Deuterated DHODH inhibitors

Abstract

The present invention relates to novel deuterated compounds of formula (I) and their use as pharmaceuticals. [Formula 1] JPEG2024515062000212.jpg28128

Description

[Technical field]

[0001] The present disclosure relates to novel deuterated dihydroorotate dehydrogenase (DHODH) inhibitors, pharmaceutical formulations containing them, methods for their preparation, and their use as medicaments, alone or in combination with one or more additional agents, to treat various diseases in which inhibition of DHODH is desirable. [Background technology]

[0002] Bidofludimus calcium (IMU-838) is a selective and potent second-generation dihydroorotate dehydrogenase (DHODH) oral immunomodulator being developed for the treatment of several chronic inflammatory diseases, including relapsing-remitting multiple sclerosis (rrMS). [ka] The mechanism of action of the small molecule selective immunomodulatory drug bidofludimus calcium is the inhibition of intracellular metabolism of activated immune T and B cells by blocking the enzyme DHODH. Inhibition of the DHODH enzyme leads to metabolic stress in metabolically activated lymphocytes, resulting in a reduction in proinflammatory cytokines and subsequent apoptosis of activated immune cells. Blocking DHODH enzyme activity has selective effects on metabolically activated immune cells, malignant cells and virus-infected cells. Thus, DHODH inhibition does not lead to a general antiproliferative effect in 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. An additional advantage of DHODH inhibitors such as IMU-838 is their direct antiviral effect. Reactivation of latent viruses has been observed during long-term treatment with immunosuppressants. This can lead to serious infections such as progressive multifocal leukoencephalopathy, which can have a fatal outcome.

[0003] 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. In animal models, it has already demonstrated high efficacy in treating dry eye disease and viral conjunctivitis.

[0004] There is a need to develop novel DHODH inhibitors. In particular, there is a need to develop DHODH inhibitors with improved pharmacokinetic properties. 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 the analogous C-D bond may be more difficult, thus decreasing the metabolic rate. Substitution of H with D in small molecules may result in a significant decrease in metabolism, resulting in a beneficial change in the biological effect of the drug. The substitution may also have the effect of reducing toxicity by reducing the formation of toxic metabolites (J.Med.Chem.2019;62:5276). Deuterated analogs share the beneficial mechanism of action, but are expected to be metabolized more slowly and with less interpatient variability compared to their non-deuterated counterparts. Overall, it is believed that differential pharmacokinetic profiles may potentially allow for improved efficacy, less frequent dosing, improved tolerability, reduced interpatient variability in drug metabolism, and reduced drug-drug interactions. Summary of the Invention [Problem to be solved by the invention]

[0005] The non-deuterated compounds of formula (I) may be prepared using the methods described in WO 2004 / 056746, WO 2004 / 056747, WO 2004 / 056797, WO 2010 / 052027, WO 2010 / 128050, WO 2012 / 001148, WO 2012 / 001151, WO 2015 / 169944, WO 2015 / 154820, WO 2015 / 154821, WO 2015 / 154822, WO 2015 / 154823, WO 2015 / 154824, WO 2015 / 154825, WO 2015 / 154826, WO 2015 / 154827, WO 2015 / 154829 ... 019 / 170848, WO 2019 / 101888, WO 2019 / 175396, and 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) have not yet been described. [Means for solving the problem]

[0006] The present invention relates to a compound according to formula (I), [ka] or an enantiomer, diastereomer, tautomer, prodrug, solvate, or pharma- ceutically acceptable salt thereof, wherein Ring A, Ring B, Ring C, X, R 1 , and R 2 is as defined in claim 1, However, A, B, C, R 2 and / or at least one hydrogen in X is replaced with deuterium, and the level of deuterium incorporation in each substituent designated as deuterium is at least 52.5%.

[0007] The compounds of the present invention relate to compounds, or their enantiomers, diastereomers, tautomers, prodrugs, solvates, or pharma- ceutically acceptable salts, that have similar or better DHODH inhibitory activity compared to known DHODH inhibitors.Furthermore, the compounds of the present invention exhibit advantageous stability or pharmacokinetic profiles when used as pharmaceuticals due to the substitution of deuterium for hydrogen.

[0008] Therefore, the present invention further relates to a pharmaceutical composition comprising a compound according to formula (I) and at least one pharma- ceutically acceptable carrier or excipient.

[0009] The present invention further relates to the compounds according to formula (I) for use in the prevention and / or treatment of diseases mediated by DHODH.

[0010] The present invention therefore relates to the prevention and / or treatment of a disease, disorder, therapeutic indication or medical condition selected from the group comprising rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy. More particularly, 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, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis. [Brief description of the drawings]

[0011] [Figure 1] Representative results of an experiment combining Example 9 with the nucleoside analog EIDD-1931 (CAS: 3258-02-4) are shown. The data show a synergistic antiviral effect against SARS-CoV-2 at various doses. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] 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 2 clinical trials for the treatment of rrMS, ulcerative colitis, primary sclerosing cholangitis, and COVID-19.

[0013] 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.

[0014] Bidofludimus, IMU-838, and PP-001 have generally been well tolerated in several clinical trials. Despite the potential beneficial activities of Bidofludimus, IMU-838, and PP-001, there remains a need for novel compounds for treating the aforementioned diseases and conditions with improved drug metabolism and pharmacokinetic (DMPK) properties. Improved DMPK properties have the potential to result in positive changes in the safety profile, efficacy, and tolerability of the compounds.

[0015] Reference will now be made in detail to certain embodiments of the invention, examples of which 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 they are not intended to limit the invention to those embodiments. Rather, the invention is intended to encompass 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 any methods and materials similar or equivalent to those described herein that may be used in the practice of the invention. In the event that one or more of the incorporated references, patents, or similar materials, including but not limited to defined terms, term usage, described techniques, etc., differ or conflict with this application, this application will take precedence.

[0016] The desired properties of DHODH inhibitors are characterized by compounds conforming to the structural pattern represented by formula (I): [ka] or an enantiomer, diastereomer, tautomer, prodrug, solvate, or pharma- ceutically acceptable salt thereof, wherein A is selected from 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl, having one or more hydrogen atoms optionally replaced with deuterium; The A is unsubstituted or is halogen, CN, NO2, oxo, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, O-Fluoro-C 1~4 - substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, CO2H, and SO3H, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; B is selected from the group consisting of 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5-10 membered heteroaryl containing 1-6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with halogen, -CN, -NO2 oxo, C 1~4 -Alkyl, C 0~6 -Alkylene-OR 27 , C 0~6 -Alkylene-(3-6 membered cycloalkyl), C 0~6 -alkylene-(3-6 membered heterocycloalkyl), C 0~6 -Alkylene-S(=O) n (=NR 29 ) m R 27 , C 0~6 -Alkylene-NR 27 S(=O) x (=NR 29 ) y R 27 , C 0~6 -Alkylene-S(=O) x (=NR 29 ) y NR 27 R 28 , C 0~6 -Alkylene-NR 27 S(=O) x (=NR 29 ) y NR 27 R 28 , C 0~6 -Alkylene-CO2R 27 , C 0~6 -Alkylene-O-COR 27 , C 0~6 -Alkylene-CONR 27 R 28 , C 0~6 -Alkylene-NR 27 -COR 27 , C 0~6 -Alkylene-NR 27 -CONR 27 R 28 , C0~6 -Alkylene-O-CONR 27 R 28 , C 0~6 -Alkylene-NR 27 -CO2R 27 , C 0~6 -Alkylene-NR 27 R 28 and is substituted with 1 to 4 substituents 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 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 6 substituents independently selected from alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing 1-3 heteroatoms independently selected from O, S, or N; The additional ring can be halogen, -CN, oxo, -OH, C 1~4 -Alkyl, halo-C 1~4 -Alkyl, -OC 1~4 -alkyl, and -O-halo-C 1~4 -alkyl; Residue on Ring B -NR 2 is in the 1,4-orientation relative to ring C, Ring B or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium; C is selected from the group consisting of 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5-10 membered heteroaryl containing 1-6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with halogen, -CN, -NO2 oxo, C 1~4 -Alkyl, C0~6 -Alkylene-OR 31 , C 0~6 -Alkylene-(3-6 membered cycloalkyl), C 0~6 -alkylene-(3-6 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 and is substituted with 1 to 4 substituents 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 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 6 substituents independently selected from alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing 1-3 heteroatoms independently selected from O, S, or N; where the further ring is halogen, -CN, oxo, -OH, C 1~4 -Alkyl, halo-C 1~4 -Alkyl, -OC 1~4 -Alkyl and -O-Halo-C 1~4 -alkyl; Ring C or a substituent thereof 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-(3-6 membered cycloalkyl), C 0~6 -alkylene-(3-6 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 , 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 wherein heterocycloalkyl contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; Alkyl, alkylene, cycloalkyl, and heterocycloalkyl are unsubstituted or can be substituted with 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 6 substituents independently selected from alkyl, X or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium; R 1 is selected from H and D; R 2 H and C 1~6 alkyl, Alkyl is unsubstituted or substituted with 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 -substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R 2 or its substituents have one or more hydrogen atoms optionally replaced with deuterium; R 27 , R 28 , R 31 , R 32 , R 41 , R 42 , H, C 1~6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; The alkyl, cycloalkyl, or heterocycloalkyl may be unsubstituted or may be substituted with 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 -substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R 27 and / or R 28 and / or R 31 and / or R 32 and / or R 41 and / or R 42 or each of its substituents has one or more hydrogen atoms optionally replaced with deuterium; or R 27 and R 28 , R 31 and R 32 , R 41 , and R 42each together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, or N; The ring is unsubstituted or substituted with 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 -substituted with 1 to 3 substituents independently selected from alkyl, R 27 and / or R 28 and / or R 31 and / or R 32 and / or R 41 and / or R 42 or each of its substituents has one or more hydrogen atoms optionally replaced with deuterium; R 29 , R 33 , R 43 H, -CN, -NO2, 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 may be unsubstituted or may be substituted with 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 -substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R 29 and / or R 33 and / or R 43or each of its substituents 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 attached to the same sulfur atom is independently selected from 0 to 2; provided that the sum of integers x and y for residues bound to the same sulfur atom is independently selected from 1 or 2; However, A, B, C, R 2 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 , R 41 , R 42 , R 43 and / or at least one hydrogen in X is replaced with deuterium; provided that the level of deuterium incorporation in each substituent designated as deuterium is at least 52.5%.

