Itaconic acid derivatives and uses thereof intreating an inflammatory disease or a disease associated with an undesirable immune response

A compound of formula (IW-e) or pharmaceutically acceptable salt or solvate thereof:

• wherein,
• RA is selected from the group consisting of C1-10 alkyl, C3-10 cycloalkyl and C5-10 spirocycloalkyl;
• wherein RA is optionally substituted by one or more substituents selected from the group consisting of oxo, R1A, OR2A, N2AR3A, SR2A, SOR9ASO2R9A, SO2NR2AR3A, C(O)R2A and CONR2AR3A;
• R1A is selected from the group consisting of fluoro, methyl, cyano, SiR4AR5AR6A, C3-8 cycloalkyl and phenyl;
• wherein methyl, C3-8 cycloalkyl and phenyl optionally substituted by R7A and/or R8A;
• R4A, R5A and R6A are independently selected from the group consisting of C1-4 alkyl and phenyl;
• R7A and R8A are independently selected from the group consisting of oxo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, hydroxy, CO2H, cyano, methanesulfonyl and halo;
• or, taken together, R7A and R8A form a C3-8 cycloalkyl or 4-7 membered heterocyclic ring;
• R2A and R3A are independently H, C1-8 alkyl, C3-8 cycloalkyl or phenyl;
• or, taken together, R2A and R3A form a 4-7 membered heterocyclic ring;
• R9A is C1-8 alkyl, C3-8 cycloalkyl or phenyl;
• and
• RB is C1-2 alkyl substituted by CO2H and is optionally further substituted by trifluoromethyl or methyl;
• RC and RD are independently selected from the group consisting of H, C1-2 alkyl, hydroxy, methoxy and fluoro;
• or a compound which is selected from the group consisting of:
• 1-(2-cyanoethyl) 4-octyl 2-methylenesuccinate;
• 1-(2-(methylsulfonyl)ethyl) 4-octyl 2-methylenesuccinate;
• 4-octyl 1-(3,3,3-trifluoropropyl) 2-methylenesuccinate;
• 4-octyl 1-(oxetan-3-yl) 2-methylenesuccinate;
• 4-octyl 1-(2-(2-oxopyrrolidin-1-yl)ethyl) 2-methylenesuccinate;
• 1-(3-(dimethylamino)-3-oxopropyl) 4-octyl 2-methylenesuccinate;
• 4-butyl 1-(2-(methylsulfonyl)ethyl) 2-methylenesuccinate;
• 1-(2-cyanoethyl) 4-butyl 2-methylenesuccinate;
• 1-(2-(2,5-dioxopyrrolidin-1-yl)ethyl) 4-octyl 2-methylenesuccinate;
• 1-(2-cyanoethyl) 4-methyl 2-methylenesuccinate;
• 1-(2-cyanoethyl) 4-hexyl 2-methylenesuccinate;
• 4-methyl 1-(2-(methylsulfonyl)ethyl) 2-methylenesuccinate;
• 4-octyl 1-(2-(trifluoromethoxy)ethyl) 2-methylenesuccinate;
• 4-hexyl 1-(2-(methylsulfonyl)ethyl) 2-methylenesuccinate;
• 4-methyl 1-(oxetan-3-yl) 2-methylenesuccinate;
• 1-(2-(N,N-dimethylsulfamoyl)ethyl) 4-octyl 2-methylenesuccinate;
• 1-(2-(dimethylamino)ethyl) 4-octyl 2-methylenesuccinate;
• 1-(3-(methylsulfonyl)propyl) 4-octyl 2-methylenesuccinate;
