DHODH inhibitors containing carboxylic acid bioisosteres

Abstract

The present invention relates to a compound represented by formula (I) The present invention relates to novel, optionally deuterated compounds of formula (I) 28170 and their use as medicines.

Description

[Technical field]

[0001] Summary of the Invention The present disclosure relates to novel dihydroorotate dehydrogenase (DHODH) inhibitors having a carboxylic acid bioisostere moiety and optionally deuterated, pharmaceutical formulations containing same, methods for their preparation, and their use as medicaments, alone or in combination with one or more additional agents, for the treatment of various diseases in which inhibition of DHODH is desirable. [Background technology]

[0002] 2. Background of the Invention Bidofludimus calcium (IMU-838) is a selective, potent, second-generation dihydroorotate dehydrogenase (DHODH) oral immunomodulator being developed for the treatment of several chronic inflammatory diseases, including relapsing-remitting multiple sclerosis (rrMS).

[0003] [ka]

[0004] The mechanism of action of Bidofludimus calcium, a small molecule selective immunomodulator, is to inhibit the intracellular metabolism of activated immune T and B cells by inhibiting the enzyme DHODH. Inhibition of the DHODH enzyme leads to metabolic stress in metabolically activated lymphocytes, leading to a reduction in proinflammatory cytokines and subsequent apoptosis of activated immune cells. Inhibition of DHODH enzyme activity has selective effects on metabolically activated immune cells, malignant cells and virus-infected cells. Thus, DHODH inhibition does not have a general antiproliferative effect on other cells. IMU-838, as a second generation DHODH inhibitor, has been developed to separate the desired immunomodulatory effect from the undesirable side effect profile caused by off-target effects such as neutropenia, alopecia and diarrhea. Another advantage of DHODH inhibitors such as IMU-838 is the direct antiviral effect. Reactivation of latent viruses has been observed during long-term treatment with immunosuppressants. This can lead to severe infections such as progressive multifocal leukoencephalopathy with potentially fatal consequences.

[0005] PP-001 is another DHODH inhibitor within the same structural class that is currently in clinical trials for the treatment of retinal diseases such as uveitis, diabetic macular edema and retinal vein occlusion. It has already demonstrated high efficacy for the treatment of dry eye disease and viral conjunctivitis in animal models.

[0006] So far, compounds of this structural class (e.g., IMU-838 or PP-001) contain a carboxylic acid functional group as a key component of the pharmacophore. However, the presence of this moiety can be a disadvantage. For example, a reduced ability to passively diffuse across biological membranes can pose significant challenges, especially in the context of central nervous system drug discovery, where the blood-brain barrier may be relatively impermeable to negatively charged carboxylates. Furthermore, idiosyncratic drug toxicity resulting from metabolism of the carboxylic acid moiety (e.g., glucuronidation) has been associated with the withdrawal of marketed drugs. Urate transporter 1 (URAT-1) is a urate transporter and urate anion exchanger that regulates uric acid levels in the blood. Drugs containing carboxylic acids (e.g., probenecid, salicylic acid or fenofibric acid) are known to be recognized by and interact with URAT-1, affecting uric acid excretion through the urine. Also, at high doses of Bidofludimus, a decrease in blood uric acid levels and an increase in urinary red blood cell count were observed, which in very rare cases manifested as symptomatic hematuria during the first 7 days of treatment (WO2019 / 101888). This effect occurs through the interaction of Bidofludimus with URAT-1 (Drugs R&D 2019;19:351).

[0007] Thus, there remains a need for the development of new DHODH inhibitors. In particular, there is a need for DHODH inhibitors with improved pharmacokinetic and pharmacodynamic properties. This can be achieved by replacing hydrogen atoms in the molecule with deuterium atoms. Covalent C-H bonds are weaker than otherwise identical C-D bonds due to kinetic isotope effects. C-H bond cleavage is a common feature of drug metabolism, and cleavage of similar C-D bonds may be more difficult, thus slowing down the metabolic rate. Substitution of H with D in small molecules significantly reduces metabolism, resulting in beneficial changes to the biological effects of the drug. Substitution may also have the effect of reducing toxicity by reducing the production of toxic metabolites (J. Med. Chem. 2019;62:5276). Deuterated analogs share the beneficial mechanism of action, but are expected to be metabolized slower and have less interpatient variability compared to non-deuterated matched pairs. It is generally believed that differentiated pharmacokinetic profiles could potentially improve efficacy, reduce dosing frequency, improve tolerability, reduce interpatient variability in drug metabolism, and reduce drug-drug interactions.

[0008] prior art Compounds of formula (I) containing a carboxylic acid instead of the residue Y have been described in WO2004 / 056746, WO2004 / 056747, WO2004 / 056797, WO2010 / 052027, WO2010 / 128050, WO2012 / 001148, WO2012 / 001151, WO2015 / 169944, WO2015 / 154820, WO2018 / 177151, WO2019 / 170848, WO2019 / 101888, WO2019 / 175396 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, and J. Med. Chem. 2006;49:1239. Deuterated compounds of formula (I) containing a carboxylic acid instead of residue Y have not yet been described. Also, compounds of formula (I) containing an acidic bioisosteric functional group have not yet been described, except for the hydroxamic acid of Example 4 of WO2004 / 056746:

[0009] [ka]

[0010] The human DHODH inhibitory activity of Example 4 is IC 50 Although the IC was in the worst category of >5 μM, matched pairs containing carboxylic acids (Bidofludimus) had IC 50 <0.8 μM (WO2003 / 006425), and more precisely, IC 50 is reported to be 0.134 μM (Bioorg. Med. Chem. Lett. 2005;15:4854). As outlined in the experimental section, it has surprisingly been discovered that replacement of the carboxylic acid moiety with other acidic bioisosteric moieties affords DHODH inhibitors with beneficial properties (e.g., improved DHODH inhibitory activity, reduced lipophilicity, improved microsomal stability / clearance and / or bioavailability). [Brief description of the drawings]

[0011] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 shows representative results from experiments combining Example 1 with the nucleoside analog EIDD-1931 (CAS: 3258-02-4). The data show a synergistic antiviral effect against SARS-CoV-2 at different doses.

[0012] [Diagram 2] FIG. 2 shows representative human DHODH inhibition curves for the matched pairs mentioned in Example 4 / 33 and the prior art. Summary of the Invention

[0013] Summary of the Invention The present invention relates to a compound represented by formula (I)

[0014] [ka]

[0015] or an enantiomer, diastereomer, tautomer, solvate, or pharma- ceutically acceptable salt thereof, wherein rings A, B, C and residues X, Y, and R 2 is as defined in claim 1, except for the following structures:

[0016] [ka]

[0017] The compounds of the present invention have comparable or superior DHODH inhibitory activity compared to known DHODH inhibitors.In addition, the compounds of the present invention exhibit additional beneficial properties such as reduced lipophilicity, reduced interaction with URAT1 transporter, improved microsomal stability / clearance, and / or improved bioavailability due to the bioisosteric moiety of the carboxylic acid.By replacing hydrogen with deuterium at certain positions, the microsomal stability and / or bioavailability can be further improved when used as a drug.

[0018] Accordingly, the present invention further relates to pharmaceutical compositions comprising a compound of formula (I) and at least one pharma- ceutically acceptable carrier or excipient.

[0019] The present invention is further directed to the compounds of formula (I) for use in the prevention and / or treatment of diseases mediated by DHODH.

[0020] The present invention therefore relates to the prevention and / or treatment of diseases, disorders, therapeutic indications or conditions selected from the group comprising rheumatism, acute immune diseases, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoan infestations in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy. More specifically, the diseases, disorders or therapeutic indications are 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, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

[0021] The present invention further relates to pharmaceutical compositions comprising a compound of formula (I) and one or more additional therapeutic agents selected from anti-inflammatory agents, antiviral agents, immunosuppressants and / or immunomodulators, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Detailed Description of the Invention The compound 2-((3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid, also known as bidofludimus, is an orally administered DHODH inhibitor. The calcium salt of bidofludimus is known as IMU-838. IMU-838 is currently in Phase 3 clinical trials for the treatment of MS, and is also in clinical trials for ulcerative colitis and primary sclerosing cholangitis. The compound 3-((2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-"1,1'-biphenyl]-4-yl)carbamoyl)thiophene-2-carboxylic acid, also known as PP-001, is a topically administered DHODH inhibitor. PP-001 is currently in clinical trials for the treatment of keratoconjunctivitis and non-infectious uveitis. Bidofludimus, IMU-838, and PP-001 have been generally well tolerated in several clinical trials. Despite the potential beneficial effects of Bidofludimus, IMU-838, and PP-001, there is a continuing need for new compounds with improved off-target and drug metabolism and pharmacokinetic (DMPK) properties to treat the aforementioned diseases and conditions. Improved off-target and DMPK properties may lead to positive changes in the safety profile, efficacy, and tolerability of the compounds. Reference will now be made in detail to certain embodiments of the invention. Examples of these embodiments are illustrated in the accompanying structures and formulas. Although the invention will be described in conjunction with the enumerated embodiments, it will be understood that these embodiments do not limit the invention to these embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. The invention is not limited to the methods and materials described herein, but includes methods and materials similar or equivalent to those described herein that can be used to practice the invention. In the event that one or more of the incorporated literature references, patents, or similar materials differs or conflicts with this application, including but not limited to defined terms, usage of terms, techniques described, etc., this application will control.

[0023] In one embodiment, the present invention provides a compound of formula (I): [ka]

[0024] or an enantiomer, diastereomer, tautomer, solvate, or pharma- ceutically acceptable salt thereof, In the above formula, A is selected from 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl, in which one or more hydrogen atoms are optionally replaced with deuterium, and said A is unsubstituted or substituted with 1 to 5 substituents, which are halogen, -CN, -NO2, oxo, -OH, C 1-4 -Alkyl, -OC 1-4 -Alkyl, Fluoro-C 1-4 -Alkyl and -O-fluoro-C 1-4 -alkyl, wherein Ring A has one or more hydrogen atoms in the alkyl optionally replaced with deuterium; B is selected from the group consisting of 5- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents, the substituents being halogen, -CN, -NO2, oxo, C 1-4 -Alkyl, C 0-6 -Alkylene-OR 21 , C 0-6 -Alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-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-CO2R 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 -CO2R 21 , C 0-6 -Alkylene-NR 21 R 22 Independently selected from the group consisting of: Alkyl, alkylene, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, the substituents being halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated ring, optionally containing 1 to 3 heteroatoms independently selected from O, S or N; The additional ring may optionally be a halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -substituted by 1 to 4 substituents independently selected from alkyl, Residue on Ring B -NR 2 is in the 1,4-position relative to ring C, B has one or more hydrogen atoms optionally replaced with deuterium; C is selected from the group consisting of 5- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents, the substituents being halogen, -CN, -NO2, oxo, C 1-4 -Alkyl, C 0-6 -Alkylene-OR 31 , C 0-6 -Alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -Alkylene-S(=O) n (=NR 33 ) m R 31 , C 0-6 -Alkylene-NR 31 S(=O) x (=NR 33 ) y R 31 , C 0-6 -Alkylene-S(=O) x (=NR 33 ) y NR31 R 32 , C 0-6 -Alkylene-NR 31 S(=O) x (=NR 33 ) y NR 31 R 32 , C 0-6 -Alkylene-CO2R 31 , C 0-6 -Alkylene-O-COR 31 , C 0-6 -Alkylene-CONR 31 R 32 , C 0-6 -Alkylene-NR 31 -COR 31 , C 0-6 -Alkylene-NR 31 -CONR 31 R 32 , C 0-6 -Alkylene-O-CONR 31 R 32 , C 0-6 -Alkylene-NR 31 -CO2R 31 , C 0-6 -Alkylene-NR 31 R 32 Independently selected from the group consisting of: Alkyl, alkylene, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, the substituents being halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated ring, optionally containing 1 to 3 heteroatoms independently selected from O, S or N; The additional ring is optionally substituted with 1 to 4 substituents, including halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4-Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, C has one or more hydrogen atoms optionally replaced with deuterium; X is H, D, halogen, -CN, -NO2, C 1-6 -Alkyl, -OC 1-6 -Alkyl, O-Halo-C 1-6 -Alkyl, C 0-6 -Alkylene-OR 41 , C 0-6 -Alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -Alkylene-S(=O) n (=NR 43 ) m R 41 , C 0-6 -Alkylene-NR 41 S(=O) x (=NR 43 ) y R 41 , C 0-6 -Alkylene-S(=O) x (=NR 43 ) y NR 41 R 42 , C 0-6 -Alkylene-NR 41 S(=O) x (=NR 43 ) y NR 41 R 42 , C 0-6 -Alkylene-CO2R 41 , C 0-6 -Alkylene-O-COR 41 , C 0-6 -Alkylene-CONR 41 R 42 , C 0-6 -Alkylene-NR 41 -COR 41 , C 0-6 -Alkylene-NR 41 -CONR 41 R 42 , C0-6 -Alkylene-O-CONR 41 R 42 , C 0-6 -Alkylene-NR 41 -CO2R 41 , C 0-6 -Alkylene-NR 41 R 42 Selected from Heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; Alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, the substituents being halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, X has one or more hydrogen atoms optionally replaced with deuterium; Y is -CONH-CN, -CONHOH, -CONHOR 10 , -CONR 10 OH, -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 , -SO3H, -S(=O) x (=NR 13 ) y NHCOR 10 , -S(=O) x (=NR 13 ) y NHR 11 , -P(=O)(OH)2, -P(=O)(NR 11 R 12 )OH, -P(=O)R 11(OH), -B(OH)2,

[0025] [ka]

[0026] Selected from Y has one or more hydrogen atoms optionally replaced with deuterium; R 2 H and C 1-6 -alkyl, Alkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 2 has one or more hydrogen atoms optionally replaced with deuterium; R 10 is C 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 10 has one or more hydrogen atoms optionally replaced with deuterium; R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , R 42 is H, C 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 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 and / or R 31 and / or R 32 and / or R 41 and / or R 42 has one or more hydrogen atoms optionally replaced with deuterium, or R 11 and R 12 , R 21 and R 22 , R 31 and R 32 , R 41 and R 42 each, when taken together with the nitrogen to which they are attached, completes a 3- to 6-membered ring containing carbon atoms and optionally 1 or 2 heteroatoms selected from O, S or N; and The ring is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, R 11 and / or R 12 and / or R 21 and / or R 22 and / or R 31 and / or R 32 and / or R 41 and / or R 42 has one or more hydrogen atoms optionally replaced with deuterium; R 13 , R 23 , R 33 , R 43 is H, -CN, -NO2, C 1-6 -Alkyl, -CO-OC 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 13 and / or R 23 and / or R 33 and / or R43 has one or more hydrogen atoms optionally replaced with deuterium; n, m, x, and y are independently selected from 0 to 2; provided that the sum of integers m and n for residues bonded to the same sulfur atom is independently selected from 0 to 2; provided that the sum of integers x and y for residues bonded to the same sulfur atom is independently selected from 1 or 2; and However, the following structures are excluded:

[0027] [ka]

[0028] In a more particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein: Y is -CONH-CN, -CONHOR 10 , -CONR 10 OH, -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 ,

[0029] [ka]

[0030] Selected from R 10 is C 1-3 -alkyl, cyclopropyl or oxetan-3-yl, Alkyl, cyclopropyl or oxetan-3-yl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R 10 has one or more hydrogen atoms optionally replaced with deuterium; R 11 and R 12 is H or C 1-3 -alkyl, 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 11 and / or R 12 has one or more hydrogen atoms optionally replaced with deuterium; R 13 is H, -CN and C 1-3 -alkyl, 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 has one or more hydrogen atoms optionally replaced with deuterium; Either x is and y is 1, or x is 2 and y is 0.

[0031] In certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0032] [ka]

[0033] teeth,

[0034] [ka]

[0035] wherein ring A is unsubstituted or substituted with 1 to 2 substituents, the substituents being halogen, oxo, -OH, C 1-4 -Alkyl, -OC 1-4 -Alkyl, Fluoro-C 1-4 -Alkyl and -O-fluoro-C 1-4 -alkyl, ring A having one or more hydrogen atoms in the alkyl optionally replaced with deuterium, and R 2 is H.

[0036] In certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0037] [ka]

[0038] teeth,

[0039] [ka]

[0040] wherein ring A is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of fluoro and methyl, and R 2 is H.

[0041] In certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0042] [ka]

[0043] teeth,

[0044] [ka]

[0045] Selected from, and R 2 is H.

[0046] In certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0047] [ka]

[0048] teeth,

[0049] [ka]

[0050] Selected from, and R 2 is H.

[0051] In certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0052] [ka]

[0053] teeth,

[0054] [ka]

[0055] Selected from, and R 2 is H.

[0056] In a more particular embodiment, the compound is represented by formula (I):

[0057] [ka]

[0058] teeth,

[0059] [ka]

[0060] Selected from, and R 2 is H.

[0061] In certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0062] [ka]

[0063] teeth,

[0064] [ka]

[0065] Selected from, and R 2 is H.

[0066] Similarly, in certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0067] [ka]

[0068] teeth,

[0069] [ka]

[0070] Selected from, and R 2 is H.

[0071] Similarly, in certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0072] [ka]

[0073] teeth,

[0074] [ka]

[0075] Selected from, and R 2 is H.

[0076] Similarly, in certain embodiments, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof:

[0077] [ka]

[0078] teeth

[0079] [ka]

[0080] Selected from, and R 2 is H.

[0081] Similarly, in certain embodiments, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof:

[0082] [ka]

[0083] teeth,

[0084] [ka]

[0085] Selected from, and R 2 is H.

[0086] In a more particular embodiment, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof, wherein one or more hydrogen atoms in any substituent are replaced with deuterium.

[0087] In a more particular embodiment, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof, wherein one or more hydrogen atoms in any substituent are replaced with deuterium, but the level of deuterium incorporation in each substituent designated as deuterium is at least 52.5%.

[0088] In a more particular embodiment, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof, wherein one or more hydrogen atoms in Ring C or any substituent of Ring C are replaced with deuterium.