[0017] In a more specific embodiment, the compound is represented by formula (I), a solvate or a pharma- ceutically acceptable salt thereof, wherein: R 1 is H and R 2 is H.

[0018] In a more specific embodiment in combination with any of the above or below embodiments, the compound is represented by formula (I), [ka] is selected from.

[0019] In specific embodiments of similarity in combination with any of the above or below embodiments, the compound is represented by formula (I), -NR 2 B is, [ka] is selected from.

[0020] In specific embodiments of similarity in combination with any of the above or below embodiments, the compound is represented by formula (I), C is phenyl, pyridyl, or thiazolyl; Phenyl, pyridyl, or thiazolyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D and F; X is D, F, Cl, -CN, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, O-Fluoro-C 1~4 -alkyl, having one or more hydrogen atoms optionally replaced with deuterium.

[0021] In a more specific embodiment in combination with any of the above or below embodiments, the compound is represented by formula (I), [ka] teeth, [ka] is selected from.

[0022] In a more specific embodiment in combination with any of the above or below embodiments, the compound is represented by formula (I), [ka] teeth, [ka] is selected from.

[0023] In a more specific embodiment in combination with any of the above or below embodiments, the compound is represented by formula (I), R 1 is H and R 2 is H, [ka] teeth, [ka] is selected from -NR 2 B is, [ka] is selected from [ka] teeth, [ka] is selected from.

[0024] In the most specific embodiments, the compound is selected from the following: [ka] [ka] Or a solvate or a pharma- ceutically acceptable salt thereof.

[0025] The present disclosure also provides compounds of the present disclosure for use as a medicament.

[0026] There is also provided the compounds of the invention for use in the prevention and / or treatment of a disease, disorder, therapeutic indication, or medical condition suitable for treatment with a DHODH inhibitor.

[0027] There is also provided a compound of the invention for use in the prophylaxis and / or treatment of a DHODH mediated disease selected from rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal invasion in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation, or arthropathy.

[0028] More particularly, the present invention relates to a compound of the present invention for use 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.

[0029] Also provided is a pharmaceutical composition comprising a compound of the invention and a pharma- ceutically acceptable carrier or excipient.

[0030] Pharmaceutical compositions are also provided comprising a compound of the invention and a pharma- ceutically acceptable carrier or excipient, and further comprising one or more additional therapeutic agents selected from antiviral agents, anti-inflammatory agents, immunosuppressants and / or immunomodulators, steroids, nonsteroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

[0031] Furthermore, the desirable properties of the DHODH inhibitors are contemplated by compounds conforming to the structural pattern represented by formula (I): [ka] or an enantiomer, diastereomer, tautomer, prodrug, solvate, or pharma- ceutically acceptable salt thereof, wherein R 1 and R 2 is independently selected from H or D; R 3 , R 4 , R 5、 and R 6H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 - independently selected from alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; R 7 , R 8 , R 9 , and R 10 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 - independently selected from alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; X is H, D, OH, OD, S(=O) y R 11 , and OR 11 is selected from R 11 is C 1~4 -Alkyl, C 3~4 -cycloalkyl and fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; y is 0 to 2; [ka] is selected from 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl; having one or more hydrogen atoms optionally replaced with deuterium; The A is unsubstituted or is halogen, CN, NO2, oxo, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl and O-Fluoro-C 1~4 - substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, CO2H and SO3H, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; However, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 At least one hydrogen in X, X, and / or A is replaced with deuterium.

[0032] In certain embodiments, the compound is represented by formula (I), or a prodrug, pharma- ceutically acceptable salt, or solvate thereof. R 1 and R 2 is independently selected from H or D; R 3 , R 4 , R 5 and R 6 is independently selected from H, D, F, and Cl; R 7 , R 8 , R 9 and R 10 is independently selected from H, D, and F; X is H, D, OH, OD, and OR 11 is selected from R 11 is C 1~4 -Alkyl and Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; [ka] teeth, [ka] and having one or more hydrogen atoms optionally replaced with deuterium, However, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R10 , R 11 and / or at least one hydrogen in A is replaced with deuterium.

[0033] In a specific embodiment, the compound is represented by formula (I), or a prodrug, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 3 is F, R 4 , R 5 , and R 6 is independently selected from H, D, and F; R 7 , R 8 , R 9 , and R 10 is independently selected from H and D; X is OH, OD, and OR 11 is selected from R 11 is selected from CH3, CD3, CHF2, CDF2, and CF3; [ka] teeth, [ka] and R 21 , R 22 , R 23 , R 24 , R 25 , and R 26 is independently selected from H and D; However, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 21 , R 22 , R 23 , R 24 , R 25 , and / or R 26 At least one hydrogen atom in the is replaced with deuterium.

[0034] In a more specific embodiment, the compound is represented by formula (I), or a prodrug, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 4 , R 5 , and R 6 is independently selected from H and D; X is OR 11 and R 11 is selected from CH3 and CD3; However, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 21 , R 22 , R 23 , R 24 , R 25 , and / or R 26 At least one hydrogen atom in the is replaced with deuterium.

[0035] In a more specific embodiment in combination with any of the above or below embodiments, R 11 is CD3.

[0036] In more specific embodiments, the compound is selected from the following: [ka] Or a solvate or a pharma- ceutically acceptable salt thereof.

[0037] In the most specific embodiments, the compound is selected from the following: [ka] Or a solvate or a pharma- ceutically acceptable salt thereof.

[0038] In an equally specific embodiment, the compound is represented by formula (I), or a prodrug, pharma- ceutically acceptable salt, or solvate thereof, wherein: R 1 and R 2 is independently selected from H or D; R 3 , R 4 , R 5 , and R 6 is independently selected from H, D, F, and Cl; R 7 , R 8 , R 9 , and R 10 is independently selected from H, D, and F; X is OR 11 and R 11 is C 1~4 -Alkyl and Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; [ka] teeth [ka] and having one or more hydrogen atoms optionally replaced with deuterium; However, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and / or at least one hydrogen in A is replaced with deuterium.

[0039] In a similar most specific embodiment, the compound is [ka] or a solvate or a pharma- ceutically acceptable salt thereof.

[0040] The present disclosure also provides compounds of the present disclosure for use as a medicament.

[0041] There is also provided the compounds of the invention for use in the prevention and / or treatment of a disease, disorder, therapeutic indication, or medical condition suitable for treatment with a DHODH inhibitor.

[0042] There is also provided a compound of the invention for use in the prophylaxis and / or treatment of a DHODH mediated disease selected from rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal invasion in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation, or arthropathy.

[0043] More particularly, the present invention relates to a compound of the present invention for use 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, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

[0044] Also provided is a pharmaceutical composition comprising a compound of the invention and a pharma- ceutically acceptable carrier or excipient.

[0045] Pharmaceutical compositions are also provided comprising a compound of the invention and a pharma- ceutically acceptable carrier or excipient, and further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, immunosuppressants and / or immunomodulators, steroids, nonsteroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

[0046] In certain embodiments, the present invention relates to compounds of formula (I) as described in the following paragraphs. 1. Compounds according to formula (I): [ka] or an enantiomer, diastereomer, tautomer, prodrug, solvate, or pharma- ceutically acceptable salt thereof, wherein R 1 and R 2 is independently selected from H or D; R 3 , R 4 , R 5 , and R 6 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 - independently selected from alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; R 7 , R 8 , R 9 , and R 10 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 - independently selected from alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; X is H, D, OH, OD, S(=O) y R 11 , and OR 11 is selected from R 11 is C 1~4 -Alkyl, C 3~4 -cycloalkyl and fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; y is 0 to 2; [ka] is selected from 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl; having one or more hydrogen atoms optionally replaced with deuterium; The A is unsubstituted or is halogen, CN, NO2, oxo, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl and O-Fluoro-C 1~4 - substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, CO2H and SO3H, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; However, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 At least one hydrogen atom in X, A, and / or X is replaced with deuterium.

[0047] 2. R 1 and R 2 is independently selected from H or D; R 3 , R 4 , R 5 , and R 6 is independently selected from H, D, F, and Cl; R 7 , R 8 , R 9 , and R 10 is independently selected from H, D, and F; X is H, D, OH, OD and OR 11 is selected from R 11 is C 1~4 -Alkyl and Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; [ka] teeth, [ka] and having one or more hydrogen atoms optionally replaced with deuterium, However, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and / or at least one hydrogen in A is replaced with deuterium, the compound according to item 1 having formula (I), or a prodrug, pharma- ceutically acceptable salt, or solvate thereof.

[0048] 3. R 3 is F, R 4 , R 5 , and R 6 is independently selected from H, D, and F; R 7 , R 8 , R 9 , and R 10 is independently selected from H and D; X is OH, OD and OR 11 is selected from R 11 is selected from CH3, CD3, CHF2, CDF2, and CF3; [ka] teeth, [ka] and R 21 , R 22 , R 23 , R 24 , R 25 , and R 26 is independently selected from H and D; However, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10, R 11 , R 21 , R 22 , R 23 , R 24 , R 25 , and / or R 26 The compound according to item 2, having the formula (I), or a prodrug, pharma- ceutically acceptable salt, or solvate thereof, wherein at least one hydrogen atom in is replaced with deuterium.

[0049] 4. R 4 , R 5 , and R 6 is independently selected from H and D; X is OR 11 and R 11 is selected from CH3 and CD3; However, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 21 , R 22 , R 23 , R 24 , R 25 , and / or R 26 4. The compound according to item 3, having formula (I), or a prodrug, pharma- ceutically acceptable salt, or solvate thereof, wherein at least one hydrogen atom in is replaced with deuterium.

[0050] 5.R 11 is CD3.

[0051] 6. [ka] The compound according to any one of the preceding items, selected from Or a solvate or a pharma- ceutically acceptable salt thereof.

[0052] 7. R1 and R 2 is independently selected from H or D; R 3 , R 4 , R 5 , and R 6 is independently selected from H, D, F, and Cl; R 7 , R 8 , R 9 , and R 10 is independently selected from H, D, and F; X is OR 11 and R 11 is C 1~4 -Alkyl and Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; [ka] teeth [ka] and having one or more hydrogen atoms optionally replaced with deuterium; However, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and / or at least one hydrogen in A is replaced by deuterium, or a prodrug, pharma- ceutically acceptable salt, or solvate thereof.

