Heterocyclic derivatives as RORgamma modulators

Patent metadata

Field	Value
Publication number	US-9902725-B2
Application number	US-201515539519-A
Country	US
Kind code	B2
Filing date	Dec 22, 2015
Priority date	Dec 23, 2014
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

The present invention provides novel compounds of formula (I) 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, fibrotic diseases, or cholestatic diseases.

First claim

The invention claimed is:

1. A compound of formula (I)

in which,
A is a C-R1b group or a nitrogen atom;
R1a is a hydrogen atom, a halogen atom, a nitrile group, a nitro group (NO 2 ), an alkyl group, an alkyloxy group, an alkylthio group, an amino group, an alkylamino group, a dialkylamino group or a heterocyclic group;
R1b is a hydrogen atom, an alkyloxy group, an alkyl group or a heterocyclic group;
or R1a and R1b can form, together with the carbon atoms to which they are attached, an aryl group or a heterocyclic group;
R1c is a hydrogen atom, a halogen atom, an alkyl group, an alkyloxy group, an alkylthio group, a heterocyclic group, a cyano group, an amido group or a hydroxyl group;
R1d is a hydrogen atom, a halogen atom, an alkyloxy group or an alkyl group;
R2 and R′2 are independently a hydrogen atom, an alkyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group, with the proviso that R2 and R′2 are not simultaneously a hydrogen atom,
or R2 and R2′ can form, together with the carbon atom to which they are attached, a cycloalkyl group or a heterocycloalkyl group;
L is a NR7-CO—CH 2 , NR7-CO—NH, NR7-CO—C(CH 3 ) 2 , NR7-CS—CH 2 , NR7-CS—NH, NR7-CS—C(CH 3 ) 2 , NR7-SO 2 —CH 2 , NR7-SO 2 —C(CH 3 ) 2 , CO—NH—CH 2 or CO—NH—C(CH 3 ) 2 group;
HET is a heterocyclic group selected from:

B1 and B2 are independently a nitrogen atom or a carbon atom;
R3 is a COR5 group, a CO-Alkyl-COR5 group or an alkyl group substituted by a COR5 group;
R4 is a hydrogen atom, an alkyl group or a hydroxyl group;
R5 is a hydroxyl group, an alkyloxy group, an alkyl group, a NR8R8′ group or a —O—CH—(CH 2 —O—CO—R6) 2 group;
R6 is a long chain alkyl group;
R7 is a hydrogen atom or an alkyl group;
R8 is a hydrogen atom or an alkyl group;
R8′ is a hydrogen atom, an alkyl group, a C(═NH)NH 2 group, a C(═NH)NHCOOtBu group or an alkoxy group; and
R9 is a hydrogen atom, an alkyl group or a halogen atom.

2. The compound according to claim 1 , wherein:
A is a C-R1b group or a nitrogen atom;
R1a is a hydrogen atom, a halogen atom, an alkyl group, an alkyloxy group, an amino group, an alkylamino group, a dialkylamino group or a heterocyclic group;
R1b is hydrogen, an alkyl group or a heterocyclic group;
R1a and R1b can form, together with the carbon atoms to which they are attached, an aryl group or a heterocyclic group;
R1c is a hydrogen atom, a halogen atom, an alkyl group, an alkyloxy group, a cyano group, an amido group or a hydroxyl group;
R1d is a hydrogen atom, a halogen atom, an alkyloxy group or an alkyl group;
R2 and R′2 are independently a hydrogen atom, an alkyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group, with the proviso that R2 and R′2 are not simultaneously a hydrogen atom,
or R2 and R2′ can form, together with the carbon atom to which they are attached, a cycloalkyl group;
L is a NR7-CO—CH 2 , NR7-CO—NH, or CO—NH—CH 2 group;
HET is a heterocyclic group selected from:

B1 and B2 are independently a nitrogen atom or a carbon atom;
R3 is a COR5 group, or a CO-Alkyl-COR5 group or an alkyl group substituted by a COR5 group;
R4 is a hydrogen atom or an alkyl group;
R5 is a hydroxyl group, an alkyloxy group, an alkyl group, a NR8R8′group or a —O—CH—(CH 2 —O—CO—R6) 2 group;
R6 is a long chain alkyl group;
R7 is a hydrogen atom;
R8 is a hydrogen atom or an alkyl group;
R8′ is a hydrogen atom, an alkyl group, a C(═NH)NH 2 group or a C(═NH)NHCOOtBu group; and
R9 is a hydrogen atom.

