.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R4 is halogen.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R7 and R7′ are hydrogen.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R8 is a five-membered heteroaryl group containing one, two or three heteroatoms selected from the group consisting of N, O and S, said heteroaryl group being unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein the five-membered heteroaryl group is selected from the group consisting of oxazolyl, isoxazolyl, pyrazolyl, thiazolyl and [1,2,4]oxadiazolyl, said heteroaryl group being unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl.

### Claim 10 (depends on 1)

The compound according to claim 1, selected from the group consisting of:
6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-amide,
6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-cyclopropyl-isoxazol-5-ylmethyl)-amide,
6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-isopropyl-thiazol-4-ylmethyl)-amide,
6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (5-isopropyl-isoxazol-3-ylmethyl)-amide,
6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (5-isopropyl-isoxazol-3-ylmethyl)-amide,
6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-cyclopropyl-oxazol-4-ylmethyl)-amide,
6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-cyclopropyl-thiazol-4-ylmethyl)-amide,
6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (5-trifluoromethyl-isoxazol-3-ylmethyl)-amide,
6-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-tert-butyl-thiazol-4-ylmethyl)-amide, and
6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-isopropyl-isoxazol-5-ylmethyl)-amide,
and pharmaceutically acceptable salts thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier and/or adjuvant.