[0053] 8. A compound according to any one of the preceding items, [ka] Or a solvate or a pharma- ceutically acceptable salt thereof.

[0054] 9. A compound according to any one of the preceding items for use as a medicament.

[0055] 10. A compound according to any one of items 1 to 9 for use in the prevention and / or treatment of a disease, disorder, therapeutic indication or medical condition suitable for treatment with a DHODH inhibitor.

[0056] 11. The compound for use according to item 10, wherein the disease, disorder, therapeutic indication or medical condition is selected from the group comprising rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation, or arthropathy.

[0057] 12. The compound for use according to item 11, 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, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis, and psoriasis.

[0058] 13. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 8 and a pharma- ceutically acceptable carrier or excipient.

[0059] 14. The pharmaceutical composition according to item 13, further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, immunosuppressants and / or immunomodulators, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

[0060] 15. Compounds according to formula (I): [ka] or an enantiomer, diastereomer, tautomer, prodrug, solvate, or pharma- ceutically acceptable salt thereof, wherein A is selected from 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl, having one or more hydrogen atoms optionally replaced with deuterium; The A is unsubstituted or is halogen, CN, NO2, oxo, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, O-Fluoro-C 1~4 - substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, CO2H, and SO3H, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; B is selected from the group consisting of 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5-10 membered heteroaryl containing 1-6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with halogen, -CN, -NO2 oxo, C 1~4 -Alkyl, C 0~6 -Alkylene-OR 27 , C 0~6 -Alkylene-(3-6 membered cycloalkyl), C 0~6 -alkylene-(3-6 membered heterocycloalkyl), C 0~6 -Alkylene-S(=O) n (=NR 29 ) m R 27 , C 0~6 -Alkylene-NR 27 S(=O) x (=NR 29 ) y R 27 , C 0~6 -Alkylene-S(=O) x (=NR 29 ) y NR 27 R 28 , C 0~6 -Alkylene-NR 27 S(=O) x (=NR 29 )y NR 27 R 28 , C 0~6 -Alkylene-CO2R 27 , C 0~6 -Alkylene-O-COR 27 , C 0~6 -Alkylene-CONR 27 R 28 , C 0~6 -Alkylene-NR 27 -COR 27 , C 0~6 -Alkylene-NR 27 -CONR 27 R 28 , C 0~6 -Alkylene-O-CONR 27 R 28 , C 0~6 -Alkylene-NR 27 -CO2R 27 , C 0~6 -Alkylene-NR 27 R 28 and is substituted with 1 to 4 substituents 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 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 6 substituents independently selected from alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing 1-3 heteroatoms independently selected from O, S, or N; The additional ring can be halogen, -CN, oxo, -OH, C 1~4 -Alkyl, halo-C 1~4 -Alkyl, -OC 1~4 -alkyl, and -O-halo-C 1~4 -alkyl; Residue on Ring B -NR 2is in the 1,4-orientation relative to ring C, Ring B or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium; C is selected from the group consisting of 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5-10 membered heteroaryl containing 1-6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with halogen, -CN, -NO2 oxo, C 1~4 -Alkyl, C 0~6 -Alkylene-OR 31 , C 0~6 -Alkylene-(3-6 membered cycloalkyl), C 0~6 -alkylene-(3-6 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 -COR31 , 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 and is substituted with 1 to 4 substituents 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 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 6 substituents independently selected from alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing 1-3 heteroatoms independently selected from O, S, or N; The additional ring can be halogen, -CN, oxo, -OH, C 1~4 -Alkyl, halo-C 1~4 -Alkyl, -OC 1~4 -alkyl, and -O-halo-C 1~4 -alkyl; Ring C or a substituent thereof 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-(3-6 membered cycloalkyl), C 0~6 -alkylene-(3-6 membered heterocycloalkyl), C0~6 -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 , 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 wherein heterocycloalkyl contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; Alkyl, alkylene, cycloalkyl, and heterocycloalkyl are unsubstituted or can be substituted with 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 6 substituents independently selected from alkyl, X or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium; R 1 is selected from H and D; R 2 H and C 1~6 alkyl, Alkyl is unsubstituted or substituted with 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 -substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R 2 or its substituents have one or more hydrogen atoms optionally replaced with deuterium; R 27 , R 28 , R 31 , R 32 , R 41 , R 42 , H, C 1~6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; The alkyl, cycloalkyl, or heterocycloalkyl may be unsubstituted or may be substituted with 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-substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R 27 and / or R 28 and / or R 31 and / or R 32 and / or R 41 and / or R 42 or each of its substituents has one or more hydrogen atoms optionally replaced with deuterium; or R 27 and R 28 , R 31 and R 32 , R 41 , and R 42 each together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, or N; The ring is unsubstituted or substituted with 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 -substituted with 1 to 3 substituents independently selected from alkyl, R 27 and / or R 28 and / or R 31 and / or R 32 and / or R 41 and / or R 42 or each of its substituents has one or more hydrogen atoms optionally replaced with deuterium; R 29 , R 33 , R 43 H, -CN, -NO2, 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 may be unsubstituted or may be substituted with 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 -substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R 29 and / or R 33 and / or R 43 or each of its substituents 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 attached to the same sulfur atom is independently selected from 0 to 2; provided that the sum of integers x and y for residues bound to the same sulfur atom is independently selected from 1 or 2; However, A, B, C, R 2 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 , R 41 , R 42 , R 43 and / or at least one hydrogen in X is replaced with deuterium; provided that the level of deuterium incorporation in each substituent designated as deuterium is at least 52.5%, or an enantiomer, diastereomer, tautomer, prodrug, solvate, or pharma- ceutically acceptable salt thereof.

[0061] 16. R 1 is H and R 2is H, or a solvate or a pharma- ceutically acceptable salt thereof.

[0062] 17. [ka] teeth, [ka] 17. The compound of formula (I) according to item 15 or 16, selected from:

[0063] 18. -NR 2 B is, [ka] 18. The compound of formula (I) according to any one of items 15 to 17, selected from:

[0064] 19. C is phenyl, pyridyl, or thiazolyl; Phenyl, pyridyl, or thiazolyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D and F; X is D, F, Cl, -CN, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, O-Fluoro-C 1~4 19. Compounds of formula (I) according to any of items 15 to 18, having one or more hydrogen atoms selected from -alkyl, optionally replaced with deuterium.

[0065] 20. [ka] teeth, [ka] 20. The compound of formula (I) according to any one of items 15 to 19, selected from:

[0066] twenty one. [ka] teeth, [ka] 21. The compound of formula (I) according to any one of items 15 to 20, selected from:

[0067] twenty two. R 1 is H and R 2 is H, [ka] teeth, [ka] is selected from -NR 2 B is, [ka] is selected from [ka] teeth, [ka] 22. The compound of formula (I) according to any one of items 15 to 21, selected from:

[0068] twenty three. [ka] [ka] A compound of formula (I) according to any one of items 15 to 22, selected from or a solvate or a pharma- ceutically acceptable salt thereof.

[0069] 24. A compound according to any one of items 15 to 23 for use as a medicine.

[0070] 25. A compound according to any one of items 15 to 24 for use in the prevention and / or treatment of a disease, disorder, therapeutic indication or medical condition suitable for treatment with a DHODH inhibitor.

[0071] 26. The compound for use according to item 25, wherein the disease, disorder, therapeutic indication or medical condition is selected from the group comprising rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation, or arthropathy.

[0072] 27. The compound for use according to item 26, 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.

[0073] 28. A pharmaceutical composition comprising a compound according to any one of embodiments 15 to 23 and a pharma- ceutically acceptable carrier or excipient.

[0074] 29. The pharmaceutical composition according to item 28, further comprising one or more additional therapeutic agents selected from antiviral agents, anti-inflammatory agents, immunosuppressants and / or immunomodulators, steroids, nonsteroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

[0075] 30. The pharmaceutical composition according to item 29, further comprising the additional therapeutic agent molnupiravir.

[0076] In specific embodiments, R 1 and R 2If any one of R is deuterium, R is designated as deuterium. 1 and R 2 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, and R 3 , R 4 , R 5 , and R 6 If any one of the is deuterium, R is designated as deuterium. 3 , R 4 , R 5 and R6 has a level of deuterium incorporation of at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, and R 7 , R 8 , R 9 , and R 10 If any one of R is deuterium, 7 , R 8 , R 9 , and R 10 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, and R 11 If any residue in contains one or more deuterium, R 11 the level of deuterium incorporation at each position in ring A is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, and if any residue in ring A contains one or more deuterium, the level of deuterium incorporation at each position in ring A is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%, and 21 , R 22 , R 23 , R 24 , R25 , and R 26 If one of R is deuterium, 21 , R 22 , R 23 , R 24 , R 25 , and R 26 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%.

[0077] Quantitative analysis of a particular deuterated compound can be performed by a number of conventional methods, for example by mass spectrometry (peak area) or by detecting signals from internal standards or other non-deuterated species in the compound. 1 Compared with the H signal, the remaining residues of a particular deuteration site 1 This can be achieved by quantifying the H-NMR signal.

[0078] In specific embodiments, the level of deuterium incorporation in each substituent designated as deuterium is at least 52.5%. More specifically, the level of deuterium incorporation in each substituent designated as deuterium is at least 90%. Even more specifically, the level of deuterium incorporation in each substituent designated as deuterium is at least 95%. Most specifically, the level of deuterium incorporation in each substituent designated as deuterium is at least 98%.

[0079] In specific embodiments, as used herein, ring A refers to a 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl having one or more hydrogen atoms optionally replaced with deuterium, and said ring A is unsubstituted or is selected from the group consisting of halogen, CN, NO, oxo, OH, C, C-C-C-D ... 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl and O-Fluoro-C 1~4-substituted with 1-5 substituents independently selected from the group consisting of alkyl, CO2H and SO3H, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, Ring A represents unsubstituted 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl, with one or more hydrogen atoms optionally replaced with deuterium. More specifically, ring [ka] teeth, [ka] and having one or more hydrogen atoms optionally replaced with deuterium.

[0080] More specifically, ring A is [ka] and having one or more hydrogen atoms optionally replaced with deuterium. Even more specifically, ring A represents [ka] R 21 , R 22 , R 23 , R 24 , R 25 and R26 is independently selected from H and D. Most particularly, ring A is [ka] R 21 , R 22 , R 23 , R 24 , R 25 , and R 26 is H.

