US 12,390,437 B2
Itaconic acid derivatives and uses thereof intreating an inflammatory disease or a disease associated with an undesirable immune response
Michael Liam Cooke, Nottingham (GB); David Cousin, Nottingham (GB); Matthew Colin Thor Fyfe, Oxfordshire (GB); Barry John Teobald, Oxfordshire (GB); Stephen Malcolm Thom, Nottingham (GB); and Thomas Michael Waugh, Nottingham (GB)
Assigned to Sitryx Therapeutics Limited, Oxford (GB)
Appl. No. 17/606,884
Filed by Sitryx Therapeutics Limited, Oxford (GB)
PCT Filed Apr. 30, 2020, PCT No. PCT/GB2020/051060
§ 371(c)(1), (2) Date Oct. 27, 2021,
PCT Pub. No. WO2020/222011, PCT Pub. Date Nov. 5, 2020.
Claims priority of application No. 19172051 (EP), filed on Apr. 30, 2019; application No. 19189910 (EP), filed on Aug. 2, 2019; application No. 19217846 (EP), filed on Dec. 19, 2019; and application No. 20162494 (EP), filed on Mar. 11, 2020.
Prior Publication US 2022/0265595 A1, Aug. 25, 2022
Int. Cl. A61K 31/225 (2006.01); A61K 31/275 (2006.01); A61K 31/337 (2006.01); A61K 31/341 (2006.01); A61K 31/351 (2006.01); A61K 31/38 (2006.01); A61K 31/397 (2006.01); A61K 31/4015 (2006.01); A61K 31/41 (2006.01); A61K 31/445 (2006.01); A61K 31/46 (2006.01); A61K 31/495 (2006.01); A61K 31/5375 (2006.01); A61K 31/54 (2006.01); C07C 69/593 (2006.01); C07C 219/08 (2006.01); C07C 233/05 (2006.01); C07C 255/14 (2006.01); C07C 311/03 (2006.01); C07C 317/18 (2006.01); C07D 205/04 (2006.01); C07D 207/27 (2006.01); C07D 207/273 (2006.01); C07D 207/277 (2006.01); C07D 211/96 (2006.01); C07D 257/04 (2006.01); C07D 295/08 (2006.01); C07D 295/088 (2006.01); C07D 305/08 (2006.01); C07D 307/20 (2006.01); C07D 309/12 (2006.01); C07D 331/04 (2006.01); C07D 451/10 (2006.01); C07D 519/00 (2006.01)
CPC A61K 31/225 (2013.01) [A61K 31/275 (2013.01); A61K 31/337 (2013.01); A61K 31/341 (2013.01); A61K 31/351 (2013.01); A61K 31/38 (2013.01); A61K 31/397 (2013.01); A61K 31/4015 (2013.01); A61K 31/41 (2013.01); A61K 31/445 (2013.01); A61K 31/46 (2013.01); A61K 31/495 (2013.01); A61K 31/5375 (2013.01); A61K 31/54 (2013.01); C07C 69/593 (2013.01); C07C 219/08 (2013.01); C07C 233/05 (2013.01); C07C 255/14 (2013.01); C07C 311/03 (2013.01); C07C 317/18 (2013.01); C07D 205/04 (2013.01); C07D 207/27 (2013.01); C07D 207/273 (2013.01); C07D 207/277 (2013.01); C07D 211/96 (2013.01); C07D 257/04 (2013.01); C07D 295/08 (2013.01); C07D 295/088 (2013.01); C07D 305/08 (2013.01); C07D 307/20 (2013.01); C07D 309/12 (2013.01); C07D 331/04 (2013.01); C07D 451/10 (2013.01); C07D 519/00 (2013.01); C07C 2601/18 (2017.05); C07C 2602/50 (2017.05)] 11 Claims
 
1. A compound of formula (IW-e) or pharmaceutically acceptable salt or solvate thereof:

OG Complex Work Unit Chemistry
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.