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US 11,077,115 B2Granted
Rorgamma modulators and uses thereof
AssigneeGenfit
InventorsJean-Francois Delhomel, Enrico Perspicace, Zouher Majd, Peggy Parroche, Robert Walczak, Pascal Bonnet, Jade Fogha
Life of this patent
Estimating the term…
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.
Claims18
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.
20 more elements
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 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 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;
- 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, R1c, R1d, and R1e is not a hydrogen atom;
- R2 is a (C6-C14)aryl group optionally substituted by a (C1-C6)alkyl group or a heteroaryl group optionally substituted by a (C1-C6)alkyl group or by a halogen;
- R′2 is a hydrogen atom;
- 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.
19 more elements
A compound of formula (Ia)
- in which,
- R1a is 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 (C1-C6)alkyl group;
- R1d and R1e are, independently, a hydrogen atom, a halogen atom, a (C1-C6)alkyloxy group or a (C1-C6)alkyl group;
- R2 is 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;
- L1 is a NH—CO— group;
- L2 is a CH2 group R4 is a hydrogen atom;
- X1, X2, X3, X4, X5 are, independently, a carbon, or a nitrogen atom;
- the cycle
- is a substituent of X1, X2 or X3;
- and
- X6 is a nitrogen atom and X7 is a SO2 group.
11 more elements
A compound, wherein the compound is one of the following compounds:
- 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;
- N-[(2-bromo-4-methylphenyl)(phenyl)methyl]-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]acetamide;
- 2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylphenyl]-N-{[4-methyl-2-(trifluoromethyl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylphenyl]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-(dimethylamino)-4-methoxyphenyl](5-methylfuran-2-yl)methyl}-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylphenyl]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;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]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-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]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;
- 2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-{[4-methyl-2-(trifluoromethyl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[6-(morpholin-4-yl)pyridin-3-yl]acetamide;
- N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}-2-[2-(morpholin-4-yl)pyrimidin-5-yl]acetamide;
- 2-[6-(1,1-dioxo-1-thiomorpholin-4-yl)pyridin-3-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)(5-methylfuran-2-yl)methyl]-2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]acetamide;
- 2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methoxyphenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- 2-[3-(1,1-dioxo-1-thiomorpholin-4-yl)-4-methoxyphenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]cyclopropane-1-carboxamide;
- 1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;
- 2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]-N-{[4-methyl-2-(trifluoromethyl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- N-[(2-bromo-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]acetamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]acetamide;
- N-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]acetamide;
- 1-[3-bromo-4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;
- 2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)-4-methylpyrimidin-5-yl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- 2-[3-(1,1-dioxo-1-thiomorpholin-4-yl)-4-hydroxyphenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-2-methylpropanamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]cyclobutane-1-carboxamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)-4-methylpyrimidin-5-yl]acetamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-2-[3-(1,1-dioxo-1-thiomorpholin-4-yl)-4-hydroxyphenyl]acetamide;
- 1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-[(4-methoxy-2-methylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;
- N-{[2-(azepan-1-yl)-4-methoxyphenyl](5-methylfuran-2-yl)methyl}-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]acetamide;
- N-{[2-(azepan-1-yl)-4-methoxyphenyl](5-methylfuran-2-yl)methyl}-1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]cyclopropane-1-carboxamide;
- 2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)pyridin-2-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-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]cyclopropane-1-carboxamide;
- N-[(4-chloro-2-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]acetamide;
- N-[(2,4-dichlorophenyl)(5-methylfuran-2-yl)methyl]-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]acetamide;
- N-[(2-chloro-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]acetamide;
- N-[(2-chloro-4-methylphenyl)(5-methylfuran-2-yl)methyl]-1-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]cyclopropane-1-carboxamide;
- N-[(4-chloro-2-methylphenyl)(5-methylfuran-2-yl)methyl]-1-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]cyclopropane-1-carboxamide;
- N-[(2,4-dichlorophenyl)(5-methylfuran-2-yl)methyl]-1-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]cyclopropane-1-carboxamide;
- 1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclobutane-1-carboxamide;
- 2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-2-methyl-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}propanamide;
- 1-[2-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-5-yl]-N-[(4-methoxy-2-methylphenyl)(5-methylfuran-2-yl)methyl]cyclopropane-1-carboxamide;
- 1-[3-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}cyclopropane-1-carboxamide;
- 1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-[3-methyl-1-[2-(piperidin-1-yl)phenyl]butyl]cyclopropane-1-carboxamide;
- 1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]-N-[(5-methylfuran-2-yl)[2-(piperidin-1-yl)phenyl]methyl]cyclopropane-1-carboxamide;
- 2-[4-(1,1-dioxo-1-thiomorpholin-4-yl)-3-hydroxyphenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- 2-[3-(1,1-dioxo-1-thiomorpholin-4-yl)-4-(methoxymethyl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- 2-[3-(1,1-dioxo-1-thiomorpholin-4-yl)-4-(hydroxymethyl)phenyl]-N-{[4-methyl-2-(piperidin-1-yl)phenyl](5-methylfuran-2-yl)methyl}acetamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]cyclopropane-1-carboxamide;
- 2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)pyrimidin-2-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-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]cyclopropane-1-carboxamide;
- N-[(5-chlorofuran-2-yl)(4-methylphenyl)methyl]-1-[4-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]cyclopropane-1-carboxamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[3-(1,1-dioxo-1-thiomorpholin-4-yl)phenyl]cyclopropane-1-carboxamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[3-(1,1-dioxo-1-thiomorpholin-4-yl)-4-methoxyphenyl]cyclopropane-1-carboxamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]cyclopropane-1-carboxamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-6-methylpyridin-2-yl]cyclopropane-1-carboxamide;
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-3-methylpyridin-2-yl]cyclopropane-1-carboxamide;
- and
- N-[(2,4-dimethylphenyl)(5-methylfuran-2-yl)methyl]-1-[5-(1,1-dioxo-1-thiomorpholin-4-yl)pyridin-2-yl]cyclopropane-1-carboxamide.
71 more elements
Dependencies are inferred from the claim text.