RORgamma modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-10987351-B2
Application number	US-201816481140-A
Country	US
Kind code	B2
Filing date	Jan 29, 2018
Priority date	Jan 27, 2017
Publication date	Apr 27, 2021
Grant date	Apr 27, 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, a —NH 2 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 R1a, R1b, R1c, R1d, and R1e is not a hydrogen atom;
R2 is 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 or a heterocyclic group optionally substituted by a (C1-C6)alkyl group,
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 by a halogen atom; or a heterocyclic group optionally substituted by a (C1-C6)alkyl group or by a halogen atom,
or R2 and R′2 can form, together with the carbon atom to which they are attached, a (C3-C14)cycloalkyl group or a heterocycloalkyl group;
L is a NR7-CO—CH2, NR7-CO-C(CH3)2, CO—NH—CH2, or CO—NH-C(CH3)2 group, a NR7-CO—(C1-C6)alkyl group, a NR7-CO—(C3-C14)cycloalkylgroup, or a NR7-CO—CR5R′5 group;
R5 and R′5 are independently, a hydrogen atom, or a (C1-C6)alkylgroup;
or R5 and R′5 can form, together with the carbon atom to which they are attached, a cycloalkyl group;
each of X1 and X2 is a nitrogen atom;
R3 is a hydrogen atom, a (C1-C6)alkyl group, a carbonyl(C1-C6)alkyl group, a SO2R′ group, a COOR′ group, an amido group, a (C1-C6)alkylamido group, or a (C1-C6)dialkylamido group;
R′ is a (C1-C6)alkyl group;
R4 is a hydrogen atom, a (C1-C6)alkyl group, or a halogen atom;
R7 is an hydrogen atom or a (C1-C6)alkyl 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, a (C1-C6)alkyloxy group, a (C1-C6)alkylthio group, a —NH 2 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 R1a, R1b, R1c, R1d, and R1e is not a hydrogen atom;
R2 is 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 or a heterocyclic group optionally substituted by a (C1-C6)alkyl group,
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 by a halogen atom; or a heterocyclic group optionally substituted by a (C1-C6)alkyl group or by a halogen atom,
or R2 and R′2 can form, together with the carbon atom to which they are attached, a (C3-C14)cycloalkyl group or a heterocycloalkyl group;
L is a NR7-CO—CH2, NR7-CO—C(CH3)2, CO—NH—CH2, or CO—NH—C(CH3)2 group;
R3 is a hydrogen atom, a (C1-C6)alkyl group, a carbonyl(C1-C6)alkyl group, a SO2R′ group, a COOR′ group, an amido group, a (C1-C6)alkylamido group, or a (C1-C6)dialkylamido group;
R′ is a (C1-C6)alkyl group;
R4 is a hydrogen atom, a (C1-C6)alkyl group, or a halogen atom;
R7 is an hydrogen atom or a (C1-C6)alkyl group.

3. 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, a (C1-C6)alkyloxy group, a (C1-C6)alkylthio group, a —NH 2 amino group, a (C1-C6)alkylamino group, a (C1-C6)dialkylamino group, a piperidinyl group, a pyrrolidinyl group, or an azepanyl group, wherein said piperidinyl, pyrrolidinyl or azepanyl group can be optionally substituted by at least one (C1-C6)alkyl group;
R1b is a hydrogen atom;
R1c is a hydrogen atom, a (C1-C6)alkyl group, or a (C1-C6)alkyloxy group; and
R2 is a (C1-C6)alkyl group, a (C3-C14)cycloalkyl group, a (C6-C14)aryl group, or a heteroaryl group, and R′2 is a hydrogen atom.

4. The compound according to claim 1 , wherein L is a NR7-CO—CH2, NR7-CO—C(CH3)2, CO—NH—CH2, or CO—NH—C(CH3)2 group.

5. The compound according to claim 1 , wherein R1b is a hydrogen atom.

6. The compound according to claim 1 , wherein R1d and R1e are hydrogen atoms.

7. The compound according to claim 1 , wherein
R1a is a heterocyclic group,
R1c is a hydrogen atom, a (C1-C6)alkyl group, or a (C1-C6)alkyloxy group,
R2 is a (C1-C6)alkyl, a phenyl or a heterocyclic group,
L represents a NH—CO—CH2 group,
R4 is a hydrogen, or a (C1-C6)alkyl group or a halogen in ortho of the L group, the cycle

is in meta or para position of the L group,
R3 represents a hydrogen atom, a carbonyl(C1-C6)alkyl group, a SO2R′ group, or a COOR′ group.

8. The compound according to claim 1 , characterized in that it is selected from:
2-[4-(4-acetylpiperazin-1-yl)phenyl]-N-{phenyl[2-(piperidin-1-yl)phenyl]methyl}acetamide;
2-[4-(4-acetylpiperazin-1-yl)phenyl]-N-{3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl}acetamide;
2-[5-(4-acetylpiperazin-1-yl)-2-methylphenyl]-N-{[4-methyl-2-(pyrrolidin-1-yl)phenyl](phenyl)methyl}acetamide;
tert-butyl 4-{4-fluoro-3-[({[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}carbamoyl)methyl]phenyl}piperazine-1-carboxylate;
tert-butyl 4-{4-methyl-3-[({[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}carbamoyl)methyl]phenyl}piperazine-1-carboxylate;
N-{[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-[2-methyl-5-(piperazin-1-yl)phenyl]acetamide;
2-[2-fluoro-5-(piperazin-1-yl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}acetamide;
tert-butyl 4-{4-methyl-3-[({[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}carbamoyl)methyl]phenyl}piperazine-1-carboxylate;
N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[2-methyl-5-(piperazin-1-yl)phenyl] acetamide;
2-[5-(4-acetylpiperazin-1-yl)-2-methylphenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[5-(4-acetylpiperazin-1-yl)-2-methylphenyl]-N-{[2-(azepan-1-yl)-4-methoxyphenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[5-(4-acetylpiperazin-1-yl)-2-fluorophenyl]-N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]acetamide;
2-[5-(4-acetylpiperazin-1-yl)-2-fluorophenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](phenyl)methyl}acetamide;
2-[5-(4-acetylpiperazin-1-yl)-2-fluorophenyl]-N-{[2-(azepan-1-yl)-4-methoxyphenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[5-(4-acetylpiperazin-1-yl)-2-methylphenyl]-N-{[2-(azepan-1-yl)-4-methoxyphenyl](phenyl)methyl}acetamide;
2-[2-fluoro-5-(4-methanesulfonylpiperazin-1-yl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
2-[5-(4-acetylpiperazin-1-yl)-2-fluoropheny

Assignees

• Genfit

Inventors

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

Classifications

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D295/185 Primary

  from aliphatic carboxylic acids · CPC title

• C07D295/155

  with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title