• 1-(1-(methylsulfonyl)propan-2-yl) 4-octyl 2-methylenesuccinate;
• 1-(2-(methylsulfonyl)ethyl) 4-(3-phenoxypropyl) 2-methylenesuccinate;
• 1-(2-(dimethylamino)-2-oxoethyl) 4-octyl 2-methylenesuccinate;
• 4-isopropyl 1-(2-(methylsulfonyl)ethyl) 2-methylenesuccinate;
• (S)-4-octyl 1-(tetrahydrofuran-3-yl) 2-methylenesuccinate;
• (R)-4-octyl 1-(tetrahydrofuran-3-yl) 2-methylenesuccinate;
• 4-cyclooctyl 1-(2-(methylsulfonyl)ethyl) 2-methylenesuccinate;
• 4-octyl 1-(tetrahydro-2H-pyran-4-yl) 2-methylenesuccinate;
• 1-(1-cyanopropan-2-yl) 4-octyl 2-methylenesuccinate;
• 1-(1-(methylsulfonyl)piperidin-4-yl) 4-octyl 2-methylenesuccinate;
• 1-(2-methoxyethyl) 4-octyl 2-methylenesuccinate;
• 1-(2-cyano-2-methylpropyl) 4-octyl 2-methylenesuccinate;
• 1-(1-methoxypropan-2-yl) 4-octyl 2-methylenesuccinate;
• 1-((1-cyanocyclopropyl)methyl) 4-octyl 2-methylenesuccinate;
• 1-(2-methoxypropyl) 4-octyl 2-methylenesuccinate;
• 1-(2-methoxy-2-methylpropyl) 4-octyl 2-methylenesuccinate;
• 1-(2-morpholinoethyl) 4-octyl 2-methylenesuccinate;
• 4-(2-(2-ethoxyethoxy)ethyl) 1-(2-(methylsulfonyl)ethyl) 2-methylenesuccinate;
• 4-butyl 1-(oxetan-3-yl) 2-methylenesuccinate;
• 4-hexyl 1-(oxetan-3-yl) 2-methylenesuccinate;
• 4-butyl 1-(2-tosylethyl) 2-methylenesuccinate;
• 4-octyl 1-(2-tosylethyl) 2-methylenesuccinate;
• 4-cyclooctyl 1-methyl 2-methylenesuccinate;
• 1-methyl 4-octyl 2-methylenesuccinate;
• dicyclobutyl 2-methylenesuccinate;
• di(oxetan-3-yl) 2-methylenesuccinate;
• 1-cyclobutyl 4-octyl 2-methylenesuccinate;
• 1-(1-acetoxyethyl) 4-octyl 2-methylenesuccinate;
• 1-(1,1-dioxidothietan-3-yl) 4-octyl 2-methylenesuccinate;
• 1-(2-(tert-butoxy)-2-oxoethyl) 4-octyl 2-methylenesuccinate;
• 1-(1-acetylazetidin-3-yl) 4-octyl 2-methylenesuccinate;
• 1-(2-(4-methylpiperazin-1-yl)ethyl) 4-octyl 2-methylenesuccinate;
• 1-(2-(1,1-dioxidothiomorpholino)ethyl) 4-octyl 2-methylenesuccinate;
• 1-(2-(methylsulfonamido)ethyl) 4-octyl 2-methylenesuccinate;
• 4-cyclooctyl 1-(1,1-dioxidothietan-3-yl) 2-methylenesuccinate;
• (R)-1-(2-(methylsulfonyl)ethyl) 4-(octan-2-yl) 2-methylenesuccinate;
• 1-(1-(methylsulfonyl)propan-2-yl) 4-((R)-octan-2-yl) 2-methylenesuccinate;
• (R)-1-(1,1-dioxidothietan-3-yl) 4-(octan-2-yl) 2-methylenesuccinate;
• (R)-1-(1-acetylazetidin-3-yl) 4-(octan-2-yl) 2-methylenesuccinate;
• 4-cyclohexyl 1-(1-(methylsulfonyl)propan-2-yl) 2-methylenesuccinate;
• 4-cyclohexyl 1-(1,1-dioxidothietan-3-yl) 2-methylenesuccinate;
• 4-cyclohexyl 1-(2-(methylsulfonyl)ethyl) 2-methylenesuccinate;
• 4-cyclooctyl 1-(1-(methylsulfonyl)propan-2-yl) 2-methylenesuccinate;
