IP Library › Granted Patent US 11,052,092
Granted Patent B2
US 11,052,092 · App. 16/481,233 · Granted Jul 6, 2021

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

Inventors: Jean-Francois Delhomel (Arras, FR); Enrico Perspicace (Phalempin, FR); Zouher Majd (Ennetieres-en-Weppes, FR); Peggy Parroche (Loos, FR); Robert Walczak (Lille, FR)
Assignee: Genfit
A61K31/536A61K31/192A61K31/357A61K31/39A61K31/40A61K31/405A61K31/428A61K31/4439A61K31/454A61K31/47A61K31/4709A61K31/498A61K31/5377A61P37/02C07D215/227C07D401/12C07D405/12C07D405/14C07D407/12C07D411/12C07D411/14C07D413/12C07D413/14C07D417/12C07D417/14
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Quick Facts
Patent No.
US 11,052,092
App. No.
16/481,233
Granted
Jul 6, 2021
Kind
B2
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.

Claims (238)

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 cyclopropyl group of formula (III)

8. 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, or a piperazin-1-yl group;

R1b, R1d and R1e represent a hydrogen atom;

R1c is a (C1-C6)alkyl group, in particular a methyl group;

R2 represents a 5 membered heteroaryl group containing an oxygen or a nitrogen atom optionally substituted by a (C1-C6)alkyl group or a halogen, in particular a 5-methylfuran-2-yl group or a 5-chlorofuran-2-yl group;

R′2 is a hydrogen atom;

L1 represents a NH—CO group;

L2 represents a (C1-C6)alkyl group, in particular a CH2- group, or a CR4R′4 group, in particular a cyclopropyl group of formula (III)

and

HET is HET1, HET6, HET30, HET38, HET44, HET47, HET67 or HET77.

9. The compound according to claim 1 , characterized in that it is selected from:

N-{[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;

N-{[4-methoxy-2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-{phenyl[2-(pyrrolidin-1-yl)phenyl]methyl}acetamide;

N-{3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

N-{[2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)acetamide;

N-[(2,4-dimethylphenyl)(phenyl)methyl]-2-(4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)acetamide;

N-{[4-methoxy-2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(4-methyl-2-oxo-1,2-dihydroquinolin-6-yl)acetamide;

2-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;

2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;

2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;

2-(2-oxo-2,3-dihydro-1H-indol-5-yl)-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

N-{[2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;

2-(2,3-dioxo-2,3-dihydro-1H-indol-5-yl)-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;

2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}acetamide;

2-(2,3-dioxo-2,3-dihydro-1H-indol-5-yl)-N-{[4-methoxy-2-(piperidin-1-yl)phenyl](phenyl)methyl}acetamide;

2-(2,3-dioxo-2,3-dihydro-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;

2-(2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-N-{[4-methoxy-2-(morpholin-4-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

N-[(2,4-dimethylphenyl)(5-ethylfuran-2-yl)methyl]-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

N-[(2-bromo-4-methoxyphenyl)(5-methylfuran-2-yl)methyl]-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)acetamide;

2-(3-hydrazinylidene-2-oxo-2,3-dihydro-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

2-(3-hydroxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

2-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-[3-(hydroxyimino)-2-oxo-2,3-dihydro-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-{3-[(dimethyl-1,2-oxazol-4-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-{3-[(2-amino-1,3-thiazol-5-yl)methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(1-methyl-2,3-dioxo-2,3-dihydro-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[(3E)-3-(2-methylpropylidene)-2-oxo-2,3-dihydro-1H-indol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-(3-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

2-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-(1-oxo-2,3-dihydro-1H-inden-5-yl)acetamide;

2-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(3-hydroxy-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-(7-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[2-oxo-3-(propan-2-ylidene)-2,3-dihydro-1H-indol-5-yl]acetamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)cyclopropane-1-carboxamide;

2-[3-(2-hydroxyethyl)-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-[3-(hydroxymethyl)-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[3-(2-hydroxyethyl)-1H-indol-5-yl]cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(2-oxo-2,3-dihydro-1H-indol-5-yl)cyclopropane-1-carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1-[3-(2-hydroxyethyl)-1H-indol-5-yl]cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)cyclopropane-1-carboxamide;

2-(3-methyl-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)cyclopropane-1-carboxamide;

1-[3-(2-hydroxyethyl)-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-(3-oxo-2,3-dihydro-1H-inden-5-yl)acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl]acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[1-(2-hydroxyethyl)-1H-indol-5-yl]cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(1-methyl-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)cyclopropane-1-carboxamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl)methyl}-1-(2,2-dioxo-1,3-dihydro-2, 1-benzothiazol-5-yl)cyclopropane-1-carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1-(2,2-dioxo-1,3-dihydro-2-benzothiophen-5-yl)cyclopropane-1-carboxamide;

