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EP-4735426-A1 - HETEROAROMATIC DHODH INHIBITORS

EP4735426A1EP 4735426 A1EP4735426 A1EP 4735426A1EP-4735426-A1

Abstract

The present relates to novel dihydroorotate dehydrogenase (DHODH) inhibitors of Formula (I) having a carboxylic acid, carboxamide or a bioisosteric moiety and being optionally deuterated, pharmaceutical formulations comprising them, a process for their preparation and their use as medicament, alone or in combination with one or more additional agents, for treating of various diseases, wherein the inhibition of DHODH is desirable (e.g. SARS-CoV-2 or IDH-mutated cancers).

Inventors

  • GEGE, CHRISTIAN
  • KOHLHOF, Hella
  • Mühler, Andreas
  • VITT, DANIEL

Assignees

  • Immunic AG

Dates

Publication Date
20260506
Application Date
20240628

Claims (16)

  1. CLAIMS: 1. A compound of Formula (I): or an enantiomer, diastereomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein A is selected from a 5-membered heteroaryl containing 2 to 3 hetereoatoms selected from N, S and O, having one or more hydrogen atoms optionally replaced by deuterium, said A is unsubstituted or substituted with one substituent independently selected from the group consisting of H, halogen, -CN, -NO 2 , SF 5 , oxo, -OH, C 1-4 -alkyl, -O-C 1-4 -alkyl, fluoro-C 1-4 -alkyl, -O-fluoro-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, -O-(3- to 6-membered cycloalkyl), 3- to 8- membered heterocycloalkyl, -O-(3- to 8-membered heterocycloalkyl), CO 2 R 11 , NR 11 R 12 , CONR 11 R 12 , phenyl, 5- or 6-membered heteroaryl wherein alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of D, halogen, -CN, OH, oxo, C1-4-alkyl, C1-4-alkyl, -O-C1-4-alkyl and -O-fluoro-C1-4-alkyl, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium; B is selected from the group consisting of phenyl and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, oxo, C1-4-alkyl, C1-4-alkyl, -O-C1-4-alkyl, -O-fluoro-C1-4-alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, oxo, -OH, C 1-4 -alkyl, halo-C 1-4 -alkyl; and wherein the residue -NR 2 on ring B is in a 1,4-orientation with respect to ring C, ring B or its substituents having one or more hydrogen atoms optionally replaced by deuterium; C is selected from the group consisting of phenyl and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, oxo, C 1-4 -alkyl, C 1-4 -alkyl, -O-C 1-4 -alkyl, -O-fluoro-C 1-4 -alkyl; and wherein optionally two adjacent substituents in the phenyl and pyridyl moiety form a 5- to 8-membered partially unsaturated cycle optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein this additional cycle is optionally substituted with 1 to 4 substituents independently selected from halogen, -CN, oxo, -OH, C1-4-alkyl, halo-C1-4-alkyl; ring C or its substituents having one or more hydrogen atoms optionally replaced by deuterium; X is selected from H, D, halogen, -CN, -NO 2 , C 1-6 -alkyl, -O-C 1-6 -alkyl, O-halo-C 1-6 -alkyl, C 0-6 - alkylene-OR 21 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 8-membered heterocycloalkyl), C 0-6 -alkylene-S(=O) n (=NR 23 ) m R 21 , C 0-6 -alkylene-NR 21 S(=O) x (=NR 23 ) y R 21 , C 0-6 - alkylene-S(=O) x (=NR 23 ) y NR 21 R 22 , C 0-6 -alkylene-NR 21 S(=O) x (=NR 23 ) y NR 21 R 22 , C 0-6 -alkylene- CO 2 R 21 , C 0-6 -alkylene-O-COR 21 , C 0-6 -alkylene-CONR 21 R 22 , C 0-6 -alkylene-NR 21 -COR 21 , C 0-6 - alkylene-NR 21 -CONR 21 R 22 , C 0-6 -alkylene-O-CONR 21 R 22 , C 0-6 -alkylene-NR 21 -CO 2 R 21 , C 0-6 - alkylene-NR 21 R 22 , wherein heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O, or S, wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 6 substituents independently selected from halogen, -CN, oxo, -OH, C1-4-alkyl, halo- C1-4-alkyl, -O-C1-4-alkyl and -O-halo-C1-4-alkyl, X or its substituents having one or more hydrogen atoms optionally replaced