[0089] In a most particular embodiment, the compound has formula (I) or a solvate or a pharma- ceutically acceptable salt thereof, wherein one or more hydrogen atoms in residue X are replaced by deuterium.

[0090] In a most particular embodiment, the compound has formula (I) or a solvate or pharma ceutically acceptable salt thereof, and residue X is OCD3.

[0091] In one particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein one or more hydrogen atoms in residue Y are replaced with deuterium.

[0092] In certain embodiments, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof, and Y is -CONH-CN, -CONHOH, -CONHOR, 10 , -CONR 10 OH, -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 , -SO3H, -S(=O) x (=NR 13 ) y NHCOR 10 , -S(=O) x (=NR 13 ) y NHR 11 , -P(=O)(OH)2, -P(=O)(NR 11 R 12 )OH, -P(=O)R 11 (OH), -B(OH)2,

[0093] [ka]

[0094] and Y has one or more hydrogen atoms optionally replaced with deuterium.

[0095] In a more particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof, and Y is -CONH-CN, -CONHOR 10 , -C(=NOH)NR 11 R 12, -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 , -SO3H, -S(=O) x (=NR 13 ) y NHCOR 10 , -S(=O) x (=NR 13 ) y NHR 11 , -P(=O)(OH)2, -P(=O)(NR 11 R 12 )OH, -P(=O)R 11 (OH), -B(OH)2,

[0096] [ka]

[0097] and Y has one or more hydrogen atoms optionally replaced with deuterium.

[0098] In one embodiment, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof, and Y is CONH-CN, -CONHOR 10 , -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 ,

[0099] [ka]

[0100] and Y has one or more hydrogen atoms optionally replaced with deuterium.

[0101] In an even more particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof, and Y is -CONH-CN, -CONHOR 10 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12

[0102] [ka]

[0103] and Y has one or more hydrogen atoms optionally replaced with deuterium.

[0104] In a more particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof, and Y is

[0105] [ka]

[0106] and Y has one or more hydrogen atoms in the alkyl portion optionally replaced with deuterium.

[0107] In a similar most particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof, and Y is

[0108] [ka]

[0109] Selected from.

[0110] In one embodiment, Y is -CONHOR 10 and R 10 is C 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents, and the substituents are 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 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, and R 10 has one or more hydrogen atoms optionally replaced with deuterium.

[0111] In one particular embodiment, Y is -CONHOR 10 and R 10 is C 1-6 -alkyl, optionally substituted with 1 to 3 substituents, the substituents being selected from fluoro, -CN, -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, and R 10 has one or more hydrogen atoms optionally replaced with deuterium.

[0112] In a more particular embodiment, Y is -CONHOR 10 and R 10 is C 1-3 -alkyl, optionally substituted with 1 to 3 substituents, the substituents being independently selected from fluoro and -OH, and R 10has one or more hydrogen atoms optionally replaced with deuterium.

[0113] In one embodiment, Y is -CONHS(=O)R 10 and R 10 is C 1-3 -alkyl, optionally substituted with 1 to 3 fluoro substituents, and R 10 has one or more hydrogen atoms optionally replaced with deuterium.

[0114] In certain embodiments, Y is -CONHS(=O)2CH3 or -CONHS(=O)2CD3.

[0115] In a more particular embodiment, Y is -CONHS(=O)2CH3.

[0116] In another specific embodiment, Y is -CONHS(=O)2NH2.

[0117] In one embodiment, R 10 is C 1-3 -alkyl, cyclopropyl or oxetan-3-yl, which are unsubstituted or substituted with 1 to 3 substituents, which are independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R 10 has one or more hydrogen atoms optionally replaced with deuterium.

[0118] In one embodiment, R 10 is C 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents, and the substituents are 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 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, R 10 has one or more hydrogen atoms optionally replaced with deuterium.

[0119] In certain embodiments, R 10 is C 1-6 -alkyl, unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl; R 10 has one or more hydrogen atoms optionally replaced with deuterium.

[0120] In a more particular embodiment, R 10 is C 1-3 -alkyl, unsubstituted or substituted with 1 to 3 substituents independently selected from fluoro, -CN and -OH; R 10 has one or more hydrogen atoms optionally replaced with deuterium.

[0121] In still more particular embodiments, R 10 is CH3, CD3, CH2CH2OH or CD2CD2OH.

[0122] In one embodiment, R 11 and R 12 is H or C 1-3-alkyl, where alkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R 11 and / or R 12 has one or more hydrogen atoms optionally replaced with deuterium.

[0123] In certain embodiments, R 11 and R 12 is independently selected from H, CH3, and CD3.

[0124] In a more particular embodiment, R 11 and R 12 is H.

[0125] In one embodiment, R 13 is H, -CN and C 1-3 -alkyl, where 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 has one or more hydrogen atoms optionally replaced with deuterium.

[0126] In a more particular embodiment, R 13 is H.

[0127] In one embodiment, R 21 , R 22 , R 31 , R 32 , R 41 , R 42 is independently selected from H, CH3, and CD3.

[0128] In a more specific embodiment, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein B is phenyl, pyridyl, isoquinolinyl, quinolinyl, naphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, bicyclo[2.2.2]octanyl, or imidazo[1,2-a]pyridinyl, wherein the phenyl, pyridyl, isoquinolinyl, quinolinyl, naphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, bicyclo[2.2.2]octanyl, or imidazo[1,2-a]pyridinyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, CHF2, and CF3, and Residue on Ring B -NR 2 is in the 1,4-position relative to ring C.

[0129] In a more particular embodiment, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof, B is phenyl or pyridyl, the phenyl or pyridyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, CHF2, and CF3, and the residue -NR on ring B is 2 is in the 1,4-position relative to ring C.

[0130] In a more particular embodiment, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof, B is phenyl, phenyl is unsubstituted or substituted with 1-4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, OMe, OCD3, CHF2, and CF3, and the residue -NR on ring B is 2 is in the 1,4-position relative to ring C.

[0131] In a more particular embodiment, the compound is represented by formula (I), or a solvate or pharma- ceutically acceptable salt thereof, B is phenyl, phenyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, CHF2, and CF3, and the residue -NR on ring B is 2 is in the 1,4-position relative to ring C.

[0132] In a more particular embodiment, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof, B is phenyl, which is unsubstituted or substituted with 1 to 4 fluoro substituents, and the residue -NR on ring B is 2 is in the 1,4-position relative to ring C.

[0133] In a most particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof, and is represented by the formula: 2 B is,

[0134] [ka]

[0135] and the residue on ring B is -NR 2 is in the 1,4-position relative to ring C.

[0136] In the most particular embodiment, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof, and is represented by the formula: 2 B is,

[0137] [ka]

[0138] and the residue on ring B is -NR 2 is in the 1,4-position relative to ring C.

[0139] In a more particular embodiment, the compound is represented by formula (I): C is phenyl, pyridyl or thiazolyl, which is unsubstituted or substituted with 1 to 4 substituents, the substituents being D, F, Cl, -CN, C 1-4 -Alkyl, Fluoro-C 1-4 -Alkyl, OC 1-4 -Alkyl and O-Fluoro-C 1-4 -alkyl, where alkyl has one or more hydrogen atoms optionally replaced with deuterium; X is D, F, Cl, -CN, C 1-4 -Alkyl, Fluoro-C 1-4 -Alkyl, OC 1-4 -Alkyl and O-Fluoro-C 1-4 -alkyl, where alkyl has one or more hydrogen atoms optionally replaced with deuterium.

[0140] In a more particular embodiment, the compound is represented by formula (I): C is phenyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, CHF2, CF3, -OMe, -OCD3, -OCHF2, and -OCF3; X is selected from D, F, Cl, -CN, Me, CD3, CHF2, CF3, Et, CD2CD3, -OMe, -OCD3, -OCHF2, -OCF3, -OEt, and -OCD2CD3.

[0141] In one particular embodiment, [ka]

[0142] teeth, [ka]

[0143] and ring C is optionally substituted with 1 to 4 substituents selected from D and F.

[0144] In one particular embodiment, [ka]

[0145] teeth, [ka]

[0146] Selected from.

[0147] In a more particular embodiment, the compound is represented by formula (I):

[0148] [ka]

[0149] teeth, [ka]

[0150] Selected from.

[0151] In certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0152] [ka]

[0153] teeth, [ka]

[0154] and ring C is optionally substituted with 1 to 4 substituents independently selected from D or F.

[0155] In certain embodiments, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0156] [ka]

[0157] teeth, [ka]

[0158] Selected from.

[0159] In one particular embodiment, the compound is represented by formula (I) or a solvate or pharma- ceutically acceptable salt thereof:

[0160] Y is [ka]

[0161] Selected from

[0162] [ka]

[0163] teeth,

[0164] [ka]

[0165] Selected from

[0166] R 2 is H, B is,

[0167] [ka]

[0168] Selected from

[0169] [ka]

[0170] teeth, [ka]

[0171] Selected from.

[0172] In an even more particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof: Y is [ka]

[0173] Selected from

[0174] [ka]

[0175] teeth, [ka]

[0176] Selected from

[0177] R 2 is H, B is,

[0178] [ka]

[0179] Selected from

[0180] [ka]

[0181] teeth, [ka]

[0182] Selected from.

[0183] In an even more particular embodiment, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof: Y is

[0184] [ka]

[0185] Selected from

[0186] [ka]

[0187] teeth, [ka]

[0188] Selected from

[0189] R 2 is H, B is,

[0190] [ka]

[0191] Selected from

[0192] [ka]

[0193] teeth, [ka]

[0194] Selected from.

[0195] Similarly, in even more particular embodiments, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof: Y is

[0196] [ka]

[0197] Selected from

[0198] [ka]

[0199] teeth, [ka]

[0200] Selected from

[0201] R 2 is H, B is, [ka]

[0202] Selected from

[0203] [ka]

[0204] teeth, [ka]

[0205] Selected from.

[0206] Similarly, in even more particular embodiments, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof: Y is

[0207] [ka]

[0208] Selected from

[0209] [ka]

[0210] teeth, [ka]

[0211] Selected from

[0212] R 2 is H, B is, [ka]

[0213] Selected from

[0214] [ka]

[0215] teeth, [ka]

[0216] Selected from.

[0217] Similarly, in even more particular embodiments, the compound has formula (I) or a solvate or pharma- ceutically acceptable salt thereof: Y is

[0218] [ka]

[0219] Selected from

[0220] [ka]

[0221] teeth, [ka]

[0222] Selected from

[0223] R 2 is H, B is, [ka]

[0224] Selected from

[0225] [ka]

[0226] teeth, [ka]

[0227] Selected from.

[0228] In certain embodiments, the compound or a solvate or pharma- ceutically acceptable salt thereof is selected from the examples set forth in the Examples section.

[0229] In a most particular embodiment, the compound or a solvate or pharma- ceutically acceptable salt thereof is

[0230] [ka]

[0231] Selected from. Likewise in a most particular embodiment, the compound or a solvate or pharma- ceutically acceptable salt thereof is

[0232] [ka]

[0233] [ka]

[0234] [ka]

[0235] [ka]

[0236] Selected from.

[0237] The present invention also relates to a compound according to any of the above embodiments for use as a medicament.

[0238] The present invention also relates to a compound according to any of the above embodiments for use in the prevention and / or treatment of a disease, disorder, therapeutic indication or condition treatable by a DHODH inhibitor.

[0239] The present invention also relates to a compound according to any of the above embodiments for use in the prophylaxis and / or treatment of a DHODH mediated disease selected from rheumatism, acute immune diseases, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoan infestations in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy.

[0240] More specifically, the present invention relates to a compound according to any of the above embodiments for use, wherein the disease, disorder or therapeutic indication is selected from the group comprising graft versus host and host versus graft reaction, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

[0241] Also provided are pharmaceutical compositions comprising a compound of the invention and a pharma- ceutically acceptable carrier or excipient.

[0242] Also provided are pharmaceutical compositions comprising a compound of the invention and a pharma- ceutically acceptable carrier or excipient, further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, antiviral agents, immunosuppressants and / or immunomodulators, steroids, nonsteroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof. As used herein, the term "pharma- ceutically acceptable carrier" indicates that the carrier is approved or approved for use in animals, particularly humans, i.e., is not toxic to the host or patient. Furthermore, the carrier selected does not interfere with the effectiveness of the biological activity of the active ingredient. The term "carrier" refers to auxiliary materials necessary for the particular mode of administration selected, including, for example, solvents, diluents, excipients, or other additives used in administering the compounds of the invention. Pharmaceutical carriers of diluents typically used include sterile liquids such as aqueous solutions and oils (e.g., of petroleum, animal, vegetable, or synthetic origin), such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Aqueous liquids typically used include water, saline, aqueous dextrose, and glycerol solutions, and the like. Suitable pharmaceutical excipients include citric acid, ascorbic acid, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene, glycol, water, ethanol, etc. Optionally, the composition may contain additives such as wetting or emulsifying agents, pH buffering agents, or binders. Examples of suitable pharmaceutical carriers are well known in the art and are described, for example, in "Remington's Pharmaceutical Sciences" by EW Martin (18th Edition, Mack Publishing Company, Easton, PA (1990)).

[0243] According to the knowledge of the expert, the compounds of the present invention and their salts may contain various amounts of solvents, for example when isolated in crystalline form.The scope of the present invention therefore includes all solvates, particularly all hydrates, of the compounds of formula (I), as well as all solvates, particularly all hydrates, of the salts of the compounds of formula (I).The present invention further relates to a method for the prevention and / or treatment of diseases, disorders, therapeutic indications or conditions described herein, in particular diseases or conditions for which inhibition of DHODH is beneficial, more particularly diseases or conditions selected from the group including rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoan parasites in humans and animals, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy, wherein said method comprises administering to a subject in need thereof an effective amount of the compounds of formula (I) as described herein. Likewise, the invention also relates to the methods as described above including the further embodiments described herein, in particular the compounds for use in medical uses and treatments as described herein.

[0244] The present invention further relates to a method for the prevention and / or treatment of the diseases, disorders, therapeutic indications or conditions described herein, particularly diseases or conditions in which inhibition of DHODH is beneficial, more particularly a disease or condition selected from graft versus host reaction and host versus graft reaction, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as described herein.

[0245] The present invention further relates to pharmaceutical compositions, kits and kits-of-parts comprising the compounds according to the invention.

[0246] The present invention further relates to the use of the compounds of the present invention for the preparation of a pharmaceutical composition for use in the treatment and / or prevention of diseases, disorders, illnesses and / or conditions as described herein.

[0247] The present invention further relates to the methods and medical uses described herein, including pharmaceutical compositions as described herein.

[0248] Pharmaceutical compositions as described herein comprise one or more compounds according to the invention and a pharma- ceutically acceptable carrier or excipient.

[0249] Pharmaceutical compositions as described herein comprise one or more compounds according to the invention and a pharma- ceutically acceptable carrier or excipient, and further comprise one or more additional therapeutic agents selected from anti-inflammatory agents, antiviral agents, immunosuppressants and / or immunomodulators, steroids, nonsteroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

[0250] The present invention further relates to an article of manufacture comprising a packaging material and a pharmaceutical agent contained within said packaging material, said pharmaceutical agent having a therapeutic effect against a medical condition as described herein, said packaging material comprising a label or package insert indicating that said pharmaceutical agent is useful for the prevention or treatment of said medical condition, said pharmaceutical agent comprising one or more compounds of formula (I) according to the present invention, wherein the packaging material, label and package insert otherwise correspond to or are similar to what would generally be considered standard packaging material, labels and package inserts for pharmaceutical products having the relevant use.

[0251] The pharmaceutical compositions according to the invention are prepared by methods known per se and familiar to those skilled in the art. As pharmaceutical compositions, the compounds of the invention (= active compounds) are used as they are or, in particular, in combination with suitable pharmaceutical auxiliaries and / or excipients, for example, in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (for example, TTS), emulsions, suspensions, gels or solutions, with an active compound content advantageously between 0.1 and 95%, and by suitable selection of the auxiliaries and / or excipients, a pharmaceutical dosage form (for example, delayed release form or enteric form) exactly suited to the active compound and / or the desired action expression can be achieved.

[0252] Those skilled in the art are familiar with the auxiliary agents, vehicles, excipients, diluents, carriers or adjuvants suitable for desired pharmaceutical formulations, preparations or compositions by their expertise.In addition to solvents, gel-forming agents, ointment bases and other active compound excipients, for example, antioxidants, dispersants, emulsifiers, preservatives, solubilizers, colorants, complexing agents or penetration enhancers can be used.Depending on the specific disease to be treated or prevented, additional therapeutic active agents that are usually administered to treat or prevent that disease can be optionally combined with the compound according to the present invention.As used herein, additional therapeutic agents that are usually administered to treat or prevent a specific disease are known to be appropriate for the disease to be treated.

[0253] In a further aspect of the present invention, the compound according to the present invention or the salt or solvate of said compound of formula (I) can be combined with standard therapeutic agents commonly used in the treatment of pathologies as described herein. Those skilled in the art will recognize, based on their expert knowledge, the total daily dosage and administration form of the additional therapeutic agent to be combined. Said total daily dosage can vary within a wide range. In carrying out the present invention, depending on the details, characteristics or purpose of the above-mentioned use, the compound according to the present invention can be administered in combination therapy with one or more standard therapeutic agents, in particular chemotherapeutic agents or target-specific anticancer agents known in the art as described above, separately, sequentially, simultaneously or chronologically staggered (for example, as a combined unit dosage form, as separate unit dosage forms or as adjacent individual unit dosage forms, as a fixed or non-fixed combination, as a kit of parts or as a mixture).

[0254] Thus, a further aspect of the present invention is a combination or pharmaceutical composition comprising a first active ingredient which is a compound according to the present invention or a pharma- ceutically acceptable salt or solvate thereof, a second active ingredient which is a standard treatment known in the art for a condition as described herein, and optionally a pharma- ceutically acceptable carrier, diluent and / or excipient, for use in a sequential, separate, simultaneous or chronologically staggered treatment in any order, for example to treat, prevent or ameliorate a condition as described herein in a patient. In this context, the present invention further relates to a combination comprising a first active ingredient which is at least one compound according to the present invention and a second active ingredient which is at least one standard treatment known in the art for a condition as described herein, for use in a separate, sequential, simultaneous or chronologically staggered treatment in a treatment, such as for example the treatment of a disease as described herein.

