Rorgamma modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-11077115-B2
Application number	US-201816481200-A
Country	US
Kind code	B2
Filing date	Jan 29, 2018
Priority date	Jan 27, 2017
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

Abstract

The present invention provides novel compounds of formula (Ia) that are modulators of RORgamma. These compounds, and pharmaceutical compositions comprising the same, are suitable means for treating any disease wherein the modulation of RORgamma has therapeutic effects, for instance in autoimmune diseases, autoimmune-related diseases, inflammatory diseases, metabolic diseases, fibrotic diseases, or cholestatic diseases.

First claim

The invention claimed is:

1. A compound of formula (Ia)

in which,
R1a is a hydrogen atom, 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, 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 a (C1-C6)alkyl group;
wherein at least one of R1a, R1b, and R1c, is a heterocyclic group;
R2 is a (C3-C6)alkyl group, a (C2-C6)alkenyl group, a (C2-C6)alkynyl group, a (C3-C14)cycloalkyl group, a (C6-C14)aryl group optionally substituted by a (C1-C6)alkyl group or a heterocyclic group optionally substituted by a (C1-C6)alkyl group or by a halogen;
R′2 is a hydrogen atom, a (C1-C6)alkyl group, a (C2-C6)alkenyl group, a (C2-C6)alkynyl group, a (C3-C14)cycloalkyl group, a (C6-C14)aryl group optionally substituted by a (C1-C6)alkyl group or a heterocyclic group, optionally substituted by a (C1-C6)alkyl group;
or R2 and R′2 can form, together with the carbon atom to which they are attached, a cycloalkyl group or a heterocycloalkyl group;
L1 is a NR7-CO—CH2, NR7-CO—, NR7-CO—C(CH3)2, CO—NH—CH2, CO—NH or CO—NH—C(CH3)2 group;
R7 represents a hydrogen atom or a (C1-C6)alkyl group;
L2 represents a bond, a (C1-C6)alkyl group, a (C3-C14)cycloalkyl group, or a CR8R′8 group;
with the proviso that when L1 is a NR7-CO— or a CO—NH group, L2 represents a (C1-C6)alkyl group, a (C3-C14)cycloalkyl group, or a CR8R′8 group;
R8 and R′8 are independently, a hydrogen atom, or a (C1-C6)alkyl group;
R8 and R′8 can form, together with the carbon atom to which they are attached, a cycloalkyl group;
X1, X2, X3, X4, X5 are, independently, a carbon, or a nitrogen atom;
X6 represents a CH group or a nitrogen atom;
X7 represents a sulfur atom, a SO2 group, or an oxygen atom; and
R4 is a hydrogen atom; an alkyl group optionally substituted by a hydroxy group or an alkoxy group; a halogen atom; an alkyloxy group or a hydroxy group.

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

3. The compound according to claim 1 , wherein:
R1a is a piperidinyl group, a morpholinyl group, an azabicyclohexanyl group or an azepanyl group, wherein said piperidinyl, pyrrolidinyl or azepanyl group can be optionally substituted by at least one (C1-C6)alkyl groups;
R1b is a hydrogen atom;
R1c is a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, or a (C1-C6)alkyloxy group;
R2 is an aryl group or a heteroaryl group; and
R′2 is a hydrogen atom.

4. The compound according to claim 1 , wherein X6 is a nitrogen atom and X7 is a SO2 group or an oxygen atom.

5. The compound according to claim 1 , wherein L1 is a NR7-CO— group and L2 is a CR8R′ 8 group.

6. The compound according to claim 1 , wherein:
R1a is a halogen atom, a (C1-C6)alkyl group optionally substituted by halogen atom, a (C1-C6)dialkylamino group, a piperidinyl group, a morpholinyl group, an azabicyclohexanyl group or an azepanyl group, wherein said piperidinyl, morpholinyl, azabicyclohexanyl or azepanyl 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, or a (C1-C6)alkoxy group;
R1d and R1e are hydrogen atoms;
R2 is a phenyl group or a heterocyclic group;
L1 represents a NH—CO— group;
L2 represents a CH2 group or a group of formula (III) or of formula (IV)

R4 is a hydrogen atom, a halogen atom, a (C1-C6)alkyl group or a (C1-C6)alkoxy group;
the cycle

is a substituent of X3 (in meta or para position of the L1-L2 group); and
X6 is a nitrogen atom and X7 is a SO2 group or an oxygen atom.

7. The compound according to claim 1 , wherein:
R1a is a heterocyclic group;
R1c is a (C1-C6)alkyl group;
R2 is a heterocyclic group;
L1 represents a NH—CO— group;
L2 represents a CH2 group;
R4 is a hydrogen atom;
the cycle

is a substituent of X1, X2 or X3 (in meta or para position of the L1-L2 group); and
X6 is a nitrogen atom and X7 is a SO2 group.

8. The compound according to claim 1 , characterized in that it is selected in the group consisting of:
2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;
2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;
2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-2-fluorophenyl]-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;
2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-2-fluorophenyl]-N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}acetamide;
2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]-N-{[4-methyl-2-(morpholin-4-yl)phenyl](phenyl)methyl}acetamide;
2-[2-fluoro-5-(morpholin-4-yl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}acetamide;
2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylphenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylphenyl]-N-{[4-methoxy-2-(4-methylpiperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylphenyl]-N-({4-methoxy-2-[4-(trifluoromethyl)piperidin-1-yl]phenyl}(5-methylfuran-2-yl)methyl)acetamide;
N-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-methoxyphenyl)(5-methylfuran-2-yl)methyl]-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylphenyl]acetamide;
2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]-N-{[5-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
N-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-methylphenyl)(phenyl)methyl]-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]acetamide;
N-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-methylphenyl)(phenyl)methyl]-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylphenyl]acetamide;
N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[6-(morpholin-4-yl)pyridin-3-yl]a

Assignees

• Genfit

Inventors

• Delhomel Jean-Francois
• Perspicace Enrico
• Majd Zouher
• Parroche Peggy
• Walczak Robert
• Bonnet Pascal
• Fogha Jade

Classifications

• A61K31/192

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

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C07D307/54

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title