N-{[2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide derivatives and related compounds as ROR-gamma modulators for treating autoimmune diseases

Patent metadata

Field	Value
Publication number	US-11052092-B2
Application number	US-201816481233-A
Country	US
Kind code	B2
Filing date	Jan 29, 2018
Priority date	Jan 27, 2017
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

Abstract

The present invention provides e.g. N-{[2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide derivatives and related compounds as ROR-gamma modulators for treating e.g. autoimmune diseases, autoimmune-related diseases, inflammatory diseases, metabolic diseases, fibrotic diseases or cholestatic diseases, such as e.g. arthitis and asthma.

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

in which,
A is a C-R1e group;
R1a is a halogen atom, a nitrile group, a nitro group (NO2), a (C1-C6) alkyl group, a (C1-C6) alkyloxy group, a (C1-C6) alkylthio group, a —NH2 group, a (C1-C6) alkylamino group, a (C1-C6)dialkylamino group or a heterocyclic group;
R1b is a hydrogen atom, a (C1-C6)alkyloxy group, a (C1-C6)alkyl group or a heterocyclic group;
R1c is a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, a (C1-C6)alkyloxy group, a (C1-C6)alkylthio group, a heterocyclic group, a cyano group, an amido group or a hydroxyl group;
R1d and R1e are, independently, a hydrogen atom, a halogen atom, a (C1-C6)alkyloxy group or an (C1-C6)alkyl group;
R2 is an unsubstituted, branched (C3-C6)alkyl group; an (C2-C6)alkynyl group; a (C3-C14)cycloalkyl group; an (C6-C14)aryl group optionally substituted by a (C1-C6)alkyl group or a halogen; a 5-membered heteroaryl group containing an oxygen or a nitrogen atom optionally substituted by a (C 1 -C 6 )alkyl group or a halogen; or a 6-membered heteroaryl group containing at least one nitrogen atom optionally substituted by a (C 1 -C 6 )alkyl group or a halogen;
R′2 is a hydrogen atom; an (C1-C6)alkyl group; an (C2-C6)alkynyl group; a (C3-C14)cycloalkyl group; a (C6-C14)aryl group optionally substituted by a (C 1 -C 6 )alkyl group or a halogen; or a heterocyclic group optionally substituted by a (C1-C6)alkyl group or a halogen;
or R2 and R2′ can form, together with the carbon atom to which they are attached, a cycloalkyl group or a heterocycloalkyl group;
L1 is a —NH—CO— or —CO—NH— group;
L2 represents a CR4R′4 group;
R4 and R′4 are independently, a hydrogen atom or a (C1-C6)alkyl group;
or R4 and R′4 can form, together with the carbon atom to which they are attached, a cycloalkyl group;
HET is one of the following bicyclic groups:

2. The compound according to claim 1 , wherein:
R1a is a halogen atom, a nitrile group, a nitro group (NO2), a (C1-C6)alkyl group, a (C1-C6) alkyloxy group, a (C1-C6)alkylthio group, an amino group, a (C1-C6) alkylamino group, a (C1-C6)dialkylamino group, a piperidinyl group, a pyrrolidinyl group, an azepanyl, piperazinyl, or morpholinyl group, wherein said piperidinyl, pyrrolidinyl, azepanyl, piperazinyl, or morpholinyl group can be optionally substituted by at least one (C1-C6)alkyl groups.

3. The compound according to claim 1 , wherein:
R1a is a halogen atom, a (C1-C6) alkyl group, a piperidinyl group (such as a piperidin-1-yl group), a morpholinyl group (such as morpholin-4-yl group), a piperazinyl group (such as a piperazin-1-yl), an azepanyl group (such as an azepan-1-yl) or a pyrrolidinyl group (such as a pyrrolidin-1-yl group).

4. The compound according to claim 1 , wherein:
R1a is a halogen atom, a nitrile group, a nitro group (NO2), a (C1-C6)alkyl group, a (C1-C6)alkyloxy group, a (C1-C6)alkylthio group, an amino group, a (C1-C6)alkylamino group, a (C1-C6)dialkylamino group, a piperidinyl group, a pyrrolidinyl group, an azepanyl group, wherein said piperidinyl, pyrrolidinyl, azepanyl, piperazinyl, or morpholinyl group can be optionally substituted by at least one (C1-C6)alkyl groups;
R1b is a hydrogen atom;
R1c is a hydrogen atom, a (C1-C6)alkyl group, or a (C1-C6)alkyloxy group;
R1d is a hydrogen atom;
R1e is a hydrogen atom;
R2 is a (C3-C6)alkyl group, an (C6-C14)aryl group, or a heteroaryl group, and R′2 is a hydrogen atom.

5. The compound according to claim 1 , wherein:
R1a is a halogen atom (such as bromine), a (C1-C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), a piperidinyl group, a pyrrolidinyl group, an azepanyl group, wherein said piperidinyl, pyrrolidinyl, azepanyl, piperazinyl, or morpholinyl group can be optionally substituted by at least one (C1-C6)alkyl groups;
R1b is a hydrogen atom;
R1c is a hydrogen, a (C1-C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group), or a (C1-C6)alkoxy group (such as a methoxy or a an ethoxy group, in particular a methoxy group);
R1d and R1e are hydrogen atoms;
R2 is a (C3-C6)alkyl group (such as an isobutyl group), a phenyl group or a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5-methylfuranyl group or a 5-ethylfuranyl group, more particularly a 5-methylfuran-2-yl group);
L1 represents a NH—CO— group,
L2 is a CH2 group or a cyclopropyl group of formula (III)

HET is chosen in the list:

6. The compound according to claim 1 , wherein:
R1a is a heterocyclic group (in particular a piperidinyl group (such as a piperidin-1-yl group)) or a (C1-C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);
R1c is a (C1-C6)alkyl group (such as a methyl or ethyl group, in particular a methyl group);
R2 is a heterocyclic group (such as a substituted or unsubstituted furanyl group, in particular a 5-methylfuranyl group or a 5-ethylfuranyl group or a 5-chlorofuranyl, more particularly a 5-chlorofuran-2-yl group);
L1 represents a NH—CO— group, L2 is a CR4R′4 group (such as a cyclopropyl group of formula (III) or cyclobutyl of formula (IV)

7. The compound according to claim 1 , wherein:
R1a represents a halogen, in particular a bromine atom; a (C1-C6)alkyl group, in particular a methyl group; a heterocyclic group, in particular a piperadin-1-yl group, a piperazin-1-yl group, or an azepan-1-yl group; a di(C1-C6)alkylamaino group, in particular a N(CH3)2 group;
R1b, R1d and R1e represent hydrogen atoms;
R1c is a (C1-C6)alkyl group, in particular a methyl group, or a (C1-C6)alkyloxy group, in particular a methoxy group;
R2 represents a 5 membered heteroaryl group containing an oxygen or a nitrogen atom optionally substituted by a (C 1 -C 6 )alkyl group or a halogen, in particular a furan-1-yl group, a 5-methylfuran-2-yl group or a 5-chlorofuran-2-yl group; a (C6-C14)aryl group optionally substituted by a (C 1 -C 6 )alkyl group, in particular a phenyl group optionally substituted by one or more methyl group or by a chlorine atom; or a heterocyclic group optionally substituted by a (C 1 -C 6 )alkyl group, in particular a 6-methylpyridin-2-yl;
R′2 is a hydrogen atom;
L1 represents a NH—CO group; and
L2 represents a (C1-C6)alkyl group, in particular a CH2- group, or a CR4R′4 group, in particular a cyclopro

Assignees

• Genfit

Inventors

• Delhomel Jean-Francois
• Perspicace Enrico
• Majd Zouher
• Parroche Peggy
• Walczak Robert

Classifications

• A61K31/192

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• C07D215/48

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/39

  having oxygen in the same ring · CPC title