3. The compound according to claim 1 , wherein:
A is a C-R1b group or a nitrogen atom;
R1a is a halogen atom, a nitrile group, a nitro group (NO 2 ), an alkyl group, an alkyloxy group, an alkylthio group, an amino group, an alkylamino group, a dialkylamino group or a heterocyclic group;
R1b is a hydrogen atom or a heterocyclic group;
wherein R1a and R1b can optionally form, together with the carbon atoms to which they are attached, an aryl group or a heterocyclic group;
R1c is a hydrogen atom, a halogen atom, an alkyl group, an alkyloxy group, an alkylthio or a heterocyclic group;
R1d is a hydrogen atom, a halogen atom or an alkyl group;
R2 and R′2 are independently a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group, with the proviso that R2 and R′2 are not simultaneously a hydrogen atom,
or R2 and R2′ can form, together with the carbon atom to which they are attached, a cycloalkyl group or a heterocycloalkyl group;
L is a NR7-CO—CH 2 , NR7-CO—NH, NR7-CO—C(CH 3 ) 2 , NR7-CS—CH 2 , NR7-CS—NH, NR7-CS—C(CH 3 ) 2 , NR7-SO 2 —CH 2 , NR7-SO 2 —C(CH 3 ) 2 , CO—NH—CH 2 or CO—NH—C(CH 3 ) 2 group;
HET is a heterocyclic group selected from:

B1 and B2 are independently a nitrogen atom or a carbon atom;
R3 is a COR5 group or an alkyl group substituted by a COR5 group;
R4 is a hydrogen atom or a hydroxyl group;
R5 is a hydroxyl group, an alkyloxy group, a NR8R8′group or a —O—CH—(CH 2 —O—CO—R6) 2 group;
R6 is a long chain alkyl group;
R7 is a hydrogen atom or an alkyl group;
R8 and R8′ are independently a hydrogen atom or an alkyl group; and
R9 is a hydrogen atom, an alkyl group or a halogen atom.

4. The compound according to claim 1 , wherein:
A is a C-R1b group;
R1a is a halogen atom, a nitrile group, a nitro group (NO 2 ), an alkyl group, an alkyloxy group, an alkylthio group, an alkylamino group, a dialkylamino group, a 1-pyrrolidinyl group, a 1-azepanyl group, a 4-morpholinyl group, a 1-piperidinyl group, a 1-piperazinyl group, wherein said piperidinyl or piperazinyl group can be optionally substituted by one or more alkyl groups;
R1b is hydrogen, a 1-pyrrolidinyl group, a 1-azepanyl group, a 4-morpholinyl group, a 1-piperidinyl group or a 1-piperazinyl group;
R1c is hydrogen, a halogen atom, an alkyl group or an alkyloxy group;
R2 is an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, and
R′2 is a hydrogen atom.

5. The compound according to claim 1 , wherein B1 and B2 are carbon atoms.

6. The compound according to claim 1 , wherein L is NH—CO—CH 2 , NH—CO—NH, NH—SO 2 —CH 2 , CO—NH—CH 2 , N(CH 3 )—CO—CH 2 or NH—CO—C(CH 3 ) 2 .

7. The compound according to claim 1 , wherein
A is a CH group,
R1a is a heterocycloalkyl group,
R1c is a hydrogen atom or an alkyl group,
R2 is a phenyl group or an alkyl group,
L represents a NH—CO—CH 2 group or a NH—CO—NH group,
HET has the following structure

in which B1 and B2 are carbon atoms,
R4 is a hydrogen atom; and
R3 represents a CH 2 —CH 2 —COR5 group, wherein R5 is a hydroxyl group or an alkyloxy group
R9 is a hydrogen atom.

8. The compound according to claim 1 , wherein:
A is a CH group;
R1a is a piperidinyl group;
R1c is a hydrogen atom or an alkyl group;
R2 is a heterocyclic group, substituted or not by an alkyl group;
L represents a NH—CO—CH 2 group,
HET has the following structure

Assignees

• Genfit

Inventors

• Delhomel Jean Francois
• Walczak Robert
• Majd Zouher
• Pihan Emilie
• Bonnet Pascal
• Perspicace Enrico

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title