by deuterium; Y is selected from -CONR 11 R 12 , -CONH-CN, -CONHOR 10 , -SO3H, -SO2H, -B(OH)2, -CONHS(=O)x(=NR 13 )yR 10 , -CONHS(=O)x(=NR 13 )yNR 11 R 12 , -S(=O)x(=NR 13 )yNHCOR 10 , Y having one or more hydrogen atoms optionally replaced by deuterium; R 2 is sele t d f H d C lk l R 2 having one or more hydrogen atoms optionally replaced by deuterium; R 10 is selected from C 1-6 -alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, C1-4-alkyl, halo-C1-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, oxo, -O-C1-4-alkyl and -O- halo-C1-4-alkyl, wherein heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O, or S, R 10 having one or more hydrogen atoms optionally replaced by deuterium; R 11 , R 12 , R 21 , R 22 are independently selected from H, C1-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, C1-4-alkyl, halo-C1-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, oxo, -O-C1-4-alkyl and -O- halo-C1-4-alkyl, wherein heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O, or S, R 11 and/or R 12 and/or R 21 and/or R 22 having one or more hydrogen atoms optionally replaced by deuterium; or R 11 and R 12 , R 21 and R 22 , respectively, when taken together with the nitrogen to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, C 1-4 -alkyl, halo-C 1-4 -alkyl, 3- to 6-membered cycloalkyl, halo- (3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, oxo, -O-C 1-4 -alkyl and -O-halo-C 1-4 -alkyl, R 11 and/or R 12 and/or R 21 and/or R 22 having one or more hydrogen atoms optionally replaced by deuterium; R 13 , R 23 are independently selected from H, -CN, -NO 2 , C 1-6 -alkyl, -CO-O-C 1-6 -alkyl, 3- to 6- membered cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, C 1-4 -alkyl, halo-C 1-4 -alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, oxo, -O-C 1-4 -alkyl and -O- halo-C1-4-alkyl, wherein heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O, or S, R 13 and/or R 23 having one or more hydrogen atoms optionally replaced by deuterium; x, y are independently selected from 0 to 2; with the proviso that the sum of integer m and n for the residue linked to the same sulfur atom is independently selected from 0 to 2; with the proviso that the sum of integer x and y for the residue linked to the same sulfur atom is independently selected from 1 or 2; and with the proviso, that the following structures are excluded: 2. A compound of Formula (I) according to claim 1, or a solvate or pharmaceutically acceptable salt thereof, wherein Y is selected from -CONR 11 R 12 , -CONH-CN, -CONHOR 10 , -CONHS(=O) x (=NR 13 ) y R 10 , R 10 is selected from C 1-4 -alkyl, cyclopropyl or oxetan-3-yl, wherein alkyl, cyclopropyl or oxetan-3-yl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF 2 , CF 3 , -OH, oxo, -OMe, -OCHF 2 and -OCF 3 , R 10 having one or more hydrogen atoms optionally replaced by deuterium; R 11 and R 12 are independently selected from H or C 1-3 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF 2 , CF 3 , -OH, oxo, -OMe, -OCHF 2 and -OCF 3 , R 11 and/or R 12 having one or more hydrogen atoms optionally replaced by deuterium; R 13 is selected from H, -CN and C 1-3 -alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3, R 13 having one or more hydrogen atoms optionally replaced by deuterium; and x is 1 and y is 1 or x is 2 and y is 0. 3. A compound of Formula (I) according to claim 1 or 2, wherein said A is unsubstituted or substituted with one substituent independently selected from the group consisting of H, F, Cl, Br, -CN, -OH, C 1-4 -alkyl, -O-C 1-4 -alkyl, fluoro-C 1-4 -alkyl, -O-fluoro-C 1-4 -alkyl, CO 2 R 11 , NR 11 R 12 and CONR 11 R 12 , ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium; R 2 is H; R 11 and R 12 are independently selected from H, C1-6-alkyl, 3- to 6-membered cycloalkyl or 3- to 8- membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -CN, C1-4-alkyl, halo-C1-4-alkyl, 3- to 6- membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, oxo, -O-C1-4-alkyl and -O- halo-C1-4-alkyl, wherein heterocycloalkyl comprises 1,