[0255] The term "combination" according to the present invention can be present as a fixed combination, a non-fixed combination, or a kit of parts. A "fixed combination" is defined as a combination in which the first active ingredient and the second active ingredient are present together in one unit dosage or as a single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present as a mixture for simultaneous administration, for example in a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the second active ingredient are present in one unit without being mixed.

[0256] A "kit of parts" is defined as a combination in which the first active ingredient and the second active ingredient are present in multiple units. An example of a "kit of parts" is a combination in which the first active ingredient and the second active ingredient are present separately. The components of the kit of parts can be administered separately, sequentially, simultaneously or chronologically staggered.

[0257] The first and second active ingredients of the combination or kit of parts according to the invention are provided as separate formulations (i.e., independent of each other) and then combined for simultaneous, sequential, separate or chronologically staggered use in a combination therapy, or packaged and provided together as separate components of a combination pack for simultaneous, sequential, separate or chronologically staggered use in a combination therapy. The types of pharmaceutical formulations of the first and second active ingredients of the combination or kit of parts according to the invention can be similar, i.e., both ingredients are formulated in separate tablets or capsules, or different, i.e., suitable for different forms of administration, e.g., one active ingredient is formulated as a tablet or capsule and the other is formulated, e.g., for intravenous administration. The amounts of the first and second active ingredients of the combination, composition or kit according to the invention can together comprise a therapeutically effective amount for the treatment, prevention or amelioration of a pathology as described herein.

[0258] A further aspect of the present invention is a method of combination treatment of a condition as described herein in a patient in need of such treatment, comprising administering to said patient separately, sequentially, simultaneously, in a fixed or non-fixed combination, a therapeutically effective and acceptable amount of one or more compounds according to the present invention and a therapeutically effective and acceptable amount of one or more art-known therapeutic agents for a condition as described herein.

[0259] References and claims relating to the use of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, in its generic and specific forms, for the manufacture of a medicament for the treatment of a disease or condition, equally apply to the corresponding method of treatment of said disease or condition, said method comprising administering a therapeutically effective and acceptable amount of a compound of formula (I) or a pharma-ceutically acceptable salt or solvate thereof to a subject in need thereof, to a composition comprising a compound of formula (I) or a pharma-ceutically acceptable salt or solvate thereof for the treatment of said disease or condition, to a compound of formula (I) or a pharma-ceutically acceptable salt or solvate thereof for use in the treatment of said disease or condition, and vice versa.

[0260] For the preparation of pharmaceutical compositions, the compounds of the present invention (=active compounds) are mixed with, in particular, suitable pharmaceutical auxiliaries and further processed into suitable pharmaceutical preparations.Suitable pharmaceutical preparations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.The pharmaceutical compositions according to the present invention are prepared by methods known per se.

[0261] The administration of the active compound is carried out in customary amounts. Thus, topical application forms (ointments, etc.) contain, for example, the active compound in a concentration of 0.1 to 99%. Customary dosages for systemic therapy (oral) are usually 0.3 to 30 mg / kg / day, and (intravenous) are usually 0.3 to 30 mg / kg / hour. The optimal administration regime and duration of administration, in particular the choice of the optimal dose and method of administration of the active compound required in each case, can be determined by a person skilled in the art on the basis of their expert knowledge.

[0262] The class of compounds of the present invention is useful for the development of medicines suitable for the treatment of autoimmune or viral diseases and chronic inflammation, or more generally, for the treatment of diseases in which inhibition of DHODH is beneficial.The compounds of the present invention are also useful for the treatment of diseases such as rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoan parasitism in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy.More specifically, the selected diseases are useful for the treatment of diseases such as graft-versus-host reaction and host-versus-graft reaction, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

[0263] The class of compounds of the present invention is useful for the treatment of acute viral infections, particularly selected from coronavirus infections, COVID-19, SARS, flu / influenza (and avian flu), HIV / AIDS, chickenpox (varicella), cytomegalovirus, dengue fever, rubella, hand, foot and mouth disease, hantavirus infections, all forms of hepatitis, Lassa fever, Marburg virus infection, measles, meningitis, MERS-CoV, mumps, norovirus infection, herpes simplex virus infection, smallpox, rotavirus infection, Ebola virus, poliovirus infection, rhinovirus infection, parainfluenza virus infection, respiratory syncytial virus infection, HCMV infection and bannavirus infection. Most preferred as COVID-19, flu / influenza and rhinovirus infection is COVID-19. It is understood that mutated forms of the virus (such as SARS-CoV-2) are also of interest.

[0264] Combination or alternating therapy The compounds as described herein, or pharma- ceutically acceptable salts thereof, can be administered in addition to the current standard of care for the patient, or in combination or alternation with other compounds or therapies that the health care provider deems beneficial to the patient. The combination and / or alternation therapy can be curative, adjunctive or palliative.

[0265] Particularly preferred is a combination or alternation therapy for the treatment of antiviral infections, especially Covid-19.

[0266] High levels of the cytokine interleukin-6 (IL-6) have been observed to be a precursor to respiratory failure and death in COVID-19 patients. To treat this surge in immune response, which may constitute a cytokine storm, patients can be administered pharmaceutical inhibitors or protein degraders, such as monoclonal antibodies targeting IL-6, bispecific compounds that bind to IL-6 and also to proteins that mediate degradation. Examples of antibodies include tocilizumab, sarilumab, siltuximab, olokizumab and clazakizumab. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination or alternation with tocilizumab or sarilumab. Additional non-limiting examples of immunosuppressants used to treat an overactive immune system include Janus kinase inhibitors (tofacitinib, baricitinib, filgotinib), calcineurin inhibitors (cyclosporine), tacrolimus, mTOR inhibitors (sirolimus, everolimus) and IMDH inhibitors (azathioprine). Additional antibodies and biologics include abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab, basiliximab and daclizumab.

[0267] IL-1 inhibits the production of IL-6 and other inflammatory cytokines. COVID patients are sometimes treated with anti-IL-1 therapies, such as intravenous anakinra, to reduce the hyperinflammatory response. Anti-IL-1 therapies can generally be targeted monoclonal antibodies, pharmaceutical inhibitors, or pharmaceutical inhibitors or protein degraders, such as bispecific compounds that bind to IL-1 and also bind to proteins that mediate degradation.

[0268] COVID patients often develop viral pneumonia, which can lead to bacterial pneumonia. Severe COVID-19 patients can also suffer from sepsis or "septic shock". Treatment of bacterial pneumonia or sepsis secondary to COVID includes administration of antibiotics, such as macrolide antibiotics, including azithromycin, clarithromycin, erythromycin, or roxithromycin. Additional antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanic acid, or levofloxacin. In one embodiment, therefore, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination or alternation with an antibiotic, such as azithromycin. Some of these antibiotics, such as azithromycin, have independent anti-inflammatory properties. Such agents can be used as anti-inflammatory agents in COVID patients and can also have a therapeutic effect against secondary bacterial infections.

[0269] A unique challenge in treating patients infected with COVID-19 is that if the patient requires mechanical ventilation, sedation is required for a relatively long period of time, which may last for 5, 10, or even 14 days or more. If pain persists during this treatment, pain medication can be added sequentially, and if anxiety persists, sedation medication can be added sequentially. Non-limiting examples of pain medication include acetaminophen, ketamine, and PRN opioids (hydromorphone, fentanyl, and morphine). Non-limiting examples of sedatives include melatonin, atypical antipsychotics with predominantly sedative effects (olanzapine, quetiapine), propofol or dexmedetomidine, haloperidol, and phenobarbital. In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt, solvate, salt hydromorphone or polymorph thereof is administered in combination or alternation with an analgesic agent, such as acetaminophen, ketamine, hydromorphone, fentanyl or morphine. In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt, solvate, salt solvate, hydrate or polymorph thereof is administered in combination or alternation with a sedative agent, such as melatonin, olanzapine, quetiapine, propofol, dexmedetomidine, haloperidol or phenobarbital.

[0270] In one embodiment, the compounds of the invention are used in an effective amount in combination with a protease inhibitor, such as PF-07304814, PF-00835231, PF-07321332 (nilmatrellvir), lopinavir or ritonavir. In another particular embodiment, the protease inhibitor is PF-07321332 (nilmatrellvir).

[0271] In one embodiment, the compounds of the present invention are used in effective amounts in combination with an RNA replication modulator, such as N4-hydroxycytidine, or a prodrug thereof may also be administered. In one particular embodiment, the RNA replication modulator is an N4-hydroxycytidine prodrug as described in WO 2019 / 113462. In another particular embodiment, the RNA replication modulator is molnupiravir.

[0272] In one embodiment, the compounds of the present invention are used in an effective amount in combination with Halofuginol or its enantiomers, tautomers, solvates or pharma- ceutically acceptable salts.In one embodiment, the compounds of the present invention are used in an effective amount in combination with dipyridamole or its solvates or pharma- ceutically acceptable salts.In one embodiment, the compounds of the present invention are used in an effective amount in combination with gemcitabine or its solvates or pharma- ceutically acceptable salts.

[0273] In one embodiment, a compound of the invention is used in an effective amount in combination with AT-527 (RO7496998), or a solvate or pharma- ceutically acceptable salt thereof.

[0274] Additional drugs that may be used to treat COVID patients include, but are not limited to, aspirin, colchicine, dimethyl fumarate, acalabrutinib, favipiravir, fingolimod, methylprednisolone, bevacizumab, tocilizumab, umifenovir, losartan, and the monoclonal antibody combination REGN3048 and REGN3051, or ribavirin. Any of these drugs or vaccines can be used in combination or alternation with the active compounds provided herein to treat viral infections susceptible to such drugs or vaccines.

[0275] In one embodiment, the compounds of the invention are used in effective amounts in combination with anti-coronavirus vaccine therapies, including but not limited to, mRNA-1273 (Moderna), AZD-1222 (AstraZeneca and University of Oxford), BNT162b2 (BioNTech), CoronaVac (Sinovac), NVX-CoV 2372 (NovoVax), SCB-2019 (Sanofi and GSK), ZyCoV-D (Zydus Cadila) and CoVaxin (Bharat Biotech). In another embodiment, the compounds of the invention are used in effective amounts in combination with passive antibody therapy or convalescent plasma therapy.

[0276] SARS-CoV-2 is constantly mutating, often increasing virulence and infection rates. Drug-resistant viral variants may emerge after long-term treatment with antiviral drugs. Drug resistance may occur through mutations in genes that code for enzymes used in viral replication. The efficacy of a drug against RNA viral infections can be extended, enhanced or restored in certain cases by administering it in combination or alternation with another antiviral compound, perhaps even two or three other antiviral compounds, that induce different mutations or act in a different pathway than the main drug. A variant of a known virus refers to a virus that has one or more nucleotide mutations in the viral genome compared to a known virus, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 60, 100, 200, 300, or more nucleotide mutations. Mutations can refer to deletions, insertions, or substitutions of nucleotides. In some cases, the variant may differ from the genome of a known virus by up to 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2% or 1%.

[0277] Alternatively, the pharmacokinetics, biodistribution, half-life or other parameters of the drugs may be modified by such combination therapy (which may include alternation therapy, if considered synergistic). Examples of other therapeutic agents that may be combined with the compounds of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of a salt, hydrate, or polymorph thereof, and that may be administered separately or in the same pharmaceutical composition, include, but are not limited to, the following: (1) Protease inhibitors (2) Polymerase inhibitors (e.g. gemcitabine) (3) Allosteric polymerase inhibitors (4) interferon alpha-2a, which may be pegylated or otherwise modified, and / or ribavirin (5) Non-substrate-based inhibitors (6) Helicase inhibitors (7) Primase helicase inhibitors (8) Antisense oligodeoxynucleotides (S-ODN) (9) Aptamers (10) Nuclease-resistant ribozymes (11) iRNA (including microRNA and siRNA) (12) Antibody, partial antibody, or domain antibody against a virus (13) Viral antigens or partial antigens that induce host antibody responses (14) NOD, LRR and pyrin domain-containing protein 3 (NLRP3) (15) Glutamylprolyl tRNA synthetase inhibitors (e.g., halofuginone) (16) Equilibrative nucleoside transporter (ENT) inhibitors (e.g., dipyridamole) (17) Other DHODH inhibitors (e.g., brequinar, teriflunomide, leflunomide, PTC299, MEDS433, AG-636, ASLAN003, JNJ-74856665, RP7214, PP-001, and BAY2402234).

[0278] It is recognized that synthetic compounds may have some variation in natural isotope abundance, depending on the origin of the chemicals used in synthesis.Therefore, preparations of Bidofuldimus and compounds according to formula (I) that do not exhibit any deuterium will inherently contain small amounts of deuterated isotopes.Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotope substitution of the compounds of the present invention.See, for example, Comp. Biochem. Physiol. 1998;119A:725.

[0279] The term "isotopic enrichment factor" at a particular position normally occupied by hydrogen refers to the ratio of the abundance of deuterium at that position to the natural abundance of deuterium at that position. For example, an isotopic enrichment factor of 3500 means that the amount of deuterium at a particular position is 3500 times the natural abundance of deuterium, or that 52.5% of compounds contain deuterium at that position (i.e., the incorporation of deuterium at the particular position is 52.5%). The abundance of deuterium in Earth's oceans is about 1 atom per 6500 hydrogen atoms (about 154 ppm). Thus, deuterium accounts for about 0.015% (0.030% by weight) of all hydrogen atoms naturally present in Earth's oceans. Abundances vary slightly in different types of natural waters.

[0280] When a particular position in a compound of the invention (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof) is designated by name or structure as containing hydrogen or deuterium, the position may contain hydrogen at its natural abundance or may contain hydrogen at its natural abundance, e.g., at least 835 (12.5% ​​deuterium incorporation), at least 1670 (25% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 500 (50% deuterium incorporation), at least 6000 (60% deuterium incorporation), at least 7000 (70% deuterium incorporation), at least 8000 (80% deuterium incorporation), at least 9000 (90% deuterium incorporation), at least 10000 (10 ... It is understood that the deuterium can be enriched in deuterium by an isotopic enrichment factor of at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0281] When a particular position in a compound of the invention (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof) is specifically designated by name or structure as "H" or "hydrogen," the position is understood to have hydrogen in its natural abundance isotopic composition.

[0282] When a particular position in a compound of the invention (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof) is specifically designated by name or structure as "D" or "deuterium," the position is at least 3340 times the natural abundance of deuterium, i.e., 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 times the natural abundance of deuterium (52.5% deuterium incorporation), at least 4500 times the natural abundance of deuterium (67.5% deuterium incorporation), at least 5000 times (75% deuterium incorporation), at least 5500 times the natural abundance of deuterium (82.5% deuterium incorporation), at least 6000 times the natural abundance of deuterium. (90% deuterium incorporation), at least 6333.3 times the natural abundance of deuterium (95% deuterium incorporation), at least 6466.7 times the natural abundance of deuterium (97% deuterium incorporation), at least 6600 times the natural abundance of deuterium (99% deuterium incorporation), or at least 6633.3 times the natural abundance of deuterium (99.5% deuterium incorporation).

[0283] Deuterium incorporation can be determined by quantitative analysis using a number of conventional methods, such as mass spectrometry (peak area) or by determining the residual concentration of specific deuterium sites. 1 The H-NMR signal may be from an internal standard or other non-deuterated 1 The signal can be obtained by quantification in comparison with the H signal.

[0284] When a chemical name or structure does not specify whether a particular position in a compound normally occupied by hydrogen is isotopically enriched, it is intended that the particular position is occupied by hydrogen at natural abundance. For example, "phenyl" or

[0285] [ka]

[0286] indicates that all hydrogen atoms are present in natural abundance, unless further specified regarding isotopic enrichment.

[0287] When ring A is a partially saturated ring, the double bond of ring A is at the position shown:

[0288] [ka]

[0289] When ring A is a 5-membered heteroaryl ring, the double bond is in a delocalized pi-system and can exist in a mesomeric form. An example is the following thiophene mesomeric form:

[0290] [ka]

[0291] Furthermore, the compounds of the present invention partially exhibit tautomerism. For example, when a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on the carbon atom adjacent to the nitrogen atom, the following tautomerism may occur:

[0292] [ka]

[0293] The cycloalkyl or heterocycloalkyl group can be attached in a linear or spirocyclic fashion, for example when cyclohexane is substituted with the heterocycloalkyl group oxetane the following structure is possible:

[0294] [ka]

[0295] The term "1,4-position" (as described for Ring B) indicates a specific relative position of two substituents on the same ring, meaning that there is at least one possibility for a substituent on the ring, and that there are four atoms between the two substituents in the ring attached to the ring system.

[0296] [ka]

[0297] The term "1,3-position" refers to a specific relative position of two substituents on the same ring, meaning that there is at least one possibility for a substituent on the ring and that there are three atoms between the two substituents attached to the ring system. For example,

[0298] [ka]

[0299] The term "compound" when referring to the compounds of the present disclosure, including a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof, refers to a collection of molecules having identical chemical structure, except for the possible isotopic variation among the constituent hydrogen atoms of the molecule. The relative amount of isotopic variation in the compounds of the present invention will depend on several factors, including the isotopic purity of the deuterated reagent used in the manufacture of the compound, and the efficiency of deuterium incorporation during the various synthetic steps used to prepare the compound. "D" and "d" both refer to deuterium. "H" refers to hydrogen. "Deuterium substitution" refers to the replacement of one or more hydrogen atoms with the corresponding number of deuterium atoms.

[0300] Any formula or structure depicted herein is also intended to represent deuterated compounds that contain isotopically enriched atoms. Examples of additional isotopes that may be incorporated into the compounds of the present disclosure include additional isotopes of hydrogen (i.e., tritium or 3 H), as well as isotopes of carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, including, but not limited to, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125The present disclosure includes: 3 H, 13 C and 14 Further included are various isotopically labeled compounds into which radioactive isotopes such as C are incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including metabolic studies, reaction kinetic studies, drug or substrate tissue distribution assays, or radiation treatment of patients.