1-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)-N-{[4-methyl-2-(pyrrolidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(2,2-dioxo-1,3-dihydro-2-benzothiophen-5-yl)cyclopropane-1-carboxamide;

2-(2-methyl-1H-1,3-benzodiazol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}acetamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl)methyl}-1-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)cyclopropane-1-carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(2-methyl-1H-1,3-benzodiazol-5-yl)acetamide;

2-(2,2-dioxo-1,3-dihydro-2-benzothiophen-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1-yl)phenyl]methyl]-2-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)acetamide;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1-yl)phenyl]methyl]-1-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-yl)cyclopropane-1-carboxamide;

N-[(2-bromo-4-methylphenyl)(phenyl)methyl]-2-(2-methyl-1H-1,3-benzodiazol-5-yl)acetamide;

2-(2-methyl-1H-1,3-benzodiazol-5-yl)-N-{[4-methyl-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl}acetamide;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1-yl)phenyl]methyl]-2-(2-oxo-2,3-dihydro-1H-indol-5-yl)acetamide;

2-[(3Z)-3-hydrazinylidene-2-oxo-2,3-dihydro-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1-(2-oxo-2,3-dihydro-1H-indol-5-yl)cyclopropane-1-carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1-(2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)cyclopropane-1-carboxamide;

2-(1H-indol-6-yl)-N-((4-methyl-2-(piperidin-1-yl)phenyl)(5-methylfuran-2-yl)methyl)acetamide;

2-[3-(hydroxymethyl)-1H-indol-6-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

1-(1H-indol-5-yl)-N-((4-methyl-2-(piperidin-1-yl)phenyl)(5-methylfuran-2-yl)methyl)cyclopropanecarboxamide;

1-[3-(hydroxymethyl)-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;

N-[(2-bromo-4-methylphenyl)(phenyl)methyl]-2-(2-ethoxy-1H-1,3-benzodiazol-5-yl)acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[6-(methylsulfanyl)naphthalen-2-yl]acetamide;

N-[(2-bromo-4-methylphenyl)(phenyl)methyl]-2-[2-(ethylsulfanyl)-1H-1,3-benzodiazol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[2-(morpholin-4-yl)-1H-1,3-benzodiazol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[3-(morpholin-4-ylmethyl)-1H-indol-5-yl]acetamide;

1-(1-cyclopropanecarbonyl-2,3-dihydro-1H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

tert-butyl 3-{5-[({[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]-1H-indol-1-yl}propanoate;

3-{5-[({[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]1H-indol-1-yl}propanoic acid;

2-[3-(2-methanesulfonylethyl)-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

tert-butyl 3-[5-({[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}methyl)-1H-indol-1-yl]propanoate;

tert-butyl 3-[5-({[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}methyl)-1H-indol-1-yl]propanoate;

3-[5-({[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}methyl)-1H-indol-1-yl]propanoic acid;

3-[5-({[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}methyl)-1H-indol-1-yl]propanoic acid;

2-[3-(2-methanesulfonylacetyl)-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[3-(2-methanesulfonylacetyl)-1H-indol-5-yl]acetamide;

2-(1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

2-(1-methanesulfonyl-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[3-(2-methanesulfonylacetyl)-1H-indol-5-yl]acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(1H-indol-5-yl)cyclopropane-1-carboxamide;

tert-butyl 3-{5-[({[2-(azepan-1-yl)-4-methoxyphenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]-1H-indol-1-yl}propanoate;

3-{5-[({[2-(azepan-1-yl)-4-methoxyphenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]-1H-indol-1-yl}propanoic acid;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(pyrrolidin-1-yl)phenyl]methyl]-2-[3-(2-methanesulfonylethyl)-1H-indol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1-(oxan-4-ylmethyl)-1H-indol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1-(morpholine-4-carbonyl)-1H-indol-6-yl]acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[3-(methylsulfamoyl)-1H-indol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1-(morpholine-4-carbonyl)-1H-indol-5-yl]acetamide;

2-[3-(2-methanesulfonylacetyl)-1H-indol-6-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1-(oxane-4-carbonyl)-1H-indol-5-yl]acetamide;

1-[3-(methanesulfonamidomethyl)-1H-indol-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[3-(morpholine-4-carbonyl)-1H-indol-5-yl]acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[2-(2-methoxyacetyl)-2,3-dihydro-1H-isoindol-5-yl]cyclopropane-1-carboxamide;

2-(1-cyclopropanecarbonyl-2,3-dihydro-1H-indol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6-yl)cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(2,3-dioxo-2,3-dihydro-1H-indol-5-yl)cyclopropane-1-carboxamide;