[0081] In specific embodiments, as used herein, ring A refers to a 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl having one or more hydrogen atoms optionally replaced with deuterium, and said ring A is unsubstituted or is selected from the group consisting of halogen, CN, NO, oxo, OH, C, C-C-C-D ... 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl and O-Fluoro-C 1~4 -substituted with 1-5 substituents independently selected from the group consisting of alkyl, CO2H and SO3H, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, Ring A represents unsubstituted 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl, with one or more hydrogen atoms optionally replaced with fluoro or deuterium. More specifically, ring [ka] teeth, [ka] Most specifically, ring A represents [ka] Represents.

[0082] In a specific embodiment of the present invention, R 1 is independently selected from H and D or a prodrug of an acid moiety. More specifically, R 1 is H.

[0083] In a specific embodiment of the present invention, R 2 H and C 1~6 -alkyl, where the alkyl is unsubstituted or 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; R 2 or its substituents have one or more hydrogen atoms optionally replaced with deuterium, more specifically R 2 is H, D, or methyl.

[0084] In a specific embodiment of the present invention, R 2 is independently selected from H and D. More specifically, R 2 is H.

[0085] In a specific embodiment of the present invention, R 1 is H and R 2 is H.

[0086] In a specific embodiment of the present invention, R 3 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, R 3 is selected from H, D, F, Cl, CH3, CHF2, CF3, CD3, OCH3, OCD3, OCHF2, and OCF3. More specifically, R 3 is selected from H, D, F, and Cl. Most particularly, R 3 is F.

[0087] In a specific embodiment of the present invention, R 4 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C1~4 -Alkyl, and O-Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, R 4 is selected from H, D, F, Cl, CH3, CHF2, CF3, CD3, OCH3, OCD3, OCHF2, and OCF3. More specifically, R 4 is selected from H, D, and F. Most particularly, R 4 is H.

[0088] In a specific embodiment of the present invention, R 5 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium, more specifically R 5 is selected from H, D, F, Cl, CH3, CHF2, CF3, CD3, OCH3, OCD3, OCHF2, and OCF3. More specifically, R 5 is selected from H, D, and F. Most particularly, R 5 is H.

[0089] In a specific embodiment of the present invention, R 6 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, R 6 is selected from H, D, F, Cl, CH3, CHF2, CF3, CD3, OCH3, OCD3, OCHF2, and OCF3. More specifically, R 5 is selected from H, D, and F. Most particularly, R 6 is H.

[0090] In a specific embodiment of the present invention, [ka] teeth, [ka] is selected from having one or more hydrogen atoms optionally replaced with deuterium. More specifically, [ka] Most particularly, [ka] teeth, [ka] It is.

[0091] In a specific embodiment of the invention, Ring B is selected from the group consisting of 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5-10 membered heteroaryl containing 1-6 heteroatoms independently selected from N, O, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or are selected from halogen, -CN, -NO2 oxo, C 1~4 -Alkyl, C 0~6 -Alkylene-OR 27 , C 0~6 -Alkylene-(3-6 membered cycloalkyl), C 0~6 -alkylene-(3-6 membered heterocycloalkyl), C 0~6 -Alkylene-S(=O) n (=NR 29 ) m R 27 , C 0~6 -Alkylene-NR 27 S(=O) x (=NR 29 ) yR 27 , C 0~6 -Alkylene-S(=O) x (=NR 29 ) y NR 27 R 28 , C 0~6 -Alkylene-NR 27 S(=O) x (=NR 29 ) y NR 27 R 28 , C 0~6 -Alkylene-CO2R 27 , C 0~6 -Alkylene-O-COR 27 , C 0~6 -Alkylene-CONR 27 R 28 , C 0~6 -Alkylene-NR 27 -COR 27 , C 0~6 -Alkylene-NR 27 -CONR 27 R 28 , C 0~6 -Alkylene-O-CONR 27 R 28 , C 0~6 -Alkylene-NR 27 -CO2R 27 , C 0~6 -Alkylene-NR 27 R 28 and wherein alkyl, alkylene, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl are unsubstituted or substituted with 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 6 substituents independently selected from alkyl, Optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring optionally containing 1-3 heteroatoms independently selected from O, S, or N, and this additional ring may be selected from halogen, -CN, oxo, -OH, C1~4 -Alkyl, halo-C 1~4 -Alkyl, -OC 1~4 -alkyl, and -O-halo-C 1~4 -alkyl; Residue on Ring B -NR 2 is in a 1,4-orientation relative to ring C, and ring B or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium.

[0092] In a more specific embodiment of the invention, -NR 2 B is selected from: [ka] It has one or more hydrogen atoms optionally replaced with deuterium.

[0093] In a more specific embodiment of the invention, -NR 2 B is selected from the following: [ka]

[0094] In an even more specific embodiment of the invention, -NR 2 B is selected from the following: [ka]

[0095] In a most specific embodiment of the invention, -NR 2 B is selected from the following: [ka]

[0096] In a specific embodiment of the present invention, R 7 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4-Alkyl, and O-Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, R 7 is selected from H and D. Most particularly, R 7 is H.

[0097] In a specific embodiment of the present invention, R 8 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, R 8 is selected from H and D. Most particularly, R 8 is H.

[0098] In a specific embodiment of the present invention, R 9 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, R 9 is selected from H and D. Most particularly, R 9 is H.

[0099] In a specific embodiment of the present invention, R 10 H, D, halogen, CN, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, and O-Fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, R 10 is selected from H and D. Most particularly, R 10 is H.

[0100] In a specific embodiment of the present invention, [ka] teeth [ka] and having one or more hydrogen atoms optionally replaced with deuterium. More specifically, [ka] teeth, [ka] Most particularly, [ka] teeth, [ka] It is.

[0101] In a specific embodiment of the invention, X is H, D, OH, OD, S(=O) y R 11 , and OR 11 More specifically, X is selected from OH and OR 11 Most particularly, X is selected from OR 11 It is.

[0102] In a specific embodiment of the present invention, R 11 is C 1~4 -Alkyl, C 3~4 -cycloalkyl and fluoro-C 1~4 -alkyl, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium. More specifically, R 11 is selected from CH3, CD3, CHF2, CDF2, and CF3. Most particularly, R 11 is CD3.

[0103] In a specific embodiment of the present invention, [ka] Most particularly, [ka] teeth, [ka] It is.

[0104] In a specific embodiment of the invention, ring C is selected from the group consisting of 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5-10 membered heteroaryl containing 1-6 heteroatoms independently selected from N, O, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or are selected from halogen, -CN, -NO2 oxo, C 1~4 -Alkyl, C 0~6 -Alkylene-OR 31 , C 0~6 -Alkylene-(3-6 membered cycloalkyl), C 0~6 -alkylene-(3-6 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 (=NR33 ) 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 and wherein alkyl, alkylene, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocycloalkyl are unsubstituted or substituted with 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 6 substituents independently selected from alkyl, Optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring optionally containing 1-3 heteroatoms independently selected from O, S, or N, and this additional ring may be selected from halogen, -CN, oxo, -OH, C 1~4 -Alkyl, halo-C 1~4 -Alkyl, -OC 1~4 -alkyl, and -O-halo-C 1~4 -alkyl; Ring C or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium; In a more specific embodiment of the invention, ring C is phenyl, pyridyl, or thiazolyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D and F, and X is D, F, Cl, -CN, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, O-Fluoro-C 1~4 -alkyl, having one or more hydrogen atoms optionally replaced with deuterium.

[0105] In more specific embodiments of the invention, Ring C is selected from: [ka]

[0106] In more specific embodiments of the invention, Ring C is selected from: [ka]

[0107] In more specific embodiments of the invention, Ring C is selected from: [ka] More specifically, ring C is [ka] It is.

[0108] In a specific embodiment of the invention, 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-(3-6 membered cycloalkyl), C 0~6-alkylene-(3-6 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 , 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 wherein heterocycloalkyl contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; and alkyl, alkylene, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 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 6 substituents independently selected from alkyl, X or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium.

[0109] In more specific embodiments of the invention, X is D, F, Cl, -CN, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, O-Fluoro-C 1~4 -alkyl, having one or more hydrogen atoms optionally replaced with deuterium.

[0110] In a more specific embodiment of the invention, X is D, F, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, O-Fluoro-C 1~4 -alkyl, having one or more hydrogen atoms optionally replaced with deuterium.

[0111] In more specific embodiments of the invention, X is selected from D, F, CD3, CD2CD3, OH, OCD3, OCD2CD3, O(CD2)3CD3, OCF3, OCDF2 and OCHF2. Most specifically, X is OCD3.

[0112] In a specific embodiment of the invention, ring C is phenyl, pyridyl, or thiazolyl, which is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D and F, and X is D, F, Cl, -CN, OH, C 1~4 -Alkyl, OC 1~4 -Alkyl, Fluoro-C 1~4 -Alkyl, O-Fluoro-C 1~4 -alkyl, having one or more hydrogen atoms optionally replaced with deuterium.

[0113] In a specific embodiment of the present invention, [ka] is selected from the following: [ka] Most specifically, [ka] is selected from the following: [ka] Most specifically, [ka] teeth, [ka] It is.

[0114] In a specific embodiment of the present invention, [ka] is selected from the following: [ka]

[0115] In a more specific embodiment of the present invention, [ka] is selected from the following: [ka] More specifically, [ka] is selected from the following: [ka] More specifically, [ka] teeth, [ka] It is.

[0116] In a specific embodiment of the present invention, R 27 , R 28 , R 31 , R 32 , R 41 , R 42 , H, C 1~6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, where alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is 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 27 and / or R 28 and / or R 31 and / or R 32 and / or R 41 and / or R 42 or each having one or more hydrogen atoms optionally replaced with deuterium; or R 27 and R 28 , R 31 and R 32 , R 41 and R 42each, when taken together with the nitrogen to which they are attached, completes a 3- to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, or N, which ring is unsubstituted or is 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; R 27 and / or R 28 and / or R 31 and / or R 32 and / or R 41 and / or R 42 or each of its substituents has one or more hydrogen atoms optionally replaced with deuterium;

[0117] In a specific embodiment of the present invention, R 27 , R 28 , R 31 , R 32 , R 41 , R 42 is independently selected from H, CH3, and CD3.