[0301] Halogen is selected from fluorine, chlorine, bromine and iodine, more preferably fluorine or chlorine, most preferably fluorine.

[0302] In the context of the present invention, "C 1-4 By "alkyl" is meant a saturated hydrocarbon chain, preferably having 1 to 4 carbon atoms, which may be linear or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. Preferably, C alkyl, such as methyl, ethyl, propyl, isopropyl, etc. 1-3 Preferably, the alkyl group is an alkyl group, most preferably methyl. The term "alkyl" by itself or other substituents, such as halo-C 1-4 When used as part of an alkyl group, unless otherwise specified, it is intended to include those derivatives of alkyl defined in more detail below as "unsaturated alkyl". Unsaturated alkyl groups are groups with one or more double or triple bonds. Preferred unsaturated alkyl substituents are vinyl, 2-propenyl or prop-2-yn-1-yl.

[0303] In the context of the present invention, "C having one or more hydrogen atoms in the alkyl group, which are optionally replaced with deuterium" 1-4 The term "alkyl" includes, but is not limited to, the following residues: -CD3, -CH2D, -CHD2, CD3CH2(CH2). n -, CD3CH2(CHD) n -, CD3CH2(CD2) n -, CH2DCH2(CH2)n -, CH2DCH2(CHD) n -, CH2DCH2(CD2) n -, CHD2CH2(CH2) n -, CHD2CH2(CHD) n -, CHD2CH2(CD2) n -, CD3CHD(CH2) n -, CD3CHD(CHD) n -, CD3CHD(CD2) n -, CH2DCHD(CH2) n -, CH2DCHD(CHD) n -, CH2DCHD(CD2) n -, CHD2CHD(CH2) n -, CHD2CHD(CHD) n -, CHD2CHD(CD2) n -, CH3CHD(CH2) n -, CH3CHD(CHD) n -, CH3CHD(CD2) n -, CD3CD2(CH2) n -, CD3CD2(CHD) n -, CD3CD2(CD2) n -, CH2DCD2(CH2) n -, CH2DCD2(CHD) n -, CH2DCD2(CD2) n -, CHD2CD2(CH2) n -, CHD2CD2(CHD) n -, CHD2CD2(CD2) n -, CH3CD2(CH2) n -, CH3CD2(CHD) n -, CH3CD2(CD2) n - (wherein n is an integer from 0 to 2) and CH3CH2(CHD) m -, CH3CH2(CD2) m - (wherein m is an integer from 1 to 2), as well as -CD(CD3)2, -CH(CD3)2 and -C(CD3)3. Preferred deuterium-containing C 1-2 -Alkyl is -CD3 and -CD3CD2, most preferably -CD3.

[0304] "C 0-6 "-alkylene" means that each group is divalent and connects the attached residue to the remainder of the molecule. Furthermore, in the context of the present invention, "C0-alkylene" is intended to represent a bond, while C1-alkylene means a methylene linker, C2-alkylene means an ethylene linker or a methyl substituted methylene linker, etc. In the context of the present invention, C 0-6 -Alkylene preferably represents a bond, methylene, an ethylene group or a propylene group. The term "alkylene" is used without limitation where appropriate (i.e., "C 2-6 -C4-alkylene), it is also intended to include unsaturated divalent chains. A representative example of an unsaturated C4-alkylene is -CH2-CH=CH-CH2-.

[0305] "Fluoro-C 1-4 -alkyl" or "O-fluoro-C 1-4 The term "-alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced with one or more fluoro atoms, respectively. Preferred are CHF2, CF3, CH2CF3 and CF2CF3. A more preferred example is the formation of the -CF3 group. The same thing happened with "Halo-C 1-4 -alkyl" or "O-halo-C 1-4 The term "-alkyl" also applies to "-alkyl", which means that one or more hydrogen atoms in the alkyl chain are replaced with one or more halogen atoms independently selected from fluoro, chloro, bromo and iodo.

[0306] In the context of the present invention, "fluoro C having one or more hydrogen atoms in the alkyl optionally replaced with deuterium" 1-4 The term "alkyl" refers to fluoroC 1-4 When the alkyl group contains one or more hydrogen atoms, one or more hydrogen atoms are replaced by fluorine, and the above-mentioned "C having one or more hydrogen atoms optionally replaced by deuterium in the alkyl group" is used. 1-4This means that the result will be the same as for "alkyl". 1-4 It is understood that the alkyl can also be fully fluorinated. Deuterium-containing fluoro-C such as CDF2, CD2CF3, and CD2CF2D. 1-2 Alkyl is preferred. Most preferred is CDF2.

[0307] A "3 to 10-membered cycloalkyl" group means a saturated or partially unsaturated monocyclic, bicyclic, spirocyclic or polycyclic ring system containing 3 to 10 carbon atoms, where each atom forming the ring system (i.e., the skeletal atoms) is a carbon atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octanyl, spiro[3.3]heptyl, bicyclo[2.2.1]heptyl, adamantyl and pentacyclo[4.2.0.0]. 2,5 .0 3,8 .0 4,7 Thus, a 3- to 6-membered cycloalkyl group means a saturated or partially unsaturated monocyclic, bicyclic or spirocyclic ring system containing 3 to 6 carbon atoms, and a 5- to 8-membered cycloalkyl group means a saturated or partially unsaturated monocyclic, bicyclic or spirocyclic ring system containing 5 to 8 carbon atoms.

[0308] The term "3- to 6-membered cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, and spiro[2.3]hexanyl. More preferred are cyclopropyl or cyclobutyl.

[0309] The "3-10-membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O and S" group refers to a saturated or partially unsaturated 3-10-membered carbon monocyclic, bicyclic, spirocyclic or polycyclic ring in which 1, 2, 3 or 4 carbon atoms are replaced by 1, 2, 3 or 4 heteroatoms, respectively, independently selected from N, O or S. The sulfur heteroatom in the ring can also be oxidized to S=O or SO2. The carbon atoms in the ring can also be oxidized to C=O. Examples include epoxydyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyltetrahydropyranyl, 1,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1,4-dihydropyridinyl and 6-azabicyclo[3.2.1]octanyl. Heterocycloalkyl groups can be attached to the remainder of the molecule through a carbon, nitrogen (such as morpholine or piperidine), or sulfur atom. An example of an S-linked heterocycloalkyl is cyclic sulfonimidamide.

[0310] [ka]

[0311] The term "3 to 6-membered heterocycloalkyl" includes, but is not limited to, epoxydyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxaspiro[3.3]heptyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, and the like. The "6 or 10-membered aryl" is phenyl or naphthyl. "5-10-membered heteroaryl containing 1-6 heteroatoms independently selected from N, O and S" refers to a 5-10-membered monocyclic or bicyclic heteroaromatic ring system (also referred to as heteroaryl in this application) containing 1-6 heteroatoms independently selected from N, O and S. Examples of monocyclic heteroaromatic rings include pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. Additionally, it refers to bicyclic ring systems in which heteroatoms may be present in one or both rings, including bridgehead atoms. Examples include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl, 1,5-naphthyridinyl, 1,7-naphthyridinyl, and pyrazolo[1,5-a]pyrimidinyl. The nitrogen or sulfur atom of the heteroaryl system may be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. "Five-membered heteroaryl" refers to a monocyclic aromatic ring system containing up to three heteroatoms independently selected from N, O, and S. Examples of monocyclic heteroaromatic rings include pyrrolyl, imidazolyl, furanyl, thiophenyl, and oxazolyl. The sulfur heteroatom in the ring may also be oxidized to S=O or SO2.

[0312] A 5-membered heterocyclopentenyl group refers to a partially unsaturated 5-membered carbomonocyclic ring in which one or two carbon atoms are replaced by one or two heteroatoms, respectively, independently selected from N, O, and S. Examples include 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl, or 2,5-dihydro-1H-pyrrole. The sulfur heteroatom in the ring can also be oxidized to S=O or SO2.

[0313] Depending on their structure, the compounds of the present invention may exist in the form of tautomers or stereoisomers (enantiomers, diastereomers). The present invention therefore also encompasses tautomers, enantiomers or diastereomers and their respective mixtures. Stereomerically homogeneous components can be isolated from such mixtures of such enantiomers and / or diastereomers by known methods. The term "diastereomers" refers to stereoisomers that are not mirror images of each other and are not superimposable on each other. The term "enantiomer" refers to individual optically active forms of the compounds of the present invention, having an optical purity or enantiomeric excess (measured by standard methods in the art) of at least 80% (i.e. at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, more preferably at least 98%.

[0314] The term "pharmaceutical acceptable salts" refers to salts prepared from pharmaceutical acceptable non-toxic bases, including inorganic and / or organic bases. Thus, compounds of the present disclosure that contain acidic groups can be present on these groups and can be used according to the present disclosure, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting with an organic or inorganic base in a solvent or dispersant, or by cation exchange with other salts. The present disclosure also includes all salts of compounds of the present disclosure that are not suitable for direct use in pharmaceuticals due to poor physiological compatibility, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutical acceptable salts.

[0315] In addition, the compounds of the present disclosure may exist in the form of solvates, such as those that include water as a solvate, or pharma- ceutically acceptable solvates, such as alcohols, especially ethanol. Stoichiometric or non-stoichiometric amounts of the solvent are bound by non-covalent intermolecular forces. When the solvent is water, the "solvate" is a "hydrate". It is understood that the "pharma-ceutically acceptable salt" can further include a "solvate" in some cases.

[0316] As used herein, the term "polymorph" refers to a crystalline form of a compound or its salt, hydrate or solvate in a particular crystal packing arrangement. All polymorphs have the same elemental composition. As used herein, the term "crystal" refers to a solid state in which structural units are arranged in an orderly manner. Different crystalline states of the same compound, or its salt, hydrate or solvate, arise from different packing of molecules in the solid state, resulting in different crystal symmetries and / or unit cell parameters. Different crystalline states usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.

[0317] The term "effective amount" is intended to include an amount of a compound sufficient when administered to prevent the onset of, or alleviate to some extent, one or more symptoms of the disorder, disease, or condition being treated. The term "effective amount" also refers to an amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician. As used herein, the term "subject" refers to any member of the animal kingdom, including humans. In some embodiments, "subject" refers to a human at any stage of development. In some embodiments, "subject" refers to a human patient. In some embodiments, "subject" refers to a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, or pig). In some embodiments, the subject includes, but is not limited to, a mammal, a bird, a reptile, an amphibian, a fish, or an insect. In some embodiments, the subject can be a transgenic animal, a genetically engineered animal, or a clone.

[0318] Compounds as detailed herein have been unexpectedly found to exhibit beneficial effects, such as, for example, improved microsomal stability, as further details are provided in the Examples section below. In the above context, the following sequentially numbered embodiments provide further particular aspects of the present invention.

[0319] 1. Formula (I): [ka]

[0320] or an enantiomer, diastereomer, tautomer, solvate, or pharma- ceutically acceptable salt thereof, In the above formula, A is selected from 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl, in which one or more hydrogen atoms are optionally replaced with deuterium, and said A is unsubstituted or substituted with 1 to 5 substituents, which are halogen, -CN, -NO2, oxo, -OH, C 1-4 -Alkyl, -OC 1-4 -Alkyl, Fluoro-C 1-4 -Alkyl and -O-fluoro-C 1-4-alkyl, wherein Ring A has one or more hydrogen atoms in the alkyl optionally replaced by deuterium; B is selected from the group consisting of 5- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents, the substituents being halogen, -CN, -NO2, oxo, C 1-4 -Alkyl, C 0-6 -Alkylene-OR 21 , C 0-6 -Alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-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-CO2R 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 -CO2R 21 , C 0-6 -Alkylene-NR 21 R 22 Independently selected from the group consisting of: Alkyl, alkylene, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, the substituents being halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated ring, optionally containing 1 to 3 heteroatoms independently selected from O, S or N; The additional ring may optionally be a halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -substituted by 1 to 4 substituents independently selected from alkyl, Residue on ring B -NR 2 is in the 1,4-position relative to ring C, B has one or more hydrogen atoms optionally replaced with deuterium; C is selected from the group consisting of 5- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents, the substituents being halogen, -CN, -NO2, oxo, C 1-4 -Alkyl, C 0-6 -Alkylene-OR 31 , C 0-6 -Alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -Alkylene-S(=O) n (=NR 33 ) m R 31 , C 0-6 -Alkylene-NR 31 S(=O) x (=NR 33 ) y R 31 , C 0-6 -Alkylene-S(=O) x (=NR 33 ) y NR 31 R 32 , C 0-6 -Alkylene-NR 31 S(=O) x (=NR 33 ) y NR 31 R 32 , C 0-6 -Alkylene-CO2R 31 , C 0-6 -Alkylene-O-COR 31 , C 0-6 -Alkylene-CONR 31 R 32 , C 0-6 -Alkylene-NR 31 -COR 31 , C 0-6 -Alkylene-NR 31-CONR 31 R 32 , C 0-6 -Alkylene-O-CONR 31 R 32 , C 0-6 -Alkylene-NR 31 -CO2R 31 , C 0-6 -Alkylene-NR 31 R 32 Independently selected from the group consisting of: Alkyl, alkylene, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, the substituents being halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated ring, optionally containing 1 to 3 heteroatoms independently selected from O, S or N; The additional ring is optionally substituted with 1 to 4 substituents, including halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, C has one or more hydrogen atoms optionally replaced with deuterium; X is H, D, halogen, -CN, -NO2, C 1-6 -Alkyl, -OC 1-6 -Alkyl, O-Halo-C 1-6 -Alkyl, C 0-6 -Alkylene-OR 41 , C 0-6 -Alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -Alkylene-S(=O) n (=NR43 ) m R 41 , C 0-6 -Alkylene-NR 41 S(=O) x (=NR 43 ) y R 41 , C 0-6 -Alkylene-S(=O) x (=NR 43 ) y NR 41 R 42 , C 0-6 -Alkylene-NR 41 S(=O) x (=NR 43 ) y NR 41 R 42 , C 0-6 -Alkylene-CO2R 41 , C 0-6 -Alkylene-O-COR 41 , C 0-6 -Alkylene-CONR 41 R 42 , C 0-6 -Alkylene-NR 41 -COR 41 , C 0-6 -Alkylene-NR 41 -CONR 41 R 42 , C 0-6 -Alkylene-O-CONR 41 R 42 , C 0-6 -Alkylene-NR 41 -CO2R 41 , C 0-6 -Alkylene-NR 41 R 42 Selected from Heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; Alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, the substituents being halogen, -CN, oxo, -OH, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, -OC1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, X has one or more hydrogen atoms optionally replaced with deuterium; Y is -CONH-CN, -CONHOH, -CONHOR 10 , -CONR 10 OH, -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 , -SO3H, -S(=O) x (=NR 13 ) y NHCOR 10 , -S(=O) x (=NR 13 ) y NHR 11 , -P(=O)(OH)2, -P(=O)(NR 11 R 12 )OH, -P(=O)R 11 (OH), -B(OH)2,

[0321] [ka]

[0322] Selected from Y has one or more hydrogen atoms optionally replaced with deuterium; R 2 H and C 1-6 -alkyl, Alkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4-Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 2 has one or more hydrogen atoms optionally replaced with deuterium; R 10 is C 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 10 has one or more hydrogen atoms optionally replaced with deuterium; R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , R 42 is H, C 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 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 and / or R 31 and / or R 32 and / or R 41 and / or R 42 has one or more hydrogen atoms optionally replaced with deuterium, or R 11 and R 12 , R 21 and R 22 , R 31 and R 32 , R 41 and R 42 each, when taken together with the nitrogen to which they are attached, completes a 3- to 6-membered ring containing carbon atoms and optionally 1 to 2 heteroatoms selected from O, S or N; and The ring is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, R 11 and / or R 12 and / or R 21 and / or R 22 and / or R 31and / or R 32 and / or R 41 and / or R 42 has one or more hydrogen atoms optionally replaced with deuterium; R 13 , R 23 , R 33 , R 43 is H, -CN, -NO2, C 1-6 -Alkyl, -CO-OC 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 13 and / or R 23 and / or R 33 and / or R 43 has one or more hydrogen atoms optionally replaced with deuterium; n, m, x, and y are independently selected from 0 to 2; provided that the sum of integers m and n for residues bonded to the same sulfur atom is independently selected from 0 to 2; provided that the sum of integers x and y for residues bonded to the same sulfur atom is independently selected from 1 or 2; and However, the following structures are excluded:

[0323] [ka]

[0324] 2. A compound of formula (I) according to embodiment 1, or a solvate or a pharma- ceutically acceptable salt thereof, wherein: Y is -CONH-CN, -CONHOR 10 , -CONR 10 OH, -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 ,

[0325] [ka]

[0326] Selected from R 10 is C 1-3 -alkyl, cyclopropyl or oxetan-3-yl, Alkyl, cyclopropyl or oxetan-3-yl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R 10 has one or more hydrogen atoms optionally replaced with deuterium; R 11 and R 12 is H or C 1-3 -alkyl, 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 11 and / or R 12 has one or more hydrogen atoms optionally replaced with deuterium; R13 is H, -CN and C 1-3 -alkyl, Alkyl is unsubstituted or substituted with 1 to 3 substituents selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R 13 has one or more hydrogen atoms optionally replaced with deuterium; Either x is and y is 1, or x is 2 and y is 0.

[0327] 3. A compound of formula (I) according to embodiment 1 or 2, or a solvate or a pharma- ceutically acceptable salt thereof, wherein Y is -CONH-CN, -CONHOR 10 , -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 ,

[0328] [ka]

[0329] Selected from R 10 is C 1-3 -alkyl, cyclopropyl or oxetan-3-yl, Alkyl, cyclopropyl or oxetan-3-yl is unsubstituted or substituted with 1 to 3 substituents independently selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R 10 has one or more hydrogen atoms optionally replaced with deuterium; R 11 and R12 is H or C 1-3 -alkyl, 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 11 and / or R 12 has one or more hydrogen atoms optionally replaced with deuterium; R 13 is H, -CN and C 1-3 -alkyl, Alkyl is unsubstituted or substituted with 1 to 3 substituents selected from F, -CN, Me, CHF2, CF3, -OH, oxo, -OMe, -OCHF2 and -OCF3; R 13 has one or more hydrogen atoms optionally replaced with deuterium; Either x is and y is 1, or x is 2 and y is 0.