• 1-(1-acetylazetidin-3-yl) 4-cyclooctyl 2-methylenesuccinate;
• 4-cyclohexyl 1-(tetrahydro-2H-pyran-4-yl) 2-methylenesuccinate;
• 4-cyclohexyl 1-(2-(2-oxopyrrolidin-1-yl)ethyl) 2-methylenesuccinate;
• (S)-1-(1-acetylazetidin-3-yl) 4-(octan-2-yl) 2-methylenesuccinate;
• (S)-1-(1,1-dioxidothietan-3-yl) 4-(octan-2-yl) 2-methylenesuccinate;
• 1-(3-methyloxetan-3-yl) 4-octyl 2-methylenesuccinate;
• 4-cyclooctyl 1-(1-(methylsulfonyl)piperidin-4-yl) 2-methylenesuccinate;
• 4-cyclooctyl 1-(tetrahydro-2H-pyran-4-yl) 2-methylenesuccinate;
• 4-cyclooctyl 1-(2-(2-oxopyrrolidin-1-yl)ethyl) 2-methylenesuccinate;
• (R)-4-(octan-2-yl) 1-(2-(2-oxopyrrolidin-1-yl)ethyl) 2-methylenesuccinate;
• (R)-4-(octan-2-yl) 1-(tetrahydro-2H-pyran-4-yl) 2-methylenesuccinate;
• 1-(1-acetylazetidin-3-yl) 4-cyclohexyl 2-methylenesuccinate;
• 4-cyclohexyl 1-(1-(methylsulfonyl)piperidin-4-yl) 2-methylenesuccinate;
• 4-hexyl 1-(1-(methylsulfonyl)piperidin-4-yl) 2-methylenesuccinate;
• 4-hexyl 1-(2-(2-oxopyrrolidin-1-yl)ethyl) 2-methylenesuccinate;
• 1-(2-(1H-tetrazol-5-yl)ethyl) 4-hexyl 2-methylenesuccinate;
• (2-((2-methylene-4-(octyloxy)-4-oxobutanoyl)oxy)acetyl)-L-proline;
• N-methyl-N-(2-((2-methylene-4-(octyloxy)-4-oxobutanoyl)oxy)propanoyl)glycine;
• (2-((2-methylene-4-(octyloxy)-4-oxobutanoyl)oxy)propanoyl)-L-proline;
• (2-((2-methylene-4-(octyloxy)-4-oxobutanoyl)oxy)propanoyl)glycine;
• N-(2-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)acetyl)-N-methylglycine;
• (2-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)acetyl)-L-proline;
• (S)—N-methyl-N-(2-((2-methylene-4-(octan-2-yloxy)-4-oxobutanoyl)oxy)acetyl)glycine;
• (S)-(2-((2-methylene-4-(octan-2-yloxy)-4-oxobutanoyl)oxy)acetyl)glycine;
• 1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl) 4-octyl 2-methylenesuccinate;
• 1-(3-morpholino-3-oxopropyl) 4-octyl 2-methylenesuccinate;
• 1-(3-(diethylamino)-3-oxopropyl) 4-octyl 2-methylenesuccinate;
• 1-(3-(methylamino)-3-oxopropyl) 4-octyl 2-methylenesuccinate;
• 3-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)-2,2-dimethylpropanoic acid;
• 1-(2-((N,N-dimethylsulfamoyl)amino)-2-oxoethyl) 4-hexyl 2-methylenesuccinate;
• 4-hexyl 1-(2-(methylsulfonamido)-2-oxoethyl) 2-methylenesuccinate;
• 4-hexyl 1-(3-(methylsulfonamido)-2-oxoethyl) 2-methylenesuccinate;
• (E)-4-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)but-2-enoic acid;
• 3-((2-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)ethyl)sulfonyl)propanoic acid;
• 1-((2H-tetrazol-5-yl)methyl) 4-cyclohexyl 2-methylenesuccinate;
• 2-((3-((2-((3-chlorophenyl)sulfonyl)ethoxy)carbonyl)but-3-enoyl)oxy)acetic acid;