  2. 2, 3 or 4 heteroatoms independently selected from N, O, or S, or R 11 and R 12 , when taken together with the nitrogen to which they are attached complete a 3- to 6-membered cycle containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N; and wherein this cycle is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen CN C alkyl haloC alkyl 3 to 6membered cycloalkyl, halo- (3- to 6-membered cycloalkyl),
  3. 3- to 8-membered heterocycloalkyl, halo-(3- to 8-membered heterocycloalkyl), -OH, oxo, -O-C 1-4 -alkyl and -O-halo-C 1-4 -alkyl, R 11 and/or R 12 having one or more hydrogen atoms optionally replaced by deuterium.
  4. 4. A compound of Formula (I) according to claim 1 or 3, wherein said A is unsubstituted or substituted with one substituent independently selected from the group consisting of D, F, Cl, -CN, -OH, Me, Et, -OMe, OEt, CHF2, CF3, -OCHF2, -OCF3, CO2Me, NH2, NHMe, NMe2, NHCOMe, CONH2, CONHMe and CONMe2, ring A or its substituents having one or more hydrogen atoms optionally replaced by deuterium; and R 2 is H.
  5. 5. A compound of Formula (I) according to any of claims 1 to 4, wherein B is phenyl, wherein phenyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, -OMe, -OCD3, CHF2 and CF3; and wherein the residue -NR 2 on ring B is in a 1,4-orientation with respect to ring C.
  6. 6. A compound of Formula (I) according to any of claims 1 to 5, wherein C is phenyl, wherein phenyl is unsubstituted or substituted with 1 to 4 substituents independently s elected from the group consisting of D, F, Cl, -CN, Me, CD 3 , CHF 2 , CF 3 , -OMe, -OCD 3 , -OCHF 2 and -OCF 3 ; and X is selected from D, F, Cl, -CN, Me, CD3, CHF2, CF3, Et, CD2CD3, -OMe, -OCD3, -OCHF2, -OCF3, -OEt, -OCD2CD3, -OCH2CH2CH3, -OCD2CD2CD3, -OCH2CH2CH2CH3 and -OCD2CD2CD2CD3.
  7. 7. A compound of Formula (I) according to any of claims 1 to 6, wherein selected from wh F.
  8. 8. A compound of Formula (I) according to any of claims 1 to 7, wherein Y is selected from
  9. 9. A compound of Formula (I) according to any of claims 1 to 8, which is selected from or a solvate or pharmaceutically acceptable salt thereof.
  10. 10. A compound according to any one of the preceding claims for the use as a medicament.
  11. 11. A compound according to any one of claims 1 to 10 for use in the prophylaxis and/or treatment of diseases, disorders, therapeutic indications or medical conditions amenable for treatment with DHODH inhibitors.
  12. 12. A compound for use according to claim 11 wherein the disease, disorder, therapeutic indication or medical condition is selected from the group comprising rheumatism, acute immunological disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases that are caused by protozoal infestations in humans and animals, diseases that are caused by viral infections and pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy.
  13. 13. A compound for use according to claim 12 wherein the disease, disorder or therapeutic indication is selected from the group comprising graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, respiratory syncytial virus, influenza, ulcerative colitis, Crohn’s disease, primary sclerosing cholangitis and psoriasis.
  14. 14. A compound for use according to claim 12 wherein the disease, disorder or therapeutic indication caused by malignant cell proliferation due to isocitrate dehydrogenase (NADP + ) 1 (IDH 1) mutation(s).
  15. 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or excipient.
  16. 16. A pharmaceutical composition of claim 15, further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, anti-viral agents, anti-cancer agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

Description

Heteroaromatic DHODH inhibitors SUMMARY OF THE INVENTION The present relates to novel dihydroorotate dehydrogenase (DHODH) inhibitors having a carboxylic acid, carboxamide or a bioisosteric moiety and being optionally deuterated, pharmaceutical formulations comprising them, a process for their preparation and their use as medicament, alone or in combination with one or more additional agents, for treating of various diseases, wherein the inhibition of DHODH is desirable (e.g. SARS-CoV-2 or IDH-mutated cancers). BACKGROUND OF THE INVENTION Vidofludimus calcium (I MU-838) is a selective and potent second-generation dihydroorotate dehydrogenase (DHODH) oral immunomodulator being developed for the treatment of several chronic inflammatory diseases, including relapsing-remitting Multiple Sclerosis (rrMS): vidofludimus The mechanism of action of vidofludimus calcium, a small molecule selective immune modulator, is the inhibition of the intracellular metabolism of activated immune T- and B-cells by blocking the enzyme DHODH. The inhibition of the DHODH enzyme leads to metabolic stress in metabolically activated lymphocytes resulting in reduction in proinflammatory cytokines and subsequently to apoptosis of activated immune cells. Blocking of the DHODH enzyme activity has a selective effect to metabolically activated immune cells, to malignant cells and to virus-infected cells. Thus, DHODH inhibition should therefore not lead to general antiproliferative effects in other cells. IMU- 838 as a second-generation DHODH inhibitor is being developed to separate the desired immunomodulatory effects from an undesirable side effect profile caused by off-target effects like neutropenia, alopecia and diarrhea. An additional benefit of DHODH inhibitors such as IMU-838 is their direct antiviral effect. During long-term treatment with immunosuppressive drugs, the reactivation of latent viruses has been observed. This can lead to serious infections, such as progressive multifocal leukoencephalopathy which can have a lethal outcome. PP-001 is another DHODH inhibitor within the same structural class for the treatment of retinal diseases like uveitis, diabetic macular edema and retinal vein occlusion currently in clinical trials. In animal models the high effectiveness to treat dry eye disease and viral conjunctivitis has already been demonstrated. So far, compounds from this structural class (e.g. IMU-838 or PP-001) contain a carboxylic acid functional group as an important constituent of the pharmacophore. However, the presence of this moiety can represent a liability. For instance, a diminished ability to passively diffuse across biological membranes can raise a significant challenge, particularly in the context of central nervous system drug discovery, where the blood-brain barrier can be relatively impermeable to negatively charged carboxylates. Furthermore, idiosyncratic drug toxicities arising from the metabolism of the carboxylic acid moiety (e.g. glucuronidation) have been linked to withdrawals of marketed drugs. The urate transporter 1 (URAT-1) is a urate transporter and urate-anion exchanger which regulates the level of urate in the blood. It is known that drugs containing a carboxylic acid (e.g. probenecid, salicylic acid or fenofibric acid) are recognized by and interact with URAT-1 affecting urinary uric acid excretion. Also, at high vidofludimus doses a decrease in blood uric acid levels and an increase in urine red blood cell count were observed, in very rare cases, presenting as symptomatic hematuria during the first 7 days of treatment (W02019/101888). This effect is caused due to interaction of vidofludimus with URAT-1 (Drugs R&D 2019;19:351). Therefore, there is still a need to develop novel DHODH inhibitors. In particular, there is a need to develop DHODH inhibitors with improved pharmacokinetic and pharmacodynamic properties. It is generally believed that a differentiated pharmacokinetic profile could enable potentially improved efficacy, less frequent dosing, improved tolerability, better brain penetration, reduced interpatient variability in drug metabolism and reduced drug-drug interactions. PRIOR ART Compounds of Formula (I) mainly containing a carboxylic acid as residue Y are described in W02004/056746, W02004/056747, W02004/056797, WO2010/052027, WO2010/128050, W02012/001148, W02012/001151 , WO2015/169944, WO2015/154820, WO2018/177151 , WO2019/170848, W02019/101888, WO2019/175396, WO2022/214691 as well as in Bioorg. Med. Chem. Lett. 2004; 14:55, Bioorg. Med. Chem. Lett. 2005; 15:4854, Bioorg. Med. Chem. Lett. 2006; 16:267, J. Med. Chem. 2006;49:1239 and J. Med. Chem. 2023;66:6391 , however no examples were presented, wherein the A-ring is a 5-membered heteroaryl containing 2 to 3 hetereoatoms selected from N, S and O. In WO2023/118576, optionally deuterated derivatives having a carboxylic acid bioisoster as residue Y have been described. The only 5-membered heteroaryl containing 2 to 3 hetereoatoms s