[0118] In a specific embodiment of the present invention, R 29 , R 33 , R 43 H, -CN, -NO2, C 1~6 -Alkyl, -CO-OC 1~6 -alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, where alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is 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; R 29 and / or R 33 and / or R 43 Or each of the substituents has one or more hydrogen atoms optionally replaced with deuterium. In a specific embodiment of the present invention, R 29 , R 33 , R 43 is independently selected from H, CH3, and CD3.

[0119] In specific embodiments of the invention, n, m, x, and y are independently selected from 0 to 2, with the proviso that the sum of the integers m and n for residues bound to the same sulfur atom is independently selected from 0 to 2, with the proviso that the sum of the integers x and y for residues bound to the same sulfur atom is independently selected from 1 or 2.

[0120] In a specific embodiment of the present invention, ring A, ring B, ring C, R 2 , R 27 , R 28 , R 29 , R 31 , R 32 , R 33 , R 41 , R 42 , R 43 and / or at least one hydrogen in X is replaced by deuterium.

[0121] In specific embodiments of the invention, at least one hydrogen in rings C and X is replaced with deuterium. More specifically, at least three hydrogens in rings C and X are replaced with deuterium. Most specifically, at least four hydrogens in rings C and X are replaced with deuterium.

[0122] In a specific embodiment of the present invention, R 1 is H and R 2 is H, [ka] teeth, [ka] is selected from -NR 2 B is, [ka] is selected from [ka] teeth, [ka] is selected from.

[0123] In a more specific embodiment of the present invention, R 1 is H, R 2 is H, [ka] teeth, [ka] is selected from -NR 2 B is, [ka] is selected from [ka] teeth, [ka] is selected from.

[0124] In a most specific embodiment of the invention, R 1 is H and R 2 is H, [ka] teeth, [ka] is selected from -NR 2 B is, [ka] is selected from [ka] teeth, [ka] is selected from.

[0125] Particular compounds of the present invention are those of the following Examples of the present invention, more particularly those of Examples 1, 2 and 6 below.

[0126] Specific compounds of the invention are selected from the following: [ka] [ka] Or a solvate or a pharma- ceutically acceptable salt thereof.

[0127] Specific compounds of the invention are selected from the following: [ka] Or a solvate or a pharma- ceutically acceptable salt thereof.

[0128] More specific compounds of the invention are selected from the following: [ka] Or a solvate or a pharma- ceutically acceptable salt thereof.

[0129] The most particular compounds of the present invention are selected from: [ka] Or a solvate or a pharma- ceutically acceptable salt thereof.

[0130] According to the knowledge of the expert, the compounds of the present invention as well as their salts, for example when isolated in crystalline form, may contain various amounts of solvents.Therefore, 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) are included within the scope of the present invention.

[0131] The present invention further relates to a method for the prevention and / or treatment of the diseases, disorders, therapeutic indications or medical conditions described herein, in particular diseases or medical conditions in which inhibition of DHODH is beneficial, more particularly a disease or medical condition selected from the group comprising rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal invasion in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as described herein. Similarly, the present invention further relates to the above methods, encompassing further embodiments as described herein, in particular the compounds for use in medical uses and medical procedures as described herein.

[0132] The present invention further relates to a method for the prevention and / or treatment of a disease, disorder, therapeutic indication, or medical condition as described herein, particularly a disease or medical condition in which inhibition of DHODH is beneficial, more particularly a disease or medical 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, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis, and psoriasis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as described herein.

[0133] The present invention further relates to pharmaceutical compositions, kits, and kits of parts comprising the compounds according to the invention.

[0134] The present invention further relates to the use of the compounds according to the invention for the preparation of a pharmaceutical composition for use in the treatment and / or prevention of the diseases, disorders, illnesses and / or conditions mentioned herein.

[0135] The present invention further relates to the methods and medical uses described herein, including the pharmaceutical compositions described herein.

[0136] The pharmaceutical compositions described herein comprise one or more compounds according to the invention and a pharma- ceutically acceptable carrier or excipient.

[0137] The pharmaceutical compositions 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 antiviral agents, anti-inflammatory agents, immunosuppressants and / or immunomodulators, steroids, nonsteroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

[0138] The invention further relates to an article of manufacture comprising packaging material and a pharmaceutical agent contained within the packaging material, the pharmaceutical agent being therapeutically effective for a medical condition as described herein, the packaging material comprising a label or package insert indicating that the pharmaceutical agent is useful for preventing or treating the medical condition, the pharmaceutical agent comprising one or more compounds of formula (I) according to the present invention, the packaging material, label, and package insert being otherwise the same or similar to what would generally be considered standard packaging material, label, and package insert for a pharmaceutical agent having the relevant utility.

[0139] 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 on their own or in combination with particularly suitable pharmaceutical auxiliaries and / or excipients, for example in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, with an active compound content advantageously between 0.1 and 95%, and by suitable selection of auxiliaries and / or excipients, a pharmaceutical dosage form (e.g. delayed release form or enteric form) exactly suitable for the active compound and / or the desired onset of action can be achieved.

[0140] Those skilled in the art are familiar with the auxiliaries, vehicles, excipients, diluents, carriers, or adjuvants that are suitable for the desired pharmaceutical formulation, preparation, or composition due to their expertise. In addition to solvents, gel-forming agents, ointment bases, and other active compound excipients, for example, antioxidants, dispersing agents, emulsifying agents, preservatives, solubilizers, coloring agents, complexing agents, or penetration enhancers may be used.

[0141] Depending on the particular disease to be treated or prevented, additional therapeutically active agents that are normally administered to treat or prevent that disease may optionally be co-administered with the compounds according to the invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease are known as appropriate for the disease being treated.

[0142] In a further aspect of the invention, the compounds according to the invention, or salts or solvates of the compounds of formula (I), may be combined with standard therapeutic agents commonly used in the treatment of the medical conditions described herein.

[0143] Those skilled in the art will recognize, based on their expert knowledge, the total daily dose and dosage form of the additional therapeutic agent to be co-administered. The total daily dose can vary within a wide range. In the implementation of the present invention, and depending on the details, characteristics or purpose of their use as described above, the compounds of the present invention can be administered separately, sequentially, simultaneously or staggered (for example, as a combined unit dosage form, as separate unit dosage forms or adjacent separate unit dosage forms, as a fixed or non-fixed combination, as a kit of parts, or as a mixture) in combination therapy with one or more standard therapeutic agents, in particular chemotherapeutic agents or target-specific anticancer agents known in the art (for example, as described above).

[0144] 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 medical condition described herein, and optionally a pharmacologically acceptable carrier, diluent, and / or excipient for use in therapy in any order, e.g., sequentially, separately, simultaneously or staggered, for treating, preventing or ameliorating a medical condition 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 medical condition described herein, for use in therapy, e.g., in treating a disease described herein, separately, sequentially, simultaneously or staggered, for use in therapy.

[0145] 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 dose or in 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 in a mixture for simultaneous administration, such as 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.

[0146] A "kit of parts" is defined as a combination in which the first active ingredient and the second active ingredient are present in two or more 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 at staggered times.

[0147] The first and second active ingredients of the combination or kit of parts according to the invention may be provided as separate formulations (i.e., independently of each other), which are then combined for simultaneous, sequential, separate or staggered use in a combination therapy, or packaged and provided together as separate components of a combination pack for simultaneous, sequential, separate or 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 may be similar, i.e., both ingredients may be formulated in separate tablets or capsules, or may be 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, for example, for intravenous administration. The amounts of the first and second active ingredients of the combination, composition or kit according to the invention, together, may comprise a therapeutically effective amount for the treatment, prevention or amelioration of a medical condition as described herein. A further aspect of the present invention is a method of coordinated therapeutic treatment of a medical condition described herein, comprising administering to a patient in need of such treatment, separately, sequentially, simultaneously, fixedly or non-fixedly, a therapeutically effective and tolerable amount of one or more of the compounds according to the present invention and a therapeutically effective and tolerable amount of one or more therapeutic agents known in the art for the medical conditions described herein.

[0148] References and claims to the use of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating a disease or medical condition in its general and specific forms similarly refer to a corresponding method of treating said disease or medical condition, which method comprises administering to a subject in need thereof a therapeutically effective and acceptable amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof for the treatment of said disease or medical condition, a composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof for use in the treatment of said disease or medical condition, and vice versa.

[0149] For the preparation of pharmaceutical compositions, the compounds of the present invention (= active compounds) are in particular mixed with suitable pharmaceutical auxiliaries and further processed to obtain 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.

[0150] The administration of the active compounds is carried out on the usual scale. Thus, topical application forms (ointments, etc.) contain the active compounds in concentrations of, for example, 0.1 to 99%. The usual dosage for systemic therapy (po) is usually 0.3 to 30 mg / kg / day, and for (iv) is usually 0.3 to 30 mg / kg / hour. The choice of the optimal dosing regime and duration, in particular the optimal dose and mode of administration of the active compounds required in each case, can be determined by a person skilled in the art on the basis of his / her expert knowledge.

[0151] The class of compounds of the present invention is useful for the development of suitable medicines 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 protozoal invasion in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation, or arthropathy. More particularly, the disease is 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.

[0152] The class of compounds of the present invention is useful for the treatment of viral diseases, particularly acute viral infections selected from coronavirus infections, COVID-19, SARS, flu / influenza (and avian flu), HIV / Aids, Varicella, cytomegalovirus, dengue, Rubella, hand, foot and mouth disease, Hantavirus infections, all types of hepatitis, Lassa fever, Marburg virus infections, measles, meningitis, MERS-CoV, mumps, norovirus infections, herpes simplex virus infections, smallpox, rotavirus infections, Ebola virus, poliovirus infections, rhinovirus infections, parainfluenza virus infections, RSV infections, HCMV infections, and Bannavirus infections. Most preferred are COVID-19, flu / influenza, and rhinovirus infections, with COVID-19 being most preferred. It is understood that mutated forms of viruses (e.g., SARS-CoV-2) are also encompassed.

[0153] Combination or alternating therapy The compounds described herein, or pharma- ceutically acceptable salts thereof, can be administered in addition to the patient's current standard of care, or in combination or alternation with any other compound or therapy that the health care provider deems beneficial to the patient. The combination and / or alternation therapy can be curative, adjunctive, or palliative.

