Pyridinylmethyl carbamimidoylcarbamate derivatives and their use as AOC3 inhibitors

Patent metadata

Field	Value
Publication number	US-10730850-B2
Application number	US-201616080328-A
Country	US
Kind code	B2
Filing date	Mar 3, 2016
Priority date	Mar 3, 2016
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

The invention relates to new heteroaryl derivatives of the formula wherein X is selected from the group consisting of: N and CH; X is selected from the group consisting of: N and CF; (with the proviso that at least one of X 1 and X 2 is N), and A is as defined in the description and claims, to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
X 1 is selected from the group X 1 -G1 consisting of: N and CH;
X 2 is selected from the group X 2 -G1 consisting of: N and CF;
with the proviso that at least one of X 1 and X 2 is N;
A is selected from the group A-G1 consisting of:

R 4 is selected from the group R 4 -G1 consisting of: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, oxazolidinyl, C 3-8 -cycloalkyl, phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, [1,3,5]triazinyl, triazolyl, thiazolyl, imidazo[1,2-a]pyridin-2-yl, 2,3-dihydro-1H-isoindolyl, oxazolyl and oxadiazolyl,
wherein each R 4 is optionally substituted with one or more groups independently of each other selected from the group consisting of halogen, OH, CO 2 H, CN, CF 3 , C 1-3 -alkyl, C 3_6 -cycloalkyl, C 1-3 -alkyl-O—, (R N ) 2 N—, C 1-3 -alkyl-C(═O)—, C 1-4 -alkyl-O—C(═O)—, (R N ) 2 N—C(═O)—, (R N ) 2 N—C 1-3 -alkyl-, C 3-6 -cycloalkyl-C 1-3 -alkyl-O—, C 1-3 -alkyl-SO 2 —, (R N ) 2 N—SO 2 —, 2-oxo-pyrrolidinyl and C 1-3 -alkyl-C(═O)—(R N )N—C 1-3 -alkyl-; and
wherein a —CH 2 — group of the pyrrolidinyl, 2,3-dihydro-1H-isoindolyl, oxazolidinyl, piperidinyl or piperazinyl group of R 4 is optionally replaced with a —C(═O), —S(═O)— or —S(═O) 2 — group;

R N is selected from the group R 4 -G1 consisting of: H and C 1-4 -alkyl, wherein, if several R N groups are present, they may be identical or different from one another;
R 5 is selected from the group R 5 -G1 consisting of: CN and OH;
or, R 4 and R 5 groups together with the carbon atom, to which they are attached, may form the following group:

wherein each of the above-mentioned alkyl and —O-alkyl groups may be linear or branched and are optionally substituted by one or more F;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein A is

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 , wherein A is

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein R 4 is selected from the group consisting of:
azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, oxazolidinyl, C 3-8 -cycloalkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, [1,3,5]triazinyl, thiazolyl, 2,3-dihydro-1H-isoindolyl and oxazolyl,
wherein each R 4 is optionally substituted with one or more groups independently of each other selected from the group consisting of halogen, CO 2 H, CN, CF 3 , C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-C(═O)—, C 1-4 -alkyl-O—C(═O)—, (R N ) 2 N—C(═O)—, (R N ) 2 N—C 1-3 -alkyl-, C 3-6 -cycloalkyl-C 1-3 -alkyl-O—, C 1-3 -alkyl-SO 2 —, (R N ) 2 N—SO 2 — and 2-oxo-pyrrolidinyl; and
wherein a —CH 2 — group of the 2,3-dihydro-1H-isoindolyl, oxazolidinyl, piperidinyl or piperazinyl group of R 4 is optionally replaced with a —C(═O)—, —S(═O)— or —S(═O) 2 — group;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4 , wherein R 4 is selected from the group consisting of:
piperidinyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl and 2,3-dihydro-1H-isoindolyl,
wherein each R 4 is optionally substituted with one or more groups independently of each other selected from the group consisting of halogen, CN, C 1-3 -alkyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-C(═O)—, C 1-4 -alkyl-O—C(═O)—, (R N ) 2 N—C(═O)—, C 1-3 -alkyl-SO 2 — and (R N ) 2 N—SO 2 —; and
wherein a —CH 2 — group of the 2,3-dihydro-1H-isoindolyl of R 4 is optionally replaced with a —C(═O)— group; and

R N is H or CH 3 ;
or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein
X 1 is N and X 2 is CF;
or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein
X 1 is N and X 2 is CF;
A is selected from the group consisting of:

R 4 is selected from the group consisting of: azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, oxazolidinyl, C 3-8 -cycloalkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, [1,3,5]triazinyl, thiazolyl, 2,3-dihydro-1H-isoindolyl and oxazolyl,
wherein each R 4 is optionally substituted with one or more groups independently of each other selected from the group consisting of halogen, CO 2 H, CN, CF 3 , C 1-3 -alkyl, C 3-6 -cycloalkyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-C(═O)—, C 1-4 -alkyl-O—C(═O)—, (R N ) 2 N—C(═O)—, (R N ) 2 N—C 1-3 -alkyl-, C 3-6 -cycloalkyl-C 1-3 -alkyl-O—, C 1-3 -alkyl-SO 2 —(R N ) 2 N—SO 2 — and 2-oxo-pyrrolidinyl; and
wherein a —CH 2 — group of the 2,3-dihydro-1H-isoindolyl, oxazolidinyl, piperidinyl or piperazinyl group of R 4 is optionally replaced with a —C(═O)— or —S(═O)— group;

R N is H or CH 3 , wherein, if several R N groups are present, they may be identical or different from one another; and
R 5 is CN;
or, R 4 and R 5 groups together with the carbon atom, to which they are attached, may form the following group:

wherein each of the above-mentioned alkyl and —O-alkyl groups may be linear or branched and are optionally substituted by one or more F;
or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein
X 1 is N and X 2 is CF, or
X 1 is CH and X 2 is N, or
X 1 is N and X 2 is N;
A is

R 4 is selected from the group consisting of piperidinyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl and 2,3-dihydro-1H-isoindolyl,
wherein each R 4 is optionally substituted with one substituent selected from the group consisting of F, Cl, CN, CH 3 , CF 3 , —CH 2 CH 3 , —CH 2 —N(CH 3 ) 2 , —CO 2 H, —(C═O)—O—CH 3 , —C(═O)—CH 3 , —C(═O)—NH 2 , —C(═O)—N(CH 3 ) 2 , —SO 2 —NH 2 and —SO 2 —CH 3 ;
or wherein R 4 may be substituted with two substituents, which are independently of each other selected from the group consisting of F, CN and CH 3 ;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 selected from:

or a pharmaceutically acceptable salt thereof.

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

11. A method for therapeutically treating NASH (non-alcoholic steatohepatitis), retinopathy or nephropathy, the method comprising administering a compound according to claim or a pharmaceutically acceptable salt thereof, to a patient in need the

Assignees

• Boehringer Ingelheim Int

Inventors

• Himmelsbach Frank
• Blum Andreas
• Peters Stefan

Classifications

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D213/84

  Nitriles · CPC title

• C07D213/85

  in position 3 · CPC title

• C07D213/72

  Nitrogen atoms (nitro radicals C07D213/61) · CPC title