1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

1-(2-acetyl-2,3-dihydro-1H-isoindol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)cyclopropane-1-carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1-(2,2-dioxo-1,3-dihydro-4,2, 1-benzoxathiazin-6-yl)cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(1-ethyl-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)cyclopropane-1-carboxamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl)methyl}-1-(1-methyl-2,2-dioxo-1,3-dihydro-2, 1-benzothiazol-5-yl)cyclopropane-1-carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(6-methylpyridin-2-yl)methyl]-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

1-(2H-1,3-benzodioxol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(furan-2-yl)methyl]-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

N-[(4-chlorophenyl)(2,4-dimethylphenyl)methyl]-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(1-oxo-2,3-dihydro-1H-inden-5-yl)cyclopropane-1-carboxamide;

1-(2,3-dihydro-1H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

N-[(3-chlorophenyl)(2,4-dimethylphenyl)methyl]-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-{2-oxo-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-6-yl}cyclopropane-1-carboxamide;

N-[(5-chlorofuran-2-yl)[4-methyl-2-(piperidin-1-yl)phenyl]methyl]-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

1-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

N-[(2-bromo-4-methoxyphenyl)(5-methylfuran-2-yl)methyl]-1-(2,2-dioxo-1,3-dihydro-4,2, 1-benzoxathiazin-6-yl)cyclopropane-1-carboxamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl)methyl}-1-(2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6-yl)cyclopropane-1-carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1-(2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6-yl)cyclopropane-1-carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-(2,2-dioxo-1,3-dihydro-4,2, 1-benzoxathiazin-6-yl)acetamide;

3-[5-(1{[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]carbamoyl}cyclopropyl)-1H-indol-1-yl]propanoic acid;

3-{5-[1-({[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)cyclopropyl]-1H-indol-1-yl}propanoic acid;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)cyclopropane-1-carboxamide;

N-{[2-(dimethylamino)-4-methylphenyl](5-methylfuran-2-yl)methyl}-1-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl]cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)cyclopropane-1-carboxamide;

1-(3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

N-[(5-chlorofuran-2-yl)(2,4-dimethylphenyl)methyl]-1-(1-methyl-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl)cyclopropane-1-carboxamide;

1-(2H-1,3-benzodioxol-5-yl)-N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-1-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl]cyclopropane-1-carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl]cyclopropane-1-carboxamide;

1-(2H-1,3-benzodioxol-5-yl)-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl]acetamide;

N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[1-(oxan-4-ylmethyl)-2,2-dioxo-1,3-dihydro-2,1-benzothiazol-5-yl]acetamide;

1-(2,2-dimethyl-2,4-dihydro-1,3-benzodioxin-7-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

1-(2,2-dimethyl-2,4-dihydro-1,3-benzodioxin-6-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[3-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl]cyclopropane-1-carboxamide;

1-(2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6-yl)-N-{[4-methyl-2-(trifluoromethyl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;

N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-(1-methyl-2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6-yl)cyclopropane-1-carboxamide;

N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1-(1-methyl-2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6-yl)cyclopropane-1-carboxamide;

1-(2,2-dioxo-1,3-dihydro-4,2,1-benzoxathiazin-6-yl)-N-[(2-methoxy-4-methylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide; and

1-(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide.

10. A combination product comprising:

i) a compound of formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof; and

ii) another therapeutically active agent, such as a PPAR activator.

11. The combination product according to claim 10 , component ii) is Elafibranor or seladelpar, saroglitazar, lanifibranor, pioglitazone or a pharmaceutically acceptable salt thereof.

12. The combination product according to claim 10 , wherein the combination product is a composition comprising components i) and ii) and a pharmaceutically acceptable carrier.

13. The combination product according to claim 10 , wherein the combination product is a kit of parts comprising components i) and ii), for sequential, separate or simultaneous use.

14. The combination product according to claim 10 , wherein components i) and ii) are formulated in an injectable suspension, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, an ointment, a cream, a patch, or means of galenic forms for a prolonged and/or slow release.

15. A method for the treatment of an autoimmune disease, an autoimmune-related disease, an inflammatory disease, a metabolic disease, a fibrotic disease or a cholestatic disease, wherein said method comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

16. A method for the treatment of an autoimmune disease, an autoimmune-related disease, an inflammatory disease, a metabolic disease, a fibrotic disease or a cholestatic disease, wherein said method comprises administering to a subject in need thereof a therapeutically effective amount of the combination product according to claim 10 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 1, 2019
From: DELHOMEL, JEAN-FRANCOIS; PERSPICACE, ENRICO; MAJD, ZOUHER; PARROCHE, PEGGY; WALCZAK, ROBERT
To: GENFIT
Reel/Frame 050888/0923 →
Priority Claims (2)
EP 17305093 · Jan 27, 2017 · regional
EP 17178888 · Jun 29, 2017 · regional
Continuity (1)
Related Publication 20190365768A1 · Dec 5, 2019
Cited By (3)
US 12,448,369 US 12,509,431 US 12,559,464