[0154] Particularly preferred is combination or alternation therapy for the treatment of antiviral infections, especially Covid-19. High levels of the cytokine interleukin-6 (IL-6) have been observed to be a predictor of 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 IL-6-targeting monoclonal antibodies, pharmaceutical inhibitors, or protein degraders, such as bispecific compounds that bind IL-6 and also bind to proteins that mediate its degradation. Examples of antibodies include tocilizumab, sarilumab, siltuximab, olokizumab, and clazakizumab. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt is administered in combination or alternation with tocilizumab or sarilumab. Further 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). Further antibodies and biologics include abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab, basiliximab, and daclizumab.

[0155] IL-1 blocks the production of IL-6 and other pro-inflammatory cytokines. COVID patients may also be treated with anti-IL-1 therapy, such as intravenous administration of anakinra, to reduce the hyperinflammatory response. Anti-IL-1 therapy may generally be, for example, a targeted monoclonal antibody, a pharmaceutical inhibitor, or a protein degrader, such as a bispecific compound that binds to IL-1 and also binds to a protein that mediates its degradation.

[0156] Patients with COVID often develop viral pneumonia, which may lead to bacterial pneumonia. Patients with severe COVID-19 may also suffer from sepsis or "septic shock". Treatment of bacterial pneumonia or sepsis secondary to COVID includes administration of macrolide antibiotics, including, for example, azithromycin, clarithromycin, erythromycin, or roxithromycin. Additional antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanic acid, or levofloxacin. Thus, in one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination or alternation with an antibiotic, for example, azithromycin. Some of these antibiotics, such as azithromycin, have independent anti-inflammatory properties. Such drugs may also be used as anti-inflammatory agents for COVID patients, and have therapeutic effects against secondary bacterial infections.

[0157] A unique challenge in treating patients infected with COVID-19 is that they require relatively long periods of sedation if they require mechanical ventilation, which may last up to 5, 10, or even 14 days or longer. Pain medications can be added sequentially for ongoing pain during this treatment, and sedatives can be added sequentially for ongoing anxiety. Non-limiting examples of analgesics include acetaminophen, ketamine, and PRN opioids (hydromorphone, fentanyl, and morphine). Non-limiting examples of sedatives include melatonin, atypical antipsychotics with predominantly sedative properties (olanzapine, quetiapine), propofol, or dexmedetomidine, haloperidol, and phenobarbital. In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt, solvate, solvate of a salt, hydrate or polymorph thereof is administered in combination or alternation with an analgesic, such as acetaminophen, ketamine, hydromorphone, fentanyl, or morphine. In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt, solvate, solvate of a salt, hydrate or polymorph thereof is administered in combination or alternation with a sedative, such as melatonin, olanzapine, quetiapine, propofol, dexmedetomidine, haloperidol, or phenobarbital.

[0158] In one embodiment, the compounds of the invention are used in effective amounts 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).

[0159] In one embodiment, the compounds of the present invention are used in effective amounts in combination with an RNA replication regulator such as N4-hydroxycytidine, or a prodrug thereof may also be administered. In a particular embodiment, the RNA replication regulator is an N4-hydroxycytidine prodrug as described in WO 2019 / 113462. In a further particular embodiment, the RNA replication regulator is molnupiravir.

[0160] In one embodiment, a compound of the invention is used in an effective amount in combination with halofuginol, or an enantiomer, tautomer, solvate, or pharma- ceutically acceptable salt thereof.

[0161] In one embodiment, a compound of the invention is used in an effective amount in combination with dipyridamole, or a solvate or pharma- ceutically acceptable salt thereof.

[0162] In one embodiment, the compounds of the invention are used in an effective amount in combination with gemcitabine, or a solvate or pharma- ceutically acceptable salt thereof.

[0163] In one embodiment, a compound of the invention is used in combination with AT-527 (RO7496998), or a solvate or pharma- ceutically acceptable salt thereof, in an effective amount.

[0164] Additional drugs that may be used to treat COVID patients include, but are not limited to, aspirin, colchicine, dimethyl fumarate, acalabrutinib, favipiravir, fingolimod, methyl-prednisolone, bevacizumab, tocilizumab, umifenovir, losartan, and monoclonal antibody combinations of 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 thereto.

[0165] 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.

[0166] SARS-CoV-2 is constantly mutating, many of which increase virulence and transmissibility. Drug-resistant mutants of the virus can emerge after long-term treatment with antiviral agents. Drug resistance can arise from mutations in genes that code for enzymes used in viral replication. The efficacy of a drug against an RNA virus infection in certain cases can be extended, enhanced, or restored by administering the compound in combination or alternation with another antiviral compound, possibly two or even three other antiviral compounds that induce different mutations or act via a different pathway than that of the primary drug. A mutant of a known virus can refer to a virus that has one or more nucleotide mutations in the viral genome, 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, compared to a known virus. A mutation can refer to a deletion, insertion, or substitution of a nucleotide. In some cases, the variant may have up to 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1% of the viral genome that differs from the genome of a known virus.

[0167] Alternatively, the pharmacokinetics, biodistribution, half-life, or other parameters of the drugs may be altered by such combination therapy (which may include alternation therapy, if considered coordinated).

[0168] Examples of other therapeutic agents that may be combined with the compounds of formula (I) or a pharma- ceutically acceptable salt, solvate, solvate of a salt, hydrate or polymorph thereof, either 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 inhibitors; (6) helicase inhibitors; (7) primase-helicase inhibitors; (8) antisense oligodeoxynucleotide (S-ODN); (9) Aptamers; (10) nuclease-resistant ribozymes; (11) iRNA, including microRNA and siRNA; (12) Antibodies, partial antibodies, or domain antibodies against viruses; (13) A viral antigen or partial antigen that induces a host antibody response; (14) NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3); (15) glutamyl-prolyl-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).

[0169] It is recognized that, depending on the origin of chemicals used in synthesis, some variation in natural isotope abundance occurs in synthesized compounds.Therefore, preparations of Bidofludimus (and other compounds according to formula (I) that are specifically substituted with deuterium) will inherently contain small amounts of deuterium isotope substitution.Despite this variation, the concentration of naturally abundant stable hydrogen and carbon isotopes is small and insignificant compared to the degree of stable isotope substitution of compounds of the present invention.See, for example, Comp.Biochem.Physiol.1998;119A:725.

[0170] The term "isotopic enrichment factor" at a particular position normally occupied by hydrogen refers to the ratio between the abundance of deuterium at that position and the natural abundance of deuterium at that position. As an 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 have deuterium at a particular position (i.e., 52.5% deuterium incorporation at a given position). The abundance of deuterium in Earth's oceans is about 1 atom in 6500 hydrogen atoms (about 154 parts per million (ppm)). Thus, deuterium accounts for about 0.015 percent (0.030 percent by weight) of all naturally occurring hydrogen atoms in Earth's oceans, with the abundance varying slightly depending on the type of natural water.

[0171] When a particular position in a compound of the invention (e.g., a compound represented by 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 at least 835 (12.5% ​​deuterium incorporation), at least 1670 (25% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4500 (51.5% deuterium incorporation), at least 500 (60% deuterium incorporation), at least 6000 (70% deuterium incorporation), at least 7000 (80% deuterium incorporation), at least 8000 (90% deuterium incorporation), at least 9000 (100% deuterium incorporation), at least 10000 (120% deuterium incorporation), at least 10000 (140% deuterium incorporation), at least 10000 (160% deuterium incorporation), at least 10000 (18 ... It should be understood that deuterium can be enriched with an isotopic enrichment factor of 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).

[0172] When a particular position in a compound of the invention (e.g., a compound represented by 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 at its natural abundance isotopic composition.

[0173] When a particular position in a compound of the invention (e.g., a compound represented by 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 preferably at least 3340 times the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium), 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 the natural abundance of deuterium (68.5% deuterium incorporation), at least 6000 times the natural abundance of deuterium (66.5% deuterium incorporation), at least 7000 times the natural abundance of deuterium (72.5% deuterium incorporation), at least 8000 times the natural abundance of deuterium (82.5% deuterium incorporation), at least 9000 times the natural abundance of deuterium (90.5% deuterium incorporation), at least 10000 times the natural abundance of deuterium (100.5% deuterium incorporation), at least 11000 times the natural abundance of deuterium (110.5% deuterium incorporation), at least 12000 times the natural abundance of deuterium (120.5% deuterium incorporation), at least 13000 times the natural abundance of deuterium (130.5% deuterium incorporation), at least 14000 times the natural abundance of deuterium (140.5% deuterium incorporation), at least 15000 times the natural abundance of deuterium (150.5% deuterium incorporation), at least 16000 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).

[0174] The percentage of deuterium incorporation can be determined by quantitative analysis using a number of conventional methods such as mass spectrometry (peak area) or by the signal from an internal standard or other non-deuterated species in the compound. 1 The remaining residues of specific deuteration sites compared to H signals 1 It can be obtained by quantifying the H-NMR signal.

[0175] When a chemical name or structure is not described as to 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 its natural abundance. [ka] Unless further specified as to isotopic enrichment, it is intended that all hydrogen atoms are present at natural abundance.

[0176] When ring A is a partially saturated ring, the double bond in ring A is located at the position shown. [ka] When ring A is a 5-membered heteroaryl ring, the double bond is in a delocalized π-system and can exist in a mesomeric form. An example is the mesomeric form of the thiophene shown below. [ka]

[0177] Furthermore, the compounds of the present invention are partially subject to 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: [ka]

[0178] The term "1,4-orientation" (as referred to in relation to Ring B) refers to a specific relative position of two substituents on the same ring, meaning that the substituents on the ring have at least one option that is between the two substituents in the ring that have four atoms attached to the ring system. [ka]

[0179] The term "compound," when referring to any compound of the present disclosure, including a compound represented by Formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof, refers to a collection of molecules having identical chemical structure, except that isotopic variation may exist among the constituent hydrogen atoms of the molecule. The relative amount of isotopic variation in the compounds of the invention will vary depending on a number of factors, including the isotopic purity of the deuterated reagent used to make the compound, and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound.

[0180] "D" and "d" both refer to deuterium. "H" means hydrogen.

[0181] "Deuterium substituted" refers to the replacement of one or more hydrogen atoms with the corresponding number of deuterium atoms.