[0330] 4. A compound of formula (I) according to any one of embodiments 1 to 3, [ka]

[0331] teeth,

[0332] [ka]

[0333] Selected from, and R 2 is H.

[0334] 5. A compound of formula (I) according to any one of embodiments 1 to 4, [ka]

[0335] teeth, [ka]

[0336] Selected from, and R 2 is H.

[0337] 6. A compound of formula (I) according to any one of embodiments 1 to 5, One or more hydrogen atoms in any substituent are replaced by deuterium.

[0338] 7. A compound of formula (I) according to any one of embodiments 1 to 6, B is phenyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, CHF2 and CF3, and the residue -NR on ring B is 2 is in the 1,4-position relative to ring C.

[0339] 8. A compound of formula (I) according to any one of embodiments 1 to 7, C is phenyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D, F, Cl, -CN, Me, CD3, CHF2, CF3, -OMe, -OCD3, -OCHF2, and -OCF3; X is selected from D, F, Cl, -CN, Me, CD3, CHF2, CF3, Et, CD2CD3, -OMe, -OCD3, -OCHF2, -OCF3, -OEt, and -OCD2CD3.

[0340] 9. A compound of formula (I) according to any one of embodiments 1 to 8, [ka]

[0341] teeth, [ka]

[0342] Selected from Ring C is optionally substituted with 1 to 4 substituents, the substituents being independently selected from D or F.

[0343] 10. A compound of formula (I) according to any one of embodiments 1 to 8, [ka]

[0344] teeth, [ka]

[0345] Selected from.

[0346] 11. A compound of formula (I) according to any one of embodiments 1 to 10, Y is [ka]

[0347] Selected from

[0348] [ka]

[0349] teeth, [ka]

[0350] Selected from R 2 is H, B is,

[0351] [ka] Selected from

[0352] [ka]

[0353] teeth, [ka]

[0354] Selected from.

[0355] 12. A compound of formula (I) according to any one of embodiments 1 to 10, Y is [ka]

[0356] Selected from

[0357] [ka]

[0358] teeth, [ka]

[0359] Selected from R 2 is H, B is,

[0360] [ka]

[0361] Selected from

[0362] [ka]

[0363] teeth, [ka]

[0364] Selected from.

[0365] 13. Formula (I) according to any one of embodiments 1 to 12 [ka] [ka]

[0366] [ka]

[0367] [ka]

[0368] or a solvate or a pharma- ceutically acceptable salt thereof.

[0369] 14. Formula (I) according to any one of embodiments 1 to 13 [ka]

[0370] or a solvate or a pharma- ceutically acceptable salt thereof.

[0371] 15. A compound according to any of the previous embodiments for use as a medicament.

[0372] 16. A compound according to any one of embodiments 1 to 15 for use in the prevention and / or treatment of a disease, disorder, therapeutic indication or condition treatable by a DHODH inhibitor.

[0373] 17. A compound for use according to embodiment 16, wherein the disease, disorder, therapeutic indication or condition is selected from the group comprising rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoan infestations in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy.

[0374] 18. A compound for use according to embodiment 17, wherein the disease, disorder or therapeutic indication is selected from the group comprising graft versus host reaction and host versus graft reaction, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

[0375] 19. A pharmaceutical composition comprising a compound according to any one of embodiments 1-14 and a pharma- ceutically acceptable carrier or excipient.

[0376] 20. The pharmaceutical composition of embodiment 19, further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, antiviral agents, immunosuppressants and / or immunomodulators, steroids, nonsteroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

[0377] Experimental part Carboxylic acid-containing intermediates of the invention can be prepared as outlined in WO2003 / 006425 and WO2004 / 056797 (and references cited therein). Deuterated intermediates can be prepared by using appropriate deuterated building blocks or via hydrogen-deuterium exchange (e.g., Synthesis 2019;51:1319 or Angew. Chem. Int. Ed. 2018;57:3022).

[0378] The compounds of the invention can be prepared by a combination of methods known in the art, including the procedure described in Scheme I below. The synthetic route starts with Suzuki coupling of B-ring Ia with C-ring Ib (V = boronic acid or boronic ester, W = Br, I or OMs, or opposite functionalization) or by using another CC coupling procedure (e.g., Example 4). The amino group of Ic reacts with carboxylic acid Id (H = H or alkyl, e.g., Example 16 or Example 9, respectively) or anhydride Ie (e.g., Example 5) via amide coupling (and optional saponification of ester in case of R = alkyl) to give carboxylic acid If. The two regioisomers formed may need to be separated (or after functionalization to a new residue Y). Finally, the carboxylic acid is converted to residue Y of formula (I), for example by coupling with alkoxyamine (e.g., Example 4), alkylsulfonamide (e.g., Example 1) or optionally substituted sulfuric acid diamide (e.g., Example 2), or by manipulation to tetrazole (e.g., Example 3) or oxadiazole (e.g., Example 4). Compounds of formula (I) can also be prepared directly by amide coupling of a suitable functionalized A-ring carboxylic acid Ig with an amine Ic (eg Example 10).

[0379] [ka] Scheme I: Synthesis of Compounds of the Invention

[0380] Abbreviation Ac Acetyl aq. Water-based Boc tert-Butyloxycarbonyl dba Dibenzylideneacetone DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EA Ethyl acetate EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Flash chromatography on FCC silica gel PE Petroleum Ether Ph Phenyl prep. rt Room temperature (20±4℃) TCFH Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TEA Triethylamine Tf triflate

[0381] Experimental Section Preparation example P1: Step 1: tert-Butyl (methoxy-d3)carbamate (P1a)

[0382] [ka]

[0383] To a solution of tert-butyl hydroxycarbamate (10 g) in MeCN (20 mL) was added K2CO3 (31 g) and CD3I (4.7 mL). The mixture was stirred at 65° C. overnight, cooled, filtered, concentrated and purified by FCC (PE:EA = 20:1) to give compound P1a as a colorless oil. 1 H-NMR (400 MHz, DMSO-d6) δ 7.23 (s, 1H), 1.49 (s, 9H). LCMS (ESI): m / z 173.1 (M+Na) + .

[0384] Step 2: O-(methyl-d3)hydroxylamine hydrochloride (P1) [ka]

[0385] To a solution of compound P1a (7.0 g) in 1,4 dioxane (15 mL) was added 4M HCl in dioxane (15 mL) and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the filter cake was washed with 1,4 dioxane (15 mL) and then with PE two more times. The solid was dried in vacuum to give P1 as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 11.03 (s, 3H). LCMS (ESI): m / z 51.1 (M-Cl) + .

[0386] Preparation example P1 / 1: Step 1: 2-(2-hydroxyethoxy-1,1,2,2-d4)isoindoline-1,3-dione (P1 / 1a)

[0387] [ka]

[0388] Intermediate P1 / 1a can be prepared by reacting 2-hydroxyisoindoline-1,3-dione with 2-bromoethane-1,1,2,2-d4-1-ol in MeCN and NEt3, similarly as described for the non-deuterated bromide in WO2014 / 081025.

[0389] Step 2: 2-(aminooxy)ethane-1,1,2,2-d4-1-ol (P1 / 1) [ka]

[0390] Building blocks P1 / 1 can be prepared by reacting intermediate P1 / 1a with hydrazine in ethanol, followed by slurrying the free amine in 4M HCl in 1,4-dioxane, and finally evaporating the solvent, similar to that described for non-deuterated alcohols in J. Chem. Soc. Perkin Trans. 1 1987:2829.

[0391] Preparation example P2: 4-Bromo-2-fluoro-6-(methoxy-d3)aniline (P2)

[0392] [ka]

[0393] To a solution of 2-amino-5-bromo-3-fluorophenol (300 mg) in MeCN (5 mL) was added K2CO3 (0.4 g) and CD3I (0.15 mL). The mixture was stirred at 65° C. overnight, cooled to room temperature, filtered, concentrated and purified by FCC (PE:EA = 20:1) to give compound P2 as an oil. LCMS (ESI): m / z 223.2 / 225.1 (M+H). + .

[0394] Preparation example P3: Step 1: Bis(3-methoxyphenyl)zinc (P3a)

[0395] [ka]

[0396] To a mixture of (3-methoxyphenyl)magnesium bromide (42 mL, 1M in THF) was added LiCl (2.67 g) and ZnCl2 (20 mL, 1M in THF) at room temperature. The mixture was stirred at room temperature for 1 hour to give compound P3a as a solution in THF.

[0397] Step 2: 1-(1,3-dioxoisoindolin-2-yl) 4-methylbicyclo[2.2.2]octane-1,4-dicarboxylate (P3b) [ka]

[0398] N,N-Diisopropylcarbodiimide (3.6 g) was added to a solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (5.0 g), 2-hydroxyisoindoline-1,3-dione (3.8 g), and DMAP (864 mg) in CHCl (50 mL) at room temperature under nitrogen atmosphere. The mixture was stirred overnight at room temperature, washed with HO (2 x 300 mL), dried (NaSO), filtered, concentrated, and purified by FCC to give compound P3b as a white solid. LCMS (ESI): m / z 380.2 (M+Na). + .

[0399] Step 3: Methyl 4-(3-methoxyphenyl)bicyclo[2.2.2]octane-1-carboxylate (P3c) [ka]

[0400] Compound P3a (ca. 20 mmol, as a THF solution) was added to a solution of compound P3b (3.0 g), 2-methyl-6-(6-methyl-2-pyridyl)pyridine (0.93 g), nickel(II)-acetylacetonate (1.08 g) and CH3CN (50 mL) at room temperature. The mixture was degassed with three vacuum nitrogen cycles, stirred at 80 °C overnight, cooled to room temperature and concentrated. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried (Na2SO4), filtered, concentrated and purified by FCC to give compound P3c as a pale yellow solid. LCMS (ESI): m / z 275.3 (M+H) + .

[0401] Step 4: Methyl 4-(3-hydroxyphenyl)bicyclo[2.2.2]octane-1-carboxylate (P3d) [ka]

[0402] To a mixture of compound P3c (1.9 g) in DCM (40 mL) was added BBr3 (1M, 10 mL), the mixture was stirred at room temperature for 4 h, poured into water (50 mL), and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine, dried, filtered, concentrated, and purified by FCC to give compound P3d as a white solid. LCMS (ESI): m / z 260.8 (M+H). + .

[0403] Step 5: Methyl 4-(3-(methoxy-d3)phenyl)bicyclo[2.2.2]octane-1-carboxylate (P3e) [ka]

[0404] To a mixture of compound P3d (1.6 g) in CH3CN (20 mL) was added CD3I (1.8 g) and K2CO3 (1.7 g), and the mixture was stirred at 60 °C for 12 h, cooled to room temperature, poured into water (80 mL), and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried, filtered, concentrated, and purified by FCC to give compound P3e as a white solid. LCMS (ESI): m / z 278.3 (M+H) + .

[0405] Step 6: 4-(3-(methoxy-d3)phenyl)bicyclo[2.2.2]octane-1-carboxylic acid (P3f) [ka]

[0406] To a mixture of compound P3e (1.6 g) in MeOH (20 mL) was added LiOH (5 mL, 2M), stirred at room temperature for 12 h, concentrated, and adjusted to pH = 6 with 1N HCl. The mixture was then purified by preparative HPLC to give compound P3f as a white solid. LCMS (ESI): m / z 264.0 (M+H). + .

[0407] Step 7: tert-Butyl (4-(3-(methoxy-d3)phenyl)bicyclo[2.2.2]octan-1-yl)carbamate (P3f) [ka]

[0408] To a mixture of compound P3f (1.5 g) in toluene (30 mL) was added (Boc)2O (1.3 g), diphenylphosphoryl azide (1.65 g) and TEA (1.2 g). The mixture was stirred at 80° C. for 12 h, cooled to room temperature, poured into water (80 mL) and extracted with EA (3×30 mL). The combined organic layers were washed with brine, dried, filtered, concentrated and purified by FCC to give compound P3g as a white solid. LCMS (ESI): m / z 335.0 (M+H) + .

[0409] Step 7: 4-(3-(methoxy-d3)phenyl)bicyclo[2.2.2]octan-1-amine hydrochloride (P3) [ka]

[0410] To a mixture of compound P3g (510 mg) in methanol was added HCl (4M in methanol). The mixture was stirred at room temperature for 3 hours and concentrated to give compound P3 as a white solid. LCMS (ESI): m / z 235.3 (M-Cl). + .

[0411] Preparation example P4: Step 1: 2-(3-(methoxy-d3)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (P4a)

[0412] [ka]

[0413] To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (10 g) in MeCN (50 mL) was added K2CO3 (18.8 g) and CD3I (3.39 mL). The mixture was stirred at 65° C. overnight, cooled to room temperature, filtered, concentrated and purified by FCC (PE:EA = 20:1) to give compound P4a as an oil.

[0414] Step 2: 4-Bromo-2,3,6-trifluoroaniline (P4b) [ka]

[0415] To a solution of 2,3,6-trifluoroaniline (1 g) in DMF (20 mL) was added N-bromosuccinimide (1.2 g), and the mixture was stirred at 0° C. for 3 h, concentrated, and purified by FCC (PE:EA = 2:1) to give compound P4b as a yellow solid.

[0416] Step 3: 2,3,5-trifluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-amine (P4) [ka]

[0417] To a solution of compound P4a (300 mg) in 1,4-dioxane (20 mL) and H2O (2 mL) was added compound P4b (379 mg), Cs2CO3 (1.3 g) and Pd(PPh3)4 (30 mg). The mixture was heated at 90°C for 3 h, cooled, diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were separated, dried over Na2SO4, filtered, concentrated and purified by FCC (PE:EA = 8:1) to give compound P4 as a yellow solid. LCMS (ESI): m / z 257.1 (M+H) + .

[0418] Preparation example P5: 1H-Furo[3,4-c]pyrrole-1,3(5H)-dione (P5) [ka]

[0419] To a solution of 1H-pyrrole-3,4-dicarboxylic acid (400 mg) in dry THF (50 mL) was added dicyclohexylcarbodiimide (797 mg). The mixture was stirred at 80° C. for 2 h, cooled to room temperature, concentrated, and purified by preparative HPLC to give compound P5 as a white solid.

[0420] Preparation example P6: Step 1: 4,4,5,5-tetramethyl-2-(3-(propoxy-d7)phenyl)-1,3,2-dioxaborolane (P6a)

[0421] [ka]

[0422] To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg) and K2CO3 (376 mg) in MeCN (2 mL) was added C3D7I (241 mg). The mixture was stirred at 60 °C overnight, cooled, diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were separated, dried over Na2SO4, filtered, concentrated and purified by FCC (PE:EA = 20:1) to give compound P6a as a colorless oil. LCMS (ESI): m / z 270.3 (M+H) + .

[0423] Step 2: 2,3,5,6-tetrafluoro-3'-(propoxy-d7)-[1,1'-biphenyl]-4-amine (P6) [ka]

[0424] To a solution of compound P6a (150 mg) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was added 4-bromo-2,3,5,6-tetrafluoroaniline (136 mg), Na2CO3 (177 mg) and Pd(dppf)Cl2 (15 mg). The mixture was heated at 90 °C for 8 h, cooled, diluted with water and extracted with ethyl acetate (3 times). The combined organic layers were separated, dried over Na2SO4, filtered, concentrated and purified by FCC (PE:EA = 8:1) to give compound P6 as a colorless oil. LCMS (ESI): m / z 307.1 (M+H) + .

[0425] Preparation examples P6 / 1~P6 / 4: The following examples were prepared similarly as described in Preparative Example 6 above using the appropriate building blocks shown below.

[0426] [Table 1]

[0427] Preparation Example P7: 5-Fluorothiophene-2,3-dicarboxylic acid (P7) [ka]

[0428] To a solution of 5-fluorothiophene-2,3-dicarbaldehyde (400 mg) in tert-butanol (4 mL) and H2O (1 mL) was added NaClO2 (3.4 g) and NaHPO4 (600 mg). The mixture was stirred at room temperature for 1 h, concentrated and purified by reverse phase flash chromatography (C18) (0.1% TFA in water, 10-100% MeCN) to give compound P7 as a white solid. LCMS (ESI): m / z 191.1 (M+H) + .

[0429] Example 1: N 1 -(Methylsulfonyl)-N 2-(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)cyclopent-1-ene-1,2-dicarboxamide (1) [ka]

[0430] To a solution of 2-((2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (120 mg, 0.25 mmol) in DCM (5 mL) was added methanesulfonamide (37 mg, 0.38 mmol), dicyclohexylcarbodiimide (80 mg, 0.38 mmol), 4-dimethylaminopyridine (32 mg, 0.25 mmol) and TEA (79 μL, 0.77 mmol). The mixture was stirred in a sealed tube at 60° C. for 8 h, cooled to room temperature and diluted with water (5 mL). The organic layer was separated, concentrated and then purified by preparative HPLC to give compound 1 as a white solid. 1 H-NMR (400 MHz, MeOD-d4) δ 7.63 (t, J = 8.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.45-7.41 (m, 2H), 3.12 (s, 3H), 2.94-2.86 (m, 4H), 1.97-1.85 (m, 2H). LCMS (ESI): m / z 541.2 (M+H) + .

[0431] Example 1 / 1~1 / 14: The following examples were prepared similarly to Example 1 above, using the appropriate building blocks shown below: The acid intermediates can be prepared as outlined in Example 4.

[0432] [Table 2]

[0433] [Table 3]

[0434] [Table 4]

[0435] Example 2: N 1 -Sulfamoyl-N 2 -(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)cyclopent-1-ene-1,2-dicarboxamide (2) [ka]

[0436] To a solution of 2-((2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (300 mg, 0.65 mmol) in DCM (5 mL) was added sulfuric acid diamide (124 mg, 1.30 mmol), dicyclohexylcarbodiimide (200 mg, 0.97 mmol), 4-dimethylaminopyridine (79 mg, 0.65 mmol) and TEA (107 μL, 0.77 mmol). The mixture was stirred in a sealed tube at 60° C. for 8 h, cooled to room temperature and diluted with water (5 mL). The organic layer was separated, concentrated and purified by preparative HPLC to give compound 2 as a white solid. 1 H-NMR (400 MHz, MeOD-d4) δ 7.64 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.46-7.43 (m, 2H), 2.99-2.93 (m, 2H), 2.88-2.83 (m, 2H), 2.13-2.04 (m, 2H). LCMS (ESI): m / z 542.2 (M+H) + .

[0437] Example 2 / 1~2 / 6: The following examples were prepared similarly to Example 2 above, using the appropriate building blocks shown below: The acid intermediates can be prepared as outlined in Example 4.

[0438] [Table 5]

[0439] Example 2-1 (Alternative synthesis of N-sulfamoylamides): N 3 -(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N 4 -Sulfamoyl-2,5-dihydrofuran-3,4-dicarboxamide (2-1) [ka]

[0440] To a solution of 5e (200 mg) in dry DCM (5 mL) was added SOCl2 (120 mg) at 0 °C. The mixture was stirred at 0 °C for 2 h and concentrated in vacuo to give the crude acid chloride intermediate. A solution of sulfuric acid diamide (457 mg) in dry DMF (5 mL) was added to the acid chloride intermediate and DIPEA (136 mg) at 0 °C. The mixture was stirred at 90 °C for 16 h, concentrated, and purified by preparative HPLC to give compound 2-1 as a white solid. 1 H-NMR (400 MHz, MeOD-d4) δ 7.40-7.36 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 2.0 Hz, 1H), 6.98 (dd, J = 2.4, 8.0 Hz, 1H), 5.20-5.17 (m, 2H), 5.06-5.03 (m, 2H). LCMS (ESI): m / z 457.1 (M+H) + .

[0441] Example 2-1 / 1: The following examples were prepared similarly as described in Example 2-1 above, using the appropriate building blocks shown below.

[0442] [Table 6]

[0443] Example 3: Step 1: N-(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)cyclopent-1-ene-1,2-dicarboxamide (3a) [ka]

[0444] To a solution of 2-((2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (500 mg, 1.08 mmol) in DMF (10 mL) was added NH4Cl (114 mg, 2.16 mmol), EDCI (207 mg, 1.08 mmol) and 4-dimethylaminopyridine (145 mg, 1.19 mmol). The mixture was heated at 60°C for 3 h, concentrated and purified by FCC (PE:EA = 5:1) to give compound 3a as a white solid. LCMS (ESI): m / z 463.0 (M+H) + .

[0445] Step 2: 2-cyano-N-(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)cyclopent-1-ene-1-carboxamide (3b) [ka]

[0446] To a solution of compound 3a (400 mg, 0.87 mmol) in DMF (5 mL), cyanuric chloride (320 mg, 1.73 mmol) was added at 0° C. for 30 min, then the mixture was stirred at room temperature for 3 h, concentrated and purified by FCC (PE:EA = 5:1) to give compound 3b as a white solid. LCMS (ESI): m / z 445.3 (M+H). + .

[0447] Step 3: N-(2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-2-(2H-tetrazol-5-yl)cyclopent-1-ene-1-carboxamide (3) [ka]

[0448] To a solution of compound 3b (180 mg, 0.41 mmol) in 1,2-dimethoxyethane (4 mL) and HO (2 mL) was added ZnBr2 (100 mg, 0.45 mmol) and NaN3 (79 mg, 1.23 mmol). The mixture was heated at 105 °C for 3 h, cooled to room temperature, concentrated, and purified by preparative HPLC to give compound 3 as a white solid. 1 H-NMR (500 MHz, MeOD-d4) δ 7.64 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.47 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 3.31-3.29 (m, 2H), 3.00 (t, J = 7.5 Hz, 2H), 2.05-1.98 (m, 2H). LCMS (ESI): m / z 488.2 (M+H) + .

[0449] Example 3 / 1: The following examples were prepared similarly as described in Example 3 above, using the appropriate carboxylic acid building blocks. [Table 7]

[0450] Example 3-1: Step 1: 2-cyano-N-(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)cyclopent-1-ene-1-carboxamide (3-1a) [ka]

[0451] Compound 3-1a was prepared starting from acid 4c as described in steps 1 and 2 of Example 3. LCMS (ESI): m / z 358.2 (M+H) + .

[0452] Step 2: (Z)-N-(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-2-(N'-hydroxycarbamimidoyl)cyclopent-1-ene-1-carboxamide (3-1) [ka]

[0453] To a solution of compound 3-1a (200 mg, 0.56 mmol) in MeOH (5 mL) was added hydroxylamine hydrochloride (58 mg) and DIPEA (108 mg). The mixture was stirred at 60° C. overnight, concentrated, and purified by preparative HPLC to give the target molecule 3-1 as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.60-7.55 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.33-7.29 (m, 2H), 6.06 (s, 2H), 6.99 (dd, J = 2.2, 8.0 Hz, 1H), 2.86-2.74 (m, 4H), 1.87-1.78 (m, 2H). LCMS (ESI): m / z 391.1 (M+H) + .

[0454] Example 3-2: N-(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopent-1-ene-1-carboxamide (3-2) [ka]

[0455] To a solution of compound 3-1a (120 mg, 0.31 mmol) in 1,4-dioxane (5 mL) was added 1,1'-carbonyldiimidazole (55 mg) and 1,8-diazabicyclo(5.4.0)undec-7-ene (56 mg). The mixture was stirred at 100°C for 2 h, cooled to room temperature, concentrated, and purified by preparative HPLC to give the target molecule 3-2 as a white solid. 1 H-NMR (500 MHz, DMSO-d6) δ 12.25 (br s, 1H), 10.01 (br s, 1H), 7.58 (t, J = 9.0 Hz, 2H), 7.40 (t, J = 8.3 Hz, 1H), 7.33-7.29 (m, 2H), 6.99 (dd, J = 1.8, 8.3 Hz, 1H), 2.94 (t, J = 6.8 Hz, 2H), 2.83 (t, J = 7.4 Hz, 2H), 2.07-1.99 (m, 2H). LCMS (ESI): m / z 417.1 (M+H) + .

[0456] Example 4: Step 1: 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4a) [ka]

[0457] To a solution of 4-bromo-2,6-difluoroaniline (10 g, 48 mmol) in 1,4-dioxane (100 mL) was added bis(pinacolato)diboron (12.8 g, 50.4 mmol), CH3COOK (14.1 g, 144 mmol) and Pd(dppf)Cl2 (1.0 g, 2.40 mmol). The mixture was stirred at 90 °C under N2 for 2 h, cooled to room temperature, concentrated and purified by FCC (PE:EA = 10:1) to give compound 4a as a yellow solid.

[0458] Step 2: 3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-amine (4b) [ka]

[0459] To a solution of compound 4a (4.50 g, 13.3 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL) was added 1-bromo-3-(methoxy-d3)benzene (3.34 g, 13.3 mmol), Na2CO3 (5.61 g, 39.4 mmol) and Pd(dppf)Cl2 (400 mg, 0.67 mmol). The mixture was stirred at 90 °C under N2 for 2 h, cooled to room temperature, concentrated and purified by FCC (PE:EA = 10:1) to give compound 4b as a yellow solid. LCMS (ESI): m / z 239.1 (M+H). + .

[0460] Step 3: 2-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (4c) [ka]

[0461] To a solution of compound 4b (3.40 g, 14.3 mmol) in DCM (20 mL) was added 1-cyclopentene-1,2-dicarboxylic anhydride (1.90 g, 14.3 mmol), and the mixture was then stirred at room temperature for 2 h. The mixture was filtered and the filter cake was washed with MeCN. The solid was dried in vacuum to give compound 4c as a white solid. LCMS (ESI): m / z 377.3 (M+H) + .

[0462] Step 4: N 1 -(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N 2 -Methoxycyclopent-1-ene-1,2-dicarboxamide (4) [ka]

[0463] To a solution of compound 4c (300 mg, 0.80 mmol) in DCM (25 mL) was added O-methylhydroxylamine (132 mg, 2.80 mmol), dicyclohexylcarbodiimide (246 mg, 1.14 mmol), 4-dimethylaminopyridine (97 mg, 0.79 mmol) and TEA (0.30 mL, 2.2 mmol). The mixture was then stirred in a sealed tube at 60° C. for 8 h, cooled to room temperature, concentrated and purified by preparative HPLC to give compound 4 as a white solid. 1 H-NMR (500 MHz, MeOD-d4) δ 7.40-7.32 (m, 3H), 7.20 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.97 (dd, J = 8.3, 2.3 Hz, 1H), 3.75 (s, 3H), 2.92-2.88 (m, 2H), 2.82-2.78 (m, 2H), 2.06-2.00 (m, 2H). LCMS (ESI): m / z 406.2 (M+H) + .

[0464] Example 4 / 1~4 / 35: The following examples were or can be prepared similarly as described in Example 4 above, using the appropriate building blocks shown below. [Table 8]

[0465] [Table 9]

[0466] [Table 10]

[0467] [Table 11]

[0468] [Table 12]

[0469] [Table 13]

[0470] [Table 14]

[0471] Example 5: Step 1: Methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (5a) [ka]

[0472] To a solution of methyl 4-hydroxy-2,5-dihydrofuran-3-carboxylate (33 g) in DCM (220 mL) was added DIPEA (88 g). Then Tf2O (76.6 mL) was added to the mixture at 0° C. The mixture was stirred at room temperature overnight, concentrated and purified by FCC (PE:EA = 20:1) to give compound 5a as an oil. LCMS (ESI): m / z = 277.0 (M+H) + .

[0473] Step 2: Dimethyl 2,5-dihydrofuran-3,4-dicarboxylate (5b) [ka]

[0474] To a solution of compound 5a (30 g) in MeOH (225 mL) and DMF (75 mL) was added dppf (6.30 g) and Pd2(dba)3 (4.70 g). The mixture was stirred under CO at 50° C. overnight, concentrated and purified by FCC (PE:EA = 10:1) to give compound 5b as a yellow oil. LCMS (ESI): m / z = 187.3 (M+H). + .

[0475] Step 3: 2,5-dihydrofuran-3,4-dicarboxylic acid (5c) [ka]

[0476] To a solution of compound 5b (20 g) was added concentrated HCl (150 mL) and HOAc (50 mL). The mixture was stirred at 100° C. for 2 h, cooled, and concentrated to give compound 5c as a yellow solid. LCMS (ESI): m / z = 159.3 (M+H). + .

[0477] Step 4: 4,6-Dihydro-1H,3H-furo[3,4-c]furan-1,3-dione (5d) [ka]

[0478] To a solution of compound 5c (400 mg) in toluene (5 mL) was added AcCl (385 mg). The mixture was stirred at 110° C. for 4 h and concentrated in vacuo to give compound 5d as a yellow solid, which was used in the next step without purification. LCMS (ESI): m / z = 140.1 (M+H). + .

[0479] Step 5: 4-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)-2,5-dihydrofuran-3-carboxylic acid (5e) [ka]

[0480] Compound 5d was reacted in a similar manner as described in Example 4, step 3 to give compound 5e as a white solid. 1 H-NMR (500 MHz, DMSO-d6) δ 10.89 (br s, 1H), 7.58 (d, J = 9.5 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.33-7.28 (m, 2H), 6.99 (dd, J = 2.3, 8.3 Hz, 1H), 4.97 (t, J = 5.3 Hz, 2H), 4.89 (t, J = 5.0 Hz, 2H), 3.43 (br s, 1H). LCMS (ESI): m / z 379.2 (M+H) + .

[0481] Step 6: N 3 -(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N 4 -Methoxy-2,5-dihydrofuran-3,4-dicarboxamide (5) [ka]

[0482] Compound 5e was reacted in the same manner as in Step 4 of Example 4 to obtain the desired compound 5 as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 11.28 (br s, 1H), 7.60 (d, J = 9.6 Hz, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.34-7.29 (m, 2H), 6.99 (dd, J = 2.0, 8.0 Hz, 1H), 4.96-4.92 (m, 4H), 3.68 (s, 3H). LCMS (ESI): m / z 408.2 (M+H) + .

[0483] Example 5 / 1~5 / 16: The following examples were prepared similarly to those described above using the appropriate building blocks shown below.

[0484] [Table 15]

[0485] [Table 16]

[0486] [Table 17]

[0487] Example 6: Step 1: 4-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)-2,5-dihydrothiophene-3-carboxylic acid (6a) [ka]

[0488] 4,6-Dihydro-1H,3H-thieno[3,4-c]furan-1,3-dione (synthesis and coupling described in Bioorg. Med. Chem. Lett. 2005;15:4854) was reacted in a similar manner as above to give the target molecule 6a as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 13.01 (br s, 1H), 10.20 (s, 1H), 7.54 (d, J = 9.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.32-2.28 (m, 2H), 6.99 (dd, J = 2.4, 8.0 Hz, 1H), 4.15-4.11 (m, 2H), 4.03-4.00 (m, 2H). LCMS (ESI): m / z 395.2 (M+H) + .

[0489] Process 2: N 3 -(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N 4 -Methoxy-2,5-dihydrothiophene-3,4-dicarboxamide (6) [ka]

[0490] Compound 6a was reacted in the same manner as above to obtain target compound 6 as a white solid. 1 H-NMR (500 MHz, MeOD-d4) δ 7.38-7.32 (m, 3H), 7.20 (d, J = 7.5 Hz, 1H), 7.16 (s, 1H), 6.96 (dd, J = 2.5, 8.0 Hz, 1H), 4.20-4.11 (m, 4H), 3.71 (s, 3H). LCMS (ESI): m / z 424.1 (M+H) + .

[0491] Example 6 / 1~6 / 3: The following examples were prepared similarly as described in Example 6 above, using the appropriate building blocks shown below.

[0492] [Table 18]

[0493] Example 7: N 1 -(N-Cyanosulfamoyl)-N 2 -(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)cyclopent-1-ene-1,2-dicarboxamide (7) [ka]

[0494] Compound 2 / 1 was reacted with cyanogen bromide in a solution of KOH in DMF / H2O to give the target molecule 7. LCMS (ESI): m / z 480.1 (M+H) + .

[0495] Example 8 (reverse coupling procedure): Step 1: 3-Fluoro-5-(3-(methoxy-d3)phenyl)pyridin-2-amine (8a) [ka]

[0496] To a solution of 5-bromo-3-fluoropyridin-2-amine (400 mg) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was added (3-(methoxy-d3)phenyl)boronic acid (389 mg), Cs2CO3 (2.4 g) and Pd(dppf)Cl2 (40 mg). The mixture was stirred at 90 °C under N2 for 2 h, cooled to room temperature, concentrated and purified by FCC (PE:EA = 10:1) to give compound 8a as a yellow solid. LCMS (ESI): m / z 222.0 (M+H) + .

[0497] Process 2: N 1-(3-fluoro-5-(3-(methoxy-d3)phenyl)pyridin-2-yl)-N 2 -Methoxycyclopent-1-ene-1,2-dicarboxamide (8) [ka]

[0498] Compound 8a was reacted as described in steps 3 and 4 of Example 4 to give the target molecule 8 as a white solid. 1 H-NMR (500 MHz, DMSO-d6) δ 11.39 (br s, 1H), 11.04 (br s, 1H), 8.62 (s, 1H), 8.15 (d, J = 11.0 Hz, 1H), 7.44-7.33 (m, 3H), 7.00 (dd, J = 2.0, 8.0 Hz, 1H), 3.63 (s, 3H), 2.79 (t, J = 6.8 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H), 1.93-1.87 (m, 2H). LCMS (ESI): m / z 389.3 (M+H) + .

[0499] Example 8 / 1~8 / 3: The following examples were prepared similarly as described in Example 8 above, using the appropriate building blocks shown below.

[0500] [Table 19]

[0501] Example 9: Step 1: Methyl 3-(chlorocarbonyl)thiophene-2-carboxylate (9a) [ka]

[0502] To a solution of 2-(methoxycarbonyl)thiophene-3-carboxylic acid (200 mg) in dry DCM (8 mL) was added SOCl2 (152 mg). The mixture was stirred at room temperature for 2 h and concentrated to give compound 9a as a yellow solid, which was used in the next step without further purification.

[0503] Step 2: Methyl 3-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)thiophene-2-carboxylate (9b) [ka]

[0504] To a solution of compound 4b (200 mg) in dry THF (2 mL) was added NaH (60%, 134 mg) at 0° C. The reaction mixture was stirred for 1 h and a solution of crude intermediate 9a (240 mg) in dry THF (1 mL) was added dropwise at 0° C. After addition, the mixture was stirred at this temperature for 30 min, quenched with saturated aqueous NH4Cl, and extracted with EA (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by FCC (PE:EA = 1:1) to give compound 9b as a red solid. LCMS (ESI): m / z 407.1 (M+H) + .

[0505] Step 3: 3-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)thiophene-2-carboxylic acid (9c) [ka]

[0506] To a solution of compound 9b (200 mg) in MeOH (4 mL) and THF (1.5 mL) was added 2N NaOH (1.0 mL) at 0° C. The mixture was then stirred at room temperature for 5 h, adjusted to pH = 5-6 with 2N HCl, and concentrated. The residue was purified by reverse phase flash chromatography (C18) (0.1% NH4HCO3 in water, 10-100% MeCN) to give compound 9c as a white solid. 1 H-NMR (400 MHz, CD3OD) δ 7.70 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.40-7.32 (m, 3H), 7.22-7.17 (m, 2H), 6.96 (dd, J = 2.0, 8.4 Hz, 1H). LCMS (ESI): m / z 393.1 (M+H) + .

[0507] Step 4: N3-(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N2-methoxythiophene-2,3-dicarboxamide (9) [ka]

[0508] To a solution of 9c (90 mg) in MeCN (5 mL) was added O-methylhydroxylamine hydrochloride (28 mg), TCFH (162 mg) and 1-methylimidazole (57 mg). The mixture was stirred at room temperature for 4 h, concentrated and purified by reversed-phase flash chromatography (C18) (0.1% TFA in water, 10-100% MeCN) to give the desired compound 9 as a white solid. 1 H-NMR (400 MHz, CD3OD) δ 7.79 (d, J = 5.2 Hz, 1H), 7.67 (d, J = 5.2 Hz, 1H), 7.42-7.36 (m, 3H), 7.24-7.18 (m, 2H), 6.99-6.96 (m, 1H), 3.82 (s, 3H). LCMS (ESI): m / z 422.1 (M+H) + .

[0509] Example 9 / 1~9 / 11: The following examples were prepared similarly as described in Example 9 or other examples above using the appropriate building blocks shown below.

[0510] [Table 20]

[0511] [Table 21]

[0512] Example 10: Step 1: Methyl 3-(methoxycarbamoyl)thiophene-2-carboxylate (10a) [ka]

[0513] To a solution of 2-(methoxycarbonyl)thiophene-3-carboxylic acid (200 mg) in MeCN (5 mL) was added O-methylhydroxylamine hydrochloride (178 mg / l), TCFH (361 mg) and 1-methylimidazole (264 mg). The mixture was stirred at room temperature for 4 h, concentrated and purified by reversed phase flash chromatography (C18) (0.1% TFA in water, 10-100% MeCN) to give compound 10a as a white solid. LCMS (ESI): m / z 216.1 (M+H) + .

[0514] Step 2: 3-(Methoxycarbamoyl)thiophene-2-carboxylic acid (10b) [ka]

[0515] To a solution of compound 10a (100 mg) in MeOH (1 mL) and THF (3 mL) was added 2N NaOH (2 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, adjusted to pH 5-6 by adding 2N HCl, concentrated, and purified by reverse phase flash chromatography (C18) (0.1% TFA in water, 10-100% MeCN) to give compound 10b as a white solid. LCMS (ESI): m / z 202.1 (M+H). + .

[0516] Process 3: N 2 -(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N 3 -Methoxythiophene-2,3-dicarboxamide (10) [ka]

[0517] To a solution of compound 10b (50 mg) in dry DCM (5 mL) was added SOCl2 (59 mg) at 0 °C. The mixture was stirred at 0 °C for 2 h and concentrated to give the crude acid chloride intermediate. To a solution of compound 4b (59 mg) in dry THF (5 mL) was added NaH (99 mg, 60% wt) at 0 °C and stirred at 0 °C for 10 min, then the acid chloride intermediate was added at 0 °C. The mixture was stirred at 0 °C for 2 h, quenched with saturated aqueous NH4Cl solution, and extracted with EA (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by reverse-phase flash chromatography (C18) (0.1% TFA in water, 10-100% MeCN) to give compound 10 as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 11.94 (s, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 9.2 Hz, 2H), 7.49 (d, J = 5.2 Hz, 1H), 7.43-7.31 (m, 3H), 7.00 (dd, J = 1.6, 8.0 Hz, 1H), 3.77 (s, 3H). LCMS (ESI): m / z 422.1 (M+H) + .

[0518] Example 10 / 1: The following examples were prepared similarly as described in Example 10 above using the appropriate building blocks shown below.

[0519] [Table 22]

[0520] Example 13: Step 1: Di-tert-butyl (3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)iminodicarbonate (13a) [ka]

[0521] To a solution of intermediate 4b (400 mg) in DMF (5 mL) was added di-tert-butylpyrocarbonate (732 mg) and DIPEA (434 mg). The mixture was stirred at room temperature for 8 h, concentrated and purified by preparative HPLC to give compound 13a as a yellow solid. LCMS (ESI): m / z 384.0 (M+H). + .

[0522] Step 2: tert-Butyl (3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamate (13b) [ka]

[0523] To a solution of compound 13a (500 mg) in THF (5 mL) was added 2M KOH (3 mL) at 0° C. The mixture was stirred at room temperature for 8 h, concentrated and purified by FCC (PE:EA = 5:1) to give compound 13b as a yellow solid. LCMS (ESI): m / z 284.0 (M+H-tert-butyl). + .

[0524] Step 3: tert-butyl (3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)(methyl)carbamate (13c) [ka]

[0525] To a solution of compound 13b (200 mg) in dry THF (5 mL) was added NaH (118 mg, 60% wt) at 0° C. The mixture was stirred at 0° C. for 1 h, then CHI (101 mg) was added and the mixture was stirred overnight, concentrated and purified by preparative HPLC to give compound 13c as a white solid. LCMS (ESI): m / z 287.1 (M+H-tert-butyl). + .

[0526] Step 4: 3,5-difluoro-3'-(methoxy-d3)-N-methyl-[1,1'-biphenyl]-4-amine (13d) [ka]

[0527] To a solution of compound 13c (190 mg) in 1,4-dioxane (5 mL) was added HCl in dioxane (4M, 5 mL). The mixture was stirred at room temperature for 1 h and concentrated in vacuo to give compound 13d as a white solid, which was used in the next step without further purification. LCMS (ESI): m / z 253.1 (M+H). + .

[0528] Step 5: 2-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)(methyl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (13e) [ka]

[0529] Compound 13e was prepared by coupling compound 13d with 1-cyclopentene-1,2-dicarboxylic anhydride as described above. LCMS (ESI): m / z 391.1 (M+H). + .

[0530] Step 6: N1-(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N2-methoxy-N1-methylcyclopent-1-ene-1,2-dicarboxamide (13) [ka]

[0531] Coupling of compound 13e with O-methylhydroxylamine hydrochloride similar to step 4 of Example 9 above afforded the desired compound 13 as a white solid after purification by preparative HPLC. 1 H-NMR (400 MHz, MeOD-d4, mixture of E / Z-isomers) δ 7.40-7.36 (m, 3H), 7.21 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 2.0, 8.4 Hz, 1H), 3.74 / 3.67 (m, 3H), 3.31-3.30 (m, 3H), 2.83-2.37 (m, 4H), 2.19-2.09 (m, 0.61H), 1.86-1.77 (m, 1.36H). LCMS (ESI): m / z 420.3 (M+H) + .

[0532] Example 14: Step 1: Methyl (3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)glycinate (14a) [ka]

[0533] To a solution of intermediate 4b (500 mg) in toluene (10 mL) was added methyl 2-bromoacetate (479 mg) and K2CO3 (580 mg). The mixture was stirred at 110 °C for 4 h, cooled to room temperature, filtered, concentrated, and purified by preparative HPLC to give compound 14a as a white solid. LCMS (ESI): m / z 311.1 (M+H). + .

[0534] Step 2: 2-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)(2-methoxy-2-oxoethyl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (14b) [ka]

[0535] The target compound 14b was prepared by coupling compound 14a with 1-cyclopentene-1,2-dicarboxylic anhydride as described above. LCMS (ESI): m / z 449.1 (M+H) + .

[0536] Step 3: Methyl N-(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N-(2-(methoxycarbamoyl)cyclopent-1-ene-1-carbonyl)glycinate (14) [ka]

[0537] Coupling of compound 14b with O-methylhydroxylamine hydrochloride similar to step 4 of Example 9 gave the target compound 14 as a white solid after purification by preparative HPLC. LCMS (ESI): m / z 478.2 (M+H) + .

[0538] Example 15: Step 1: N1-(3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)-N1-(2-hydroxyethyl)-N2-methoxy-cyclopent-1-ene-1,2-dicarboxamide (15) [ka]

[0539] To a solution of compound 14 (150 mg) in dry THF (3 mL) was added LiAlH4 (25 mg) at 0°C. The mixture was stirred at this temperature for 2 h, quenched with water (0.25 mL), and then diluted with 10% NaOH (0.5 mL) and water (0.75 mL). The organic layer of the reaction mixture was concentrated and purified by preparative HPLC to give the desired compound 15 as a white solid. 1 H-NMR (400 MHz, MeOD-d4, mixture of E / Z-isomers) δ 7.40-7.36 (m, 3H), 7.23-7.17 (m, 2H), 6.98 (dd, J = 1.8, 8.2 Hz, 1H), 3.92-3.58 (m, 7H), 2.88-2.37 (m, 4H), 2.15-1.75 (m, 2H). LCMS (ESI): m / z 450.1 (M+H) + .

[0540] Example 16-1 and Example 16-2: Step 1: Thiazole-4,5-dicarbonyl dichloride (16a) [ka]

[0541] To a solution of thiazole-4,5-dicarboxylic acid (200 mg) in dry DCM (2 mL) at 0 °C was added SOCl2 (275 mg), and the mixture was stirred at 0 °C for 2 h and concentrated in vacuo to give the crude acid chloride intermediate 16a.

[0542] Step 2: 4-((2,3,5,6-tetrafluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)thiazole-5-carboxylic acid (16b-1) and 5-((2,3,5,6-tetrafluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)thiazole-4-carboxylic acid (16b-2) [ka]

[0543] To a solution of 2,3,5,6-tetrafluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-amine (250 mg) in dry THF (2 mL) was added NaH (219 mg, 60% wt) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, intermediate 16a was added at 0 °C, and the mixture was stirred at room temperature for 16 h, quenched with saturated aqueous NH4Cl, and extracted with EA (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a mixture of compounds 16b-1 and 16b-2 as a yellow solid. LCMS (ESI): m / z 483.3 (M+H) + .

[0544] Step 3: N5-Methoxy-N4-(2,3,5,6-tetrafluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)thiazole-4,5-dicarboxamide (16-1) and N4-Methoxy-N5-(2,3,5,6-tetrafluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)thiazole-4,5-dicarboxamide (16-2) [ka]

[0545] To a solution of a mixture of compounds 16b-1 and 16b-2 (100 mg) in THF (1 mL) and N-methyl-2-pyrrolidone (1 mL) was added O-methylhydroxylamine (60 mg) and EDCI (92 mg). The mixture was stirred at room temperature for 4 hours, concentrated, and purified by preparative HPLC to separate compounds 16-1 and 16-2 as white solids. 16-1: 1 H-NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 11.04 (s, 1H), 9.40 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.16-7.09 (m, 3H), 3.73 (s, 3H). LCMS (ESI): m / z 549.1 (M+H) + 16-2: 1 H-NMR (400 MHz, DMSO-d6) δ 13.38 (br s, 1H), 12.72 (br s, 1H), 9.39 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.14-7.09 (m, 3H), 3.78 (s, 3H). LCMS (ESI): m / z 549.0 (M+H) + .

[0546] Example 16 / 1~16 / 3: The following examples were prepared in a similar manner as described above in Examples 16-1 / 16-2 using the appropriate building blocks shown below.

[0547] [Table 23]

[0548] Example 17-1 and Example 17-2: Step 1: 2-(methoxycarbamoyl)-5-methylthiophene-3-carboxylic acid (17a-1) and 3-(methoxycarbamoyl)-5-methylthiophene-2-carboxylic acid (17a-2) [ka]

[0549] To a solution of 5-methylthiophene-2,3-dicarboxylic acid (200 mg) and O-methylhydroxylamine hydrochloride (268 mg) in THF (1 mL) and N-methyl-2-pyrrolidone (1 mL) was added EDCI (411 mg) in three portions. The mixture was stirred at room temperature for 4 h, diluted with water and extracted with EA (3 times). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by reversed-phase flash chromatography (C18) (0.1% TFA in water, 10-100% MeCN) to give a mixture of compounds 17a-1 and 17a-2 as a white solid. LCMS (ESI): m / z 215.9 (M+H) + .

[0550] Step 2: N2-Methoxy-5-methyl-N3-(2,3,5,6-tetrafluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)thiophene-2,3-dicarboxamide (17-1) and N3-Methoxy-5-methyl-N2-(2,3,5,6-tetrafluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)thiophene-2,3-dicarboxamide (17-2) [ka]

[0551] To a solution of mixture 17a-1 and 17a-2 (100 mg) in dry DCM (2 mL) was added SOCl2 (111 mg) at 0 °C. The mixture was then stirred at 0 °C for 2 h and concentrated in vacuo to give the crude acid chloride intermediate. To a solution of 2,3,5,6-tetrafluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-amine (127 mg) in dry THF (2 mL) was added NaH (93 mg, 60% wt) at 0 °C and the mixture was stirred at 0 °C for 10 min. The acid chloride intermediate was then added at 0 °C and the mixture was stirred at room temperature for 16 h, quenched with saturated aqueous NH4Cl and extracted with EA (3 x 30 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by reverse-phase flash chromatography (C18) (0.1% TFA in water, 10-100% MeCN) to isolate 17-1 and 17-2, respectively, as white solids. 17-1: 1 H-NMR (400 MHz, DMSO-d6) δ 11.99 (br s, 1H), 11.03 (br s, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.36 (s, 1H), 7.15-7.08 (m, 3H), 3.69 (s, 3H), 2.53 (s, 3H). Confirm isomers using NOESY. LCMS (ESI): m / z 472.0 (M+H) + ; 17-2: 1 H-NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 12.28 (s, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 0.4 Hz, 1H), 7.13-7.08 (m, 3H), 3.76 (s, 3H), 2.52 (s, 3H). Confirm isomers using NOESY. LCMS (ESI): m / z 472.0 (M+H) + .

[0552] Additional examples: The following examples can be prepared similarly to those above using the appropriate building blocks.

[0553] [Table 24]

[0554] [Table 25]

[0555] Example 200: Human DHODH Inhibition Assay In vitro inhibition of hDHODH was measured using N-terminally truncated recombinant hDHODH enzyme as described in J. Med. Chem. 2006;49:1239. Briefly, hDHODH concentration was adjusted so that an average slope of approximately 0.2 AU / min served as a positive control (i.e., no inhibitor). The standard assay mixture contained 60 μM 2,6-dichloroindophenol, 50 μM decylubiquinone, and 100 μM dihydroorotic acid. hDHODH enzyme was added with or without at least six different concentrations of compounds and measurements were performed at pH 8.0, 30°C in 50 mM TrisHCl, 150 mM KCl, and 0.1% Triton® X-100. The reaction was started by adding dihydroorotic acid and absorbance was measured at 600 nm for 2 min. IC 50 To determine values, each data point was recorded three times. Each data point was recorded twice. The following data was obtained:

[0556] [Table 26]

[0557] [ka]

[0558] [Table 27]

[0559] Conclusion: Example 4 / 33 has a similar DHODH inhibitory effect as its matched carboxylic acid (Bidofludimus), whereas its matched hydroxamate (Comparative Example C6, corresponding to Example 4 in WO2004 / 056746) is much less effective, as previously mentioned. Also, its matched carboxamide (Comparative Example C7) is only a weak DHODH inhibitor. Figure 2 shows a representative human DHODH inhibition curve from this experiment.

[0560] [ka]

[0561] [Table 28]

[0562] Conclusion: Example 4 shows a similar trend, with the matched pair carboxylic acid (Comparative Example C1) having similar DHODH inhibition, but the matched pair hydroxamate (Comparative Example C4) being much less potent. A similar trend is seen with the matched pair carboxamide (Comparative Example C5), which also shows weak DHODH inhibition.

[0563] Example 201: In vitro interaction study of DHODH inhibitors with human URAT1 uptake transporter The human URAT1 uptake transporter assay (host cell line: MDCKII) measured the cellular accumulation of a probe substrate in the presence of a DHODH inhibitor (concentration 10 μM). The assay was performed at SOLVO with catalog number MDCKII-URAT1-LV. 20 μM uric acid was used as the probe substrate. The reference inhibitor, benzbromarone at a concentration of 300 μM, was used as an internal control. The following data were obtained:

[0564] [ka]

[0565] [Table 29]

[0566] Conclusion: Comparative Example C1 (containing a carboxylic acid moiety) stimulated URAT1-mediated uric acid accumulation by 173%, which is unfavorable in the conditions investigated, whereas matched pairs containing a carboxylic acid bioisosteric moiety stimulated URAT1-mediated uric acid accumulation only slightly, i.e., in the range of <20-26%. A similar trend was observed for Comparative Example C2, where at least matched pairs containing an N-(methylsulfonyl)carboxamide (Example 1) or a tetrazole moiety (Example 3) instead of a carboxylic acid stimulated URAT1-mediated uric acid accumulation only slightly, i.e., 28% and <20%, respectively. In summary, the examples of the present invention show less interaction with the URAT1 transporter compared to matched pairs of carboxylic acids, resulting in less disturbance of uric acid homeostasis and a reduced risk of developing hematuria.

[0567] Example 202a: AB and BA permeability (Caco-2, pH 7.4 / 7.4) The Caco-2 cell line is a human colon adenocarcinoma cell line that has been differentiated in culture and resembles the epithelial lining of the human small intestine. The apparent permeability ( Papp ) was measured. The following data was obtained:

[0568] [ka]

[0569] [Table 30]

[0570] Absorption of orally administered drugs requires that the drug cross the intestinal epithelial barrier. Intestinal permeability is an important property that determines the rate and extent of in vivo absorption and correlates with the bioavailability of drug candidates. Comparative Example C1 (containing a carboxylic acid moiety) has low permeability, whereas the matched pair containing a carboxylic acid bioisosteric moiety (Example 4) is much more permeable from the apical (A) to the basal (B) compartment.

[0571] Example 202b: Dynamic water solubility and logD Dynamic aqueous solubility in PBS at pH 7.4 was determined by comparing the peak area of ​​the main peak of the calibration standard (200 μM) with organic solvent (MeOH / water, 60 / 40 v / v) with the peak area of ​​the corresponding peak of the PBS buffer sample. Furthermore, chromatographic purity (%) was defined as the peak area of ​​the main peak relative to the total integrated peak area in the HPLC chromatogram of the calibration standard. Chromatograms of the calibration standards for each test compound and UV / VIS spectra with absorbance maxima labeled were generated. Dynamic aqueous solubility was measured at a wavelength of 230 nm using the standard protocol from Eurofins Discovery Services (item no. 435).

[0572] The total amount of compound was determined as the peak area of ​​the main peak in a calibration standard (100 μM) containing organic solvent (MeOH / water, 60 / 40 v / v). The amount of compound in buffer was determined as the sum, volume-corrected and weighted area of ​​the corresponding peak in the aqueous phase of three organic-aqueous samples of different composition. An automatic weighting system was used to ensure preferential use of raw data from samples with sufficiently quantifiable peak signals. The amount of compound in the organic was calculated by subtraction. The partition coefficient (logD, n-octanol / PBS, pH 7.4) was then calculated as the Log of the amount of compound in the organic phase divided by the amount of compound in the aqueous phase. 10 (Eurofins Discovery Services Item# 417) The following data were obtained (nt = not tested):

[0573] [Table 31]

[0574] The lower partition coefficient logD values ​​of the examples of the present invention compared to the carboxylic acid matched pairs indicate that the compounds are more abundant in aqueous environments (such as serum) compared to lipophilic environments (such as lipid bilayers), which is beneficial for their druggability and pharmacokinetics. The examples of the present invention also have higher water solubility compared to the carboxylic acid matched pairs.

[0575] Example 203: Antiviral activity against SARS-CoV-2 Assays for viral replication (YFP) and cell viability are generally described in Pathogens 2021;10:1076 and when applied to the compounds of the present invention, the following results were obtained: EC for SARS-CoV-2 assay as described herein 50 range:

[0576] [Table 32]

[0577] Example 204: Synergistic antiviral activity against SARS-CoV-2 by nucleoside analogues The synergistic effect of Example 1 with the nucleoside analog EIDD-1931 (CAS: 3258-02-4) was evaluated. The method for drug combination evaluation by viral replication inhibition assay is published in Pathogens 2021;10:1076. Caco-2 cells were cultured at 25000 cells / well in 96-well plates, infected with SARS-CoV-2 d6-YFP at an MOI of 0.003, and treated with Ex. 1, EIDD-1931, or drug combinations, starting at 4 × EC50 concentrations of each of the single compounds. Viral replication was determined 30 hours post-infection (pi) by quantitative fluorescent detection of virus-driven YFP expression in fixed cells. Inhibition profiles of viral replication, as measured by virally encoded YFP reporter expression, are shown in bar graphs of quadruplicate determinations (mean ± SD). Drug combination evaluation was calculated using the CompuSyn algorithm as described in Int. J. Mol. Sci. 2021;22:575. A representative experiment is shown in Figure 1. Compound 1, when combined with the nucleoside analog EIDD-1931 (CAS:3258-02-4), exhibits synergistic antiviral effects against SARS-CoV-2.

[0578] Example 205: Pharmacokinetics in mice The pharmacokinetics of the compounds of the present invention were evaluated in three male and three female mice (C57BL / 6J, 8 weeks old) after oral or intravenous cassette administration to assess oral bioavailability. The doses were 5 mg / kg (oral) and 1 mg / kg (intravenous), the administration volumes were 5 mL / kg (oral) and 0.5 mL / kg (intravenous), and the vehicle was 5% solutol, 95% NaCl solution (0.9% saline concentration) for oral administration and 5% solutol, 5% ethanol, 90% NaCl solution (0.9% saline concentration) for intravenous administration. At each designated time point (0.5, 1, 2, 4, 8, and 24 hours after administration), 20 μL of whole blood was collected from the tail vein into lithium heparin tubes, frozen on dry ice within 1-2 minutes after collection, and stored at -20°C until processed for LC-MS analysis. The data obtained are as follows:

[0579] [Table 33]

[0580] Conclusion: This study shows that good PK properties can be obtained with carboxylic acid bioisosteres. In another matched-pair analysis, the benefit of deuteration of the N-methoxyacetamide moiety was tested. The pharmacokinetic properties of the compound were evaluated in three female mice (C57BL / 6J, 8 weeks old) after oral or intravenous cassette administration to assess oral bioavailability. The doses were 5 mg / kg (oral) and 1 mg / kg (intravenous), the dose volumes were 5 mL / kg (oral) and 2 mL / kg (intravenous), and the vehicle was 5% solutol, 95% NaCl solution (0.9% saline concentration) for oral administration and 5% solutol, 5% ethanol, 90% NaCl solution (0.9% saline concentration) for intravenous administration. At each designated time point (0.25, 0.5, 1, 2, 4, and 8 hours after oral administration; 0.083, 0.25, 0.5, 1, 4, and 8 hours after intravenous administration), 20 μL of whole blood was collected from the tail vein into lithium heparin tubes, frozen on dry ice within 1-2 minutes of collection, and stored at -20°C until processed for LC-MS analysis. The data obtained are as follows:

[0581] [Table 34]

[0582] Example 206: Antiviral activity against SARS-CoV-2 variants of concern The antiviral activity of Example 9 against Delta and Omicron variants of concern was tested in the same way as for SARS-CoV-2 WT. Caco-2 cells were treated with serial dilutions of the indicated compounds and then infected with clinical isolates of SARS-CoV-2 reporter virus d6-YFP (WT) or Delta or Omicron variants. The number of infected cells was quantified by immunofluorescence staining with WT YFP expression or dsRNA specific antibodies and fluorochrome-conjugated secondary antibodies, and the respective EC 50The concentrations were calculated, with the following results:

[0583] [Table 35]

[0584] Example 207: Antiviral activity against respiratory syncytial virus (RSV) Hep-2 cells were treated with Example 9 or DMSO for 2 days and cell viability was quantified by measuring intracellular ATP levels using the CellTiter-Glo Luminescent Cell Viability Assay (Promega). Mean values ​​± SD of triplicates relative to DMSO control were determined. The 50% cytotoxic concentration (CC 50 ) was calculated. Again, Hep-2 cells were treated with Example 9 or DMSO and infected with the three different RSV strains. Infected cells were quantified by internal GFP fluorescence (RSV-A2) or ICC staining with RSV-specific antibodies (RSV-Long and RSV-B) at day 2 post-infection. Mean values ​​± SD of triplicates relative to DMSO controls were determined. Median inhibitory concentrations (IC 50 ) was calculated, and the following results were obtained:

[0585] [Table 36]

[0586] Example 208: Antiviral activity against human rhinovirus The antiviral activity of the compounds of the present invention was also tested against human rhinovirus HRV-14. The following results were obtained:

[0587] [Table 37]

[0588] Example 209: Metabolic stability in rat and human microsomes Example 9 (deuterated at one position) and Example 9 / 1 (deuterated at two positions) and the non-deuterated matched pair (Example 9 / 9) were incubated for 60 min with two different batches of pooled SD rat liver microsomes (RLM) and human liver microsomes (HLM), respectively. A similar procedure was applied to Example 1 / 7 and its non-deuterated matched pair Example 1 / 13. Metabolism was monitored by HPLC-MS / MS. Verapamil was used as a positive control. Intrinsic clearance Cl int was calculated from the residual compound values ​​(in duplicate) measured at 0, 10, 30 and 60 minutes. The 60 minute data points are:

[0589] [Table 38]

[0590] Conclusion: Selective deuteration of sensitive positions (especially the anisole alkyl moiety) can improve metabolic stability. Additional deuteration of the N-methoxyacetamide moiety can further improve stability (Example 9 to Example 9 / 1).

[0591] Example 210: Pharmacokinetics in rats The pharmacokinetics of the compounds of the present invention were evaluated in three female Sprague Dawley rats (8 weeks old) after oral cassette administration (vehicle: 5% Solutol / 95% NaCl solution (0.9% saline concentration, administration volume: 5 mL / kg) to assess the exposure of the test substance. At each designated time point (0.25, 0.5, 1, 2, 4 and 8 hours after administration), 20 μL of blood was collected from the tail vein into lithium heparin tubes, cooled on ice and stored at -20°C until processed for LC-MS analysis. The data obtained are as follows:

[0592] [Table 39]

[0593] Conclusion: The metabolic stability from microsomes (Example 209) is well reflected in the improved bioavailability in in vivo PK studies. Again, the deuterated derivatives Example 5 / 4 and Example 5 / 5 are more stable and have better bioavailability compared to the non-deuterated matched pair Example 5 / 9.

Claims

1. Formula (I): 【Chemistry 1】 or an enantiomer, diastereomer, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein A is selected from 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl, wherein one or more hydrogen atoms are optionally replaced with deuterium; A is unsubstituted or substituted with 1 to 5 substituents, and the substituents are halogen, -CN, -NO 2 , oxo, -OH, C 1-4 -Alkyl, -OC 1-4 -Alkyl, Fluoro-C 1-4 -Alkyl and -O-fluoro-C 1-4 -alkyl, wherein Ring A has one or more hydrogen atoms in the alkyl optionally replaced by deuterium; B is selected from the group consisting of 5- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O, and S; The cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents, which may include halogen, -CN, -NO 2 , Oxo, C 1-4 -Alkyl, C 0-6 -Alkylene-OR 21 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-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 independently selected from the group consisting of Alkyl, alkylene, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, which substituents include halogen, —CN, oxo, —OH, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated ring, optionally containing 1 to 3 heteroatoms independently selected from O, S, or N; The additional ring may optionally be a halogen, -CN, oxo, -OH, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -substituted with 1 to 4 substituents independently selected from alkyl; Residue on ring B -NR 2 is in the 1,4-position relative to ring C, B has one or more hydrogen atoms optionally replaced with deuterium; C is selected from the group consisting of 5- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5- to 10-membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O, and S; The cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents, which may include halogen, -CN, -NO 2 , Oxo, C 1-4 -Alkyl, C 0-6 -Alkylene-OR 31 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -Alkylene-S(=O) n (=NR 33 ) m R 31 , C 0-6 -Alkylene-NR 31 S(=O) x (=NR 33 ) y R 31 , C 0-6 -Alkylene-S(=O) x (=NR 33 ) y NR 31 R 32 , C 0-6 -Alkylene-NR 31 S(=O) x (=NR 33 ) y NR 31 R 32 , C 0-6 -Alkylene-CO 2 R 31 , C 0-6 -Alkylene-O-COR 31 , C 0-6 -Alkylene-CONR 31 R 32 , C 0-6 -Alkylene-NR 31 -COR 31 , C 0-6 -Alkylene-NR 31 -CONR 31 R 32 , C 0-6 -Alkylene-O-CONR 31 R 32 , C 0-6 -Alkylene-NR 31 -CO 2 R 31 , C 0-6 -Alkylene-NR 31 R 32 independently selected from the group consisting of Alkyl, alkylene, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, which substituents include halogen, —CN, oxo, —OH, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5- to 8-membered partially unsaturated ring, optionally containing 1 to 3 heteroatoms independently selected from O, S, or N; The additional ring is optionally substituted with 1 to 4 substituents, which may include halogen, —CN, oxo, —OH, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, C has one or more hydrogen atoms optionally replaced with deuterium; X is H, D, halogen, -CN, -NO 2 , C 1-6 -Alkyl, -OC 1-6 -Alkyl, O-Halo-C 1-6 -Alkyl, C 0-6 -Alkylene-OR 41 , C 0-6 -alkylene-(3- to 6-membered cycloalkyl), C 0-6 -alkylene-(3- to 6-membered heterocycloalkyl), C 0-6 -Alkylene-S(=O) n (=NR 43 ) m R 41 , C 0-6 -Alkylene-NR 41 S(=O) x (=NR 43 ) y R 41 , C 0-6 -Alkylene-S(=O) x (=NR 43 ) y NR 41 R 42 , C 0-6 -Alkylene-NR 41 S(=O) x (=NR 43 ) y NR 41 R 42 , C 0-6 -Alkylene-CO 2 R 41 , C 0-6 -Alkylene-O-COR 41 , C 0-6 -Alkylene-CONR 41 R 42 , C 0-6 -Alkylene-NR 41 -COR 41 , C 0-6 -Alkylene-NR 41 -CONR 41 R 42 , C 0-6 -Alkylene-O-CONR 41 R 42 , C 0-6 -Alkylene-NR 41 -CO 2 R 41 , C 0-6 -Alkylene-NR 41 R 42 wherein heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; Alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents, which substituents include halogen, -CN, oxo, -OH, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, X has one or more hydrogen atoms optionally replaced with deuterium; Yは、-CONH-CN, -CONHOH, -CONHOR 10 , -CONR 10 OH, -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR) 13 ) y R 10 , -CONHS(=O) y (=NR) 13 ) y NR 11 R 12 , -SO 3 H, -S(=O) x (=NR) 13 ) y NHCOR 10 , -S(=O) x (=NR) 13 ) y NHR 11 , -P(=O)(OH) 2 , -P(=O)(NR 11 R 12 )OH, -P(=O)R 11 (OH), -B(OH) 2 , 【Chemistry 2】 Selected from Y has one or more hydrogen atoms optionally replaced with deuterium; R 2 is H and C 1-6 - alkyl, Alkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, -CN, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, wherein heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 2 has one or more hydrogen atoms optionally replaced with deuterium; R 10 is C 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; Alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, —CN, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, wherein heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 10 has one or more hydrogen atoms optionally replaced with deuterium; R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , R 42 is H, C 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; The alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, —CN, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, wherein heterocycloalkyl contains 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 and / or R 31 and / or R 32 and / or R 41 and / or R 42 has one or more hydrogen atoms optionally replaced with deuterium, or R 11 and R 12 , R 21 and R 22 , R 31 and R 32 , R 41 and R 42 each, when taken together with the nitrogen to which they are attached, completes a 3- to 6-membered ring containing carbon atoms and optionally 1 or 2 heteroatoms selected from O, S or N, and The ring is unsubstituted or substituted with 1 to 3 substituents, which may be halogen, —CN, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, R 11 and / or R 12 and / or R 21 and / or R 22 and / or R 31 and / or R 32 and / or R 41 and / or R 42 has one or more hydrogen atoms optionally replaced with deuterium; R 13 , R 23 , R 33 , R 43 is H, -CN, -NO 2 , C 1-6 -Alkyl, -CO-OC 1-6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; The alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being halogen, —CN, C 1-4 -Alkyl, Halo-C 1-4 -Alkyl, 3- to 6-membered cycloalkyl, halo-(3- to 6-membered cycloalkyl), 3- to 6-membered heterocycloalkyl, halo-(3- to 6-membered heterocycloalkyl), -OH, oxo, -OC 1-4 -Alkyl and -O-Halo-C 1-4 -alkyl, wherein heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; R 13 and / or R 23 and / or R 33 and / or R 43 has one or more hydrogen atoms optionally replaced with deuterium; n, m, x, and y are independently selected from 0 to 2; provided that the sum of integers m and n for residues bonded to the same sulfur atom is independently selected from 0 to 2; provided that the sum of integers x and y for residues attached to the same sulfur atom is independently selected from 1 or 2; and However, the following structure 【Transformation 3】 or an enantiomer, diastereomer, tautomer, solvate or pharmaceutically acceptable salt thereof, excluding:

2. Yは、-CONH-CN, -CONHOR 10 , -C(=NOH)NR 11 R 12 , -CONHS(=O) x (=NR 13 ) y R 10 , -CONHS(=O) y (=NR 13 ) y NR 11 R 12 , 【Chemistry 4】 Selected from R 10 is C 1-3 -alkyl, cyclopropyl or oxetan-3-yl, Alkyl, cyclopropyl or oxetan-3-yl is unsubstituted or substituted with 1 to 3 substituents, the substituents being F, —CN, Me, CHF 2 , CF 3 , -OH, oxo, -OMe, -OCHF 2 and -OCF 3 are independently selected from R 10 has one or more hydrogen atoms optionally replaced with deuterium; R 11 and R 12 is H or C 1-3 -alkyl, Alkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being F, -CN, Me, CHF 2 , CF 3 , -OH, oxo, -OMe, -OCHF 2 and -OCF 3 are independently selected from R 11 and / or R 12 has one or more hydrogen atoms optionally replaced with deuterium; R 13 is H, -CN and C 1-3 - alkyl, Alkyl is unsubstituted or substituted with 1 to 3 substituents, the substituents being F, -CN, Me, CHF 2 , CF 3 , -OH, oxo, -OMe, -OCHF 2 and -OCF 3 are independently selected from R 13 has one or more hydrogen atoms optionally replaced with deuterium; 2. A compound of formula (I) according to claim 1, wherein x is and y is 1, or x is 2 and y is 0, or a solvate or pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 5】 teeth, 【Transformation 6】 Selected from, and R 2 The compound of formula (I) according to claim 1, wherein is H.

4. 2. A compound of formula (I) according to claim 1, wherein one or more hydrogen atoms in any substituent are replaced by deuterium.

5. B is phenyl; The phenyl is unsubstituted or substituted with 1 to 4 substituents, the substituents being D, F, Cl, —CN, Me, CD 3 , CHF 2 and CF 3 and the residue on ring B is -NR 2 The compound of formula (I) according to claim 1, wherein is in the 1,4-position relative to ring C.

6. C is phenyl; The phenyl is unsubstituted or substituted with 1 to 4 substituents, the substituents being D, F, Cl, —CN, Me, CD 3 , CHF 2 , CF 3 , -OMe, -OCD 3 , -OCHF 2 and -OCF 3 independently selected from the group consisting of X is D, F, Cl, -CN, Me, CD 3 , CHF 2 , CF 3 , Et, CD 2 CD 3 , -OMe, -OCD 3 , -OCHF 2 , -OCF 3 , -OEt and -OCD 2 CD 3 2. The compound of formula (I) according to claim 1, selected from: 【Request Item 7】 【Chemistry 7】 teeth, 【Transformation 8】 Selected from 2. The compound of formula (I) according to claim 1, wherein ring C is optionally substituted with 1 to 4 substituents, said substituents being independently selected from D or F.

8. Y is 【Chemistry 9】 Selected from 【Chemistry 10】 teeth, 【Chemistry 11】 Selected from R 2 is H, B is 【Chemistry 12】 Selected from 【Chemistry 13】 teeth, 【Chemistry 14】 2. The compound of formula (I) according to claim 1, selected from: 【Request Item 9】 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 16】 【Chemistry 17】 2. The compound of formula (I) according to claim 1, selected from: or a solvate or a pharmaceutically acceptable salt thereof.

10. 10. A compound according to claim 1 for use as a medicine.

11. A compound according to any one of claims 1 to 10 for use in the prevention and / or treatment of a disease, disorder, therapeutic indication or condition treatable by a DHODH inhibitor.

12. 12. The compound for use according to claim 11, wherein the disease, disorder, therapeutic indication or condition is selected from the group comprising rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoan infestations in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy.

13. 13. The compound for use according to claim 12, wherein the disease, disorder or therapeutic indication is selected from the group comprising graft versus host reaction and host versus graft reaction, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or excipient.

15. 15. The pharmaceutical composition of claim 14, further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, antiviral agents, immunosuppressants and / or immunomodulators, steroids, nonsteroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

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