• (R)-2-((4-(cyclohexyloxy)-2-methylene-4-oxobutanoyl)oxy)-2-phenylacetic acid;
• 1-(2-(1H-tetrazol-5-yl)ethyl) 4-cyclohexyl 2-methylenesuccinate;
• (S)-1-(2-(1H-tetrazol-5-yl)ethyl) 4-octan-2-yl 2-methylenesuccinate;
• 1-(2-(1H-tetrazol-5-yl)ethyl) 4-cyclooctyl 2-methylenesuccinate;
• 1-(2-((3-chlorophenyl)sulfonyl)-2-methylpropyl) 4-cyclooctyl 2-methylenesuccinate;
• 4-cyclooctyl 1-(2-methyl-2-(methylsulfonyl)propyl) 2-methylenesuccinate;
• 1-(1-(1H-tetrazol-5-yl)ethyl) 4-cyclooctyl 2-methylenesuccinate;
• 1-((1H-tetrazol-5-yl)methyl) 4-cyclooctyl 2-methylenesuccinate;
• (R)-1-(2-(1H-tetrazol-5-yl)ethyl) 4-octan-2-yl 2-methylenesuccinate;
• (2R,3S)-2-acetamido-3-((4-(cyclooctyloxy)-2-methylene-4-oxobutanoyl)oxy)butanoic acid;
• 4-cyclooctyl 1-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl) 2-methylenesuccinate;
• 4-(2-(methylsulfonyl)ethyl) 1-octyl 2-methyl-3-methylenesuccinate;
• 1-octyl 4-((S)-tetrahydrofuran-3-yl) 2-methyl-3-methylenesuccinate;
• 1-(1-(1H-tetrazol-5-yl)propan-2-yl) 4-((R)-octan-2-yl) 2-methylenesuccinate;
• 1-(1-(1H-tetrazol-5-yl)propan-2-yl) 4-((S)-octan-2-yl) 2-methylenesuccinate;
• 4-cyclohexyl 1-((2-methyl-2H-tetrazol-5-yl)methyl) 2-methylenesuccinate;
• 4-cyclohexyl 1-((1-methyl-1H-tetrazol-5-yl)methyl) 2-methylenesuccinate;
• bis((endo)-3-(methylsulfonyl)-3-azabicyclo[3.2.1]octan-8-yl) 2-methylenesuccinate;
• 1-((endo)-3-(methylsulfonyl)-3-azabicyclo[3.2.1]octan-8-yl) 4-(2-oxaspiro[3.3]heptan-6-yl) 2-methylenesuccinate;
• 1-((endo)-3-(methylsulfonyl)-3-azabicyclo[3.2.1]octan-8-yl) 4-(oxepan-4-yl) 2-methylenesuccinate;
• 4-(1-butoxypropan-2-yl) 1-((endo)-3-(methylsulfonyl)-3-azabicyclo[3.2.1]octan-8-yl) 2-methylenesuccinate;
• 4-spiro[3.3]heptan-2-yl 1-(3,3,3-trifluoro-2,2-dihydroxypropyl) 2-methylenesuccinate hydrate;
• (R)-1-((2H-tetrazol-5-yl)methyl) 4-(octan-2-yl) 2-methylenesuccinate;
• 1-(2H-tetrazol-5-yl)methyl 4-cycloheptyl 2-methylenesuccinate;
• 1-(2H-tetrazol-5-yl)methyl 4-spiro[3.3]heptan-2-yl 2-methylenesuccinate;
• (S)-1-(2H-tetrazol-5-yl)methyl 4-octan-2-yl 2-methylenesuccinate;
• 1-(1-(1H-tetrazol-5-yl)ethyl) 4-((S)-octan-2-yl) 2-methylenesuccinate;
• 1-(cyclopropyl(1H-tetrazol-5-yl)methyl) 4-((S)-octan-2-yl) 2-methylenesuccinate;
• dicyclohexyl 2-methylenesuccinate;
• 1-(3,3-difluorocyclobutyl) 4-octyl 2-methylenesuccinate;
• 1-((endo)-3-(methylsulfonyl)-3-azabicyclo[3.2.1]octan-8-yl) 4-((R)-octan-2-yl) 2-methylenesuccinate;
• and
• (R)-4-(octan-2-yl) 1-((3-oxo-2,3-dihydroisoxazol-5-yl)methyl) 2-methylenesuccinate;
• or a pharmaceutically acceptable salt or solvate thereof.