[0182] Any formula or structure given herein is also intended to represent deuterated compounds containing isotopically enriched atoms. Examples of additional isotopes that can be incorporated into the compounds of the present disclosure include additional isotopes of hydrogen (i.e., tritium or 3 H), and 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 125 The 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 metabolic studies, reaction kinetic studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT) involving drug or substrate tissue distribution assays or radioactive treatment of patients).

[0183] Halogen is selected from fluorine, chlorine, bromine and iodine, more preferably fluorine or chlorine, most preferably fluorine.

[0184] In the context of the present invention, "C 1~4 "-Alkyl" means a preferably saturated hydrocarbon chain having 1 to 4 carbon atoms, which may be linear or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. 1~3-alkyl, such as methyl, ethyl, propyl, and isopropyl, with methyl being most preferred. The term "alkyl" by itself or as part of another substituent, such as halo-C 1~4 -Alkyl, unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as "unsaturated alkyl". Unsaturated alkyl groups are those having one or more double or triple bonds. Preferred unsaturated alkyl substituents are vinyl, 2-propenyl, or prop-2-yn-1-yl.

[0185] In the context of the present invention, the term "C alkyl group having one or more hydrogen atoms optionally replaced with deuterium" is used. 1~4 -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 (In the formula, n is an integer from 0 to 2. CH3CH2(CHD) m -, CH3CH2(CD2) m (wherein m is an integer from 1 to 2), as well as -CD3)2, -CH(CD3)2 and -C(CD3)3. Preferred deuterium-containing C 1~2 -Alkyl is -CD3 and -CD3CD2, and most preferred is -CD3.

[0186] "C 0~6 "-alkylene" means that the respective 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 meant to represent a bond, while C1-alkylene means a methylene linker, C2-alkylene means an ethylene linker or a methyl substituted methylene linker, etc. 0~6 -Alkylene preferably represents a bond, methylene, an ethylene group or a propylene group. The term "alkylene", unless otherwise specified, is also meant to include unsaturated divalent chains, where appropriate (i.e., "C 2~6 A representative example of an unsaturated C4-alkylene is -CH2-CH=CH-CH2-.

[0187] "Fluoro-C 1~4 -alkyl" or "O-fluoro-C 1~4The term "-alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced by one or more fluoro atoms, respectively. Preferred are CHF2, CF3, CH2CF3, and CF2CF3. A more preferred example is the formation of the -CF3 group.

[0188] The same thing happened with "Halo-C 1~4 -alkyl" or "O-halo-C 1~4 The term "-alkyl" means that one or more hydrogen atoms in the alkyl chain are replaced by one or more halogen atoms independently selected from fluoro, chloro, bromo, and iodo.

[0189] 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 "fluoro-C 1~4 -If the alkyl group contains one or more hydrogen atoms, one or more hydrogen atoms are optionally replaced by fluorine, and "C having one or more hydrogen atoms in the alkyl group optionally replaced by deuterium" is defined as 1~4 The term "fluoro-C-alkyl" means the same as described above. 1~4 It is understood that the -alkyl can also be fully fluorinated. Deuterium-containing fluoro-C, such as CDF, CDCF, and CDCFD. 1~2 -alkyl is preferred. Most preferred is CDF2.

[0190] A "3- to 10-membered cycloalkyl" group means a saturated or partially unsaturated monocyclic, bicyclic, spiro or polycyclic ring system containing 3 to 10 carbon atoms, where each of the atoms 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]octyl. 2,5 .0 3,8 .04,7 Thus, a 3- to 6-membered cycloalkyl group refers to 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 refers to a saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic ring system containing 5 to 8 carbon atoms.

[0191] 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 preferably, it is cyclopropyl or cyclobutyl.

[0192] "C having one or more hydrogen atoms in the alkyl optionally replaced with deuterium 3~4 The term "cycloalkyl" includes, but is not limited to, the following moieties: [ka]

[0193] The cycloalkyl or heterocyclyl groups 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: [ka]

[0194] A "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 monocyclic, bicyclic, spiro or polycyclic carbocyclic ring in which 1, 2, 3, or 4 carbon atoms are replaced with 1, 2, 3, or 4 heteroatoms, respectively, and the heteroatoms are 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, a nitrogen (for example in morpholine or piperidine), or a sulfur atom. An example of an S-linked heterocycloalkyl is cyclic sulfonimidamide. [ka]

[0195] 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.

[0196] The "6- or 10-membered aryl" is phenyl or naphthyl.

[0197] "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 within this application) containing up to 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. It further refers to bicyclic ring systems in which the heteroatoms may be present in one or both rings, including the 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 a heteroaryl system can also be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide.

[0198] "5-membered heteroaryl" means 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 can also be oxidized to S=O or SO2.

[0199] A 5-membered heterocyclopentenyl group refers to a partially unsaturated 5-membered monocyclic ring in which one or two carbon atoms are replaced with one or two heteroatoms, each 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.

[0200] Depending on their structure, the compounds of the present invention may exist in tautomeric or stereoisomeric forms (enantiomers, diastereomers).The present invention therefore also encompasses tautomers, enantiomers or diastereomers and their respective mixtures.Stereoisomerically homogeneous components can be isolated from such mixtures of enantiomers and / or diastereomers in known manner.

[0201] The term "diastereomers" refers to stereoisomers that are not mirror images of each other and are not superimposable with each other. The term "enantiomers" refers to each individual optically active form of the compounds of the invention having an optical purity or enantiomeric excess (as determined 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%. The compounds of the invention may be in the form of prodrug compounds. "Prodrugs" refer to derivatives that are converted to the compounds according to the invention under physiological conditions in vivo by reaction with enzymes, gastric acid, etc., e.g., by oxidation, reduction, hydrolysis, etc., each of which is enzymatic. Other examples of prodrugs are compounds in which the carboxylic acid in the compounds of the invention is converted to, e.g., alkyl-, aryl-, arylalkylene-, amino-, choline-, acyloxyalkyl-, 1-((alkoxycarbonyl)oxy)-2-alkyl, or linolenoyl-esters. Exemplary structures of prodrugs of carboxylic acids are as follows: [ka]

[0202] The term "pharmaceutical acceptable salts" refers to salts prepared from pharmaceutical non-toxic bases, including inorganic and 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 them with organic or inorganic bases 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 directly suitable for use in pharmaceuticals due to low physiological compatibility, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutical acceptable salts.

[0203] Furthermore, 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" may further optionally include a "solvate".

[0204] The term "polymorph" as used herein 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. The term "crystalline" as used herein refers to a solid form consisting of a regular arrangement of structural units. Different crystalline forms of the same compound, or its salt, hydrate, or solvate, result from different packing of molecules in the solid state, resulting in different crystal symmetries and / or unit cell parameters. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.

[0205] The term "effective amount" is meant to include an amount of a compound that, when administered, is sufficient 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 being sought by a researcher, veterinarian, physician, or clinician.

[0206] As used herein, the term "subject" refers to any member of the animal kingdom, including humans. In some embodiments, "subject" refers to humans 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 a worm. In some embodiments, the subject may be a transgenic animal, a genetically engineered animal, or a clone.

[0207] The deuterated compounds detailed herein have unexpectedly been found to exhibit greater microsomal stability and improved pharmacokinetic behavior in rats and mice. The Examples section below provides further details.

[0208] Experimental section The compounds of the invention can be prepared by using appropriate deuterated building blocks or via hydrogen-deuterium exchange, as outlined in WO 2003 / 006425 and WO 2004 / 056797 (and references cited therein) (e.g., Synthesis 2019; J. 51:1319 or Angew. Chem. Intl. Ed. 2018; 57:3022).

[0209] Abbreviation DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EA Ethyl acetate Flash chromatography on FCC silica gel PE Petroleum Ether rt Room temperature (20±4℃) Experimental Section Preparation example P1: Step 1: 5-Bromo-1-fluoro-3-(methoxy-d3)-2-nitrobenzene (P1a) [ka] 5-Bromo-1,3-difluoro-2-nitrobenzene can be treated with CD3OD in KOH to give the target compound P1a, similar to that described in WO 2018 / 059314.

[0210] Step 2: 4-Bromo-2-fluoro-6-(methoxy-d3)aniline (P1) [ka] Compound P1a can be treated with hydrazine hydrate and Raney nickel as a catalyst to give target compound P1, similar to that described in WO 2018 / 059314.

[0211] Preparation example P2:1-(3λ 6 -Propoxy-d9)-3-bromobenzene (P2). [ka] Compound P2 is 1-iodo-3λ 6 -propane-1,1,2,2,3,3,3,3,3-d9 can be prepared by reacting with 3-bromophenol and potassium carbonate in DMF.

[0212] Preparation Example P3: 2,6-Difluoro-4-(morpholino-d8)aniline (P3). [ka] As described in WO 2008 / 018426, the target compound P3 can be prepared by reacting tert-butyl (4-bromo-2,6-difluorophenyl)carbamate with morpholine-2,2,3,3,5,5,6,6-d8 using palladium diacetate, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, and potassium tert-butoxide in toluene at 60°C for 14 hours, after deprotection of the Boc group with 4N HCl in dioxane and aqueous workup under basic conditions.

[0213] Preparation example P4: Step 1: 1-(1,3-dioxoisoindolin-2-yl) 4-methylbicyclo[2.2.2]octane-1,4-dicarboxylate (P4a). [ka] 4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid was coupled with phthalimide using dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine as catalysts in CH2Cl2 at room temperature.

[0214] Step 2: Methyl 4-(3-methoxyphenyl)bicyclo[2.2.2]octane-1-carboxylate (P4b). [ka] Compound P4a was coupled with bis(3-methoxyphenyl)zinc using 1,2-bis(diphenylphosphino)benzene and iron(III) acetylacetonate (Fe(acac)3) as catalyst as outlined in J. Am. Chem. Soc. 2016;138:11132 to give the target compound P4b.

[0215] Step 3: Methyl 4-(3-hydroxyphenyl)bicyclo[2.2.2]octane-1-carboxylate (P4c). [ka] Compound P4b was treated with BBr3 in CH2Cl2 at -78 °C to room temperature to give the target compound P4c.

[0216] Step 4: Methyl 4-(3-(methoxy-d3)phenyl)bicyclo[2.2.2]octane-1-carboxylate (P4d). [ka] Compound P4c was alkylated with CD3I as described in Example 2, Step 2 to give the target compound P4d.

[0217] Step 5: 4-(3-(methoxy-d3)phenyl)bicyclo[2.2.2]octane-1-carboxylic acid (P4e). [ka] Compound P4d was saponified to give the target compound P4e.

[0218] Step 6: tert-Butyl (4-(3-(methoxy-d3)phenyl)bicyclo[2.2.2]octan-1-yl)carbamate (P4f). [ka] Compound P4e was treated with diphenylphosphoryl azide, Boc2O and NEt3 in tert-butanol under reflux for 16 hours, similar to that outlined in WO2016 / 045587, to give the target compound P4f.

[0219] Step 7: 4-(3-(methoxy-d3)phenyl)bicyclo[2.2.2]octan-1-amine (P4). [ka] Compound P4e was treated with 4N HCl in dioxane to give P4 after aqueous workup under basic conditions.

[0220] Example 1: Step 1: 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1a). [ka] To a solution of 4-bromo-2-fluoroaniline (4.00 g, 21.1 mmol) in 1,4-dioxane (30 mL) was added bis(pinacolato)diboron (5.38 g, 21.2 mmol), KOAc (6.23 g, 63.5 mmol), and Pd(dppf)Cl2 (776 mg, 1.1 mmol). The mixture was then heated at 90° C. for 1 h, cooled to room temperature, filtered, concentrated, and purified by FCC (PE:EA=8:1) to give compound 1a as a white solid.

[0221] Step 2: 3-Fluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-amine (1b). [ka] To a solution of compound 1a (800 mg, 3.37 mmol) in 1,4-dioxane (10 mL) and HO (1 mL) was added 1-bromo-3-(methoxy-d3)benzene (638 mg, 3.36 mmol), Na2CO3 (1.07 g, 10.1 mmol), and Pd(dppf)Cl2 (124 mg, 0.17 mmol), and the mixture was then heated at 90 °C for 2 h, cooled to room temperature, filtered, concentrated, and purified by FCC (PE:EA = 10:1) to give compound 1b as an oil.

[0222] Step 3: 2-((3-fluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (1) [ka] A solution of compound 1b (120 mg, 545 μmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (74 mg, 540 μmol) in DCM (2.5 mL) was heated at 40° C. for 4 h. The mixture was filtered and the filter cake was washed with MeCN (2×2 mL). The solid was dried in vacuum to give compound 1 as a pale yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ13.04(br s,1H),10.58(s,1H),8.07(t,J=8.4Hz,1H),7.63(d,J=12.4Hz,1H),7.53(d,J=8.4Hz ,1H),7.37(t,J=8.0Hz,1H),7.27-7.23(m,2H),6.94(dd,J=8.0,2.0Hz,1H),2.80(br s,2H),2.69(br s,2H),1.93-1.85(m,2H). LCMS(ESI):m / z359.0(M+H) + .

[0223] Example 1 / 1 to 1 / 13: The following examples were prepared similarly as described for Example 1 above, using the appropriate components indicated below. [Table 1-1] [Table 1-2] Example 2: Step 1: 3-Bromophen-2,4,6-d3-ol (2a) [ka] A solution of 1-bromo-3-(methoxy-d3)benzene (800 mg, 4.21 mmol) in 20 mL of DCl (35% in D2O) was heated at 105 °C in an autoclave for 2 days, cooled, and diluted with Et2O. The organic layer was separated, dried over Na2SO4, concentrated, and purified by FCC (PE:EA = 100:1 to 1:100) to give compound 2a as an oil.

[0224] Step 2: 1-Bromo-3-(methoxy-d3)benzene-2,4,6-d3 (2b). [ka] To a solution of 2a (300 mg, 1.70 mmol) in MeCN (10 mL) was added iodomethane-d3 (0.13 mL, 2.1 mmol) and K2CO3 (472 mg, 3.41 mmol). The mixture was heated at 65° C. for 5 h, cooled to room temperature, filtered, concentrated and purified by FCC (PE:EA=20:1) to give compound 2b as an oil.

[0225] Step 3: 3-Fluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-2',4',6'-d3-4-amine (2c). [ka] To a solution of compound 1a (237 mg, 1.00 mmol) in 1,4-dioxane (5 mL) and HO (0.5 mL) was added compound 2b (192 mg, 994 μmol), NaCO (0.32 g, 3.0 mmol), and Pd(dppf)Cl (36 mg, 49 μmol), and the mixture was then heated at 90° C. for 2 h, cooled to room temperature, filtered, concentrated, and purified by FCC (PE:EA=10:1) to give compound 2c as an oil.

[0226] Step 4: 2-((3-fluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl-2',4',6'-d3)carbamoyl)cyclopent-1-ene-1-carboxylic acid (2). [ka] A solution of compound 2c (100 mg, 0.45 mmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (62 mg, 0.45 mmol) in DCM (2.5 mL) was heated at 40° C. for 4 h. The mixture was filtered and the filter cake was washed with MeCN (2×2 mL). The solid was dried in vacuum to give compound 1b as a yellow solid. 1 H-NMR(500MHz,DMSO-d6)δ13.04(br s,1H),10.57(s,1H),8.07(t,J=7.8Hz,1H),7.63(d,J=12.5Hz,1H),7.53(d,J=8.0Hz,1H),7.37(s,1H),2.80(br s,2H),2.69(br s,2H),1.93-1.85(m,2H). LCMS(ESI):m / z362.0(M+H) + .

[0227] Example 2 / 1-2 / 2: The following examples were prepared similarly as described for Examples 1 and 2 above, using the appropriate components indicated below. [Table 2] Example 3: Step 1: Ethyl 2-(3-bromophenoxy-2,4,6-d3)-2,2-difluoroacetate (3a). [ka] To a suspension of compound 2a (2.0 g, 11.4 mmol) and DBU (4.3 g, 28.2 mmol) in DMF (38 mL) was added ethyl 2-bromo-2,2-difluoroacetate (5.8 g, 28.6 mmol) slowly at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 16 h, poured into water (50 mL) and extracted with EA (3×100 mL). The organic layer was dried over Na2SO4, concentrated and purified by FCC (PE:EA=10:1) to give compound 3a as a colorless oil.

[0228] Step 2: 2-(3-bromophenoxy-2,4,6-d3)-2,2-difluoroacetic acid (3b). [ka] To a solution of compound 3a (2.8 g, 9.4 mmol) in MeOH (20 mL) and THF (5 mL) was added 3M aqueous NaOH (5 mL). The mixture was stirred at room temperature for 30 min, acidified to pH 1, concentrated, and purified by reverse phase chromatography (C18) (0.1% NH4HCO3 in H2O / MeCN=9:1 to 0:1 as gradient) to give compound 3b as an oil. LCMS (ESI): m / z 268.1 (MH). - .

[0229] Step 3: 1-Bromo-3-(trifluoromethoxy)benzene-2,4,6-d3 (3c). [ka] To a solution of compound 3b (2.4 g, 8.9 mmol) in CDCl3 (25 mL) was added XeF2 (1.5 g, 8.8 mmol). The mixture was stirred at room temperature for 10 min, concentrated, and purified by FCC (PE:EA=40:1) to give compound 3c as a colorless oil.

[0230] Step 4: 3-(Trifluoromethoxy)phenyl-2,4,6-d3)boronic acid (3d). [ka] To a solution of compound 3c (1.3 g, 5.3 mmol) in dry THF (25 mL) was added n-BuLi (2.5 M, 2.1 mL, 5.3 mmol) at -78 °C. The mixture was stirred for 30 min, then a solution of triisopropyl borate (1.5 g, 8.0 mmol) in dry THF (5 mL) was added dropwise with stirring and cooled to maintain the temperature at about -78 °C. After addition, the mixture was stirred at this temperature for 30 min, then warmed to room temperature over 1 h. 2N HCl (3.1 mL) was added with stirring, and the resulting mixture was concentrated and purified by reverse phase chromatography (C18) (0.1% TFA in H2O / MeCN = 9:1 to 0:1 as gradient) to give compound 3d as a white solid. LCMS (ESI): m / z 208.2 (M-H). - .

[0231] Step 5: 2,3,5,6-Tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-2',4',6'-d3-4-amine (3e). [ka] To a solution of compound 3d (150 mg, 0.72 mmol) in 1,2-dimethoxyethane (3 mL) and H2O (0.6 mL) was added 4-bromo-2,3,5,6-tetrafluoroaniline (174 mg, 0.71 mmol), Cs2CO3 (702 mg, 2.15 mmol), and Pd(PPh3)4 (46 mg, 40 μmol). The mixture was heated at 90 °C for 3 h, cooled, and diluted with EA (20 mL). The organic layer was separated, dried over Na2SO4, concentrated, and purified by FCC (PE:EA = 8:1) to give compound 3e as a colorless oil. LCMS (ESI): m / z 329.2 (M + H). + .

[0232] Step 6: 2-((2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl-2',4',6'-d3)carbamoyl)cyclopent-1-ene-1-carboxylic acid (3). [ka] A solution of compound 3e (100 mg, 0.30 mmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (50 mg, 0.36 mmol) in acetic acid (3 mL) was heated at 110 °C for 4 h, concentrated, and purified by reverse phase chromatography (C18) (0.1% NHHCO in H2O / MeCN = 9:1 to 0:1 as gradient) to give compound 3 as a white solid. 1 H-NMR (500MHz, CD3OD) δ7.63 (s, 1H), 2.94-2.89 (m, 2H), 2.87-2.83 (m, 2H), 2.03-1.97. LCMS(ESI):m / z467.1(M+H) + , 489.2(M+Na) + .

[0233] Example 4: Step 1: Methyl 3-(chlorocarbonyl)thiophene-2-carboxylate (4a). [ka] To a solution of 2-(methoxycarbonyl)thiophene-3-carboxylic acid (200 mg, 1.07 mmol) in dry DCM (8 mL) was added SOCl2 (152 mg, 1.28 mmol). The reaction mixture was stirred at room temperature for 2 h and concentrated to give compound 4a as a yellow solid, which was used in the next step without further purification.

[0234] Step 2: 3-((2,3,5,6-tetrafluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl-2',4',6'-d3)carbamoyl)thiophene-2-carboxylic acid (4). [ka] To a solution of compound 3e (100 mg, 0.30 mmol) in dry THF (2 mL) was added NaH (60%, 30 mg, 0.75 mmol) at 0° C. The mixture was stirred at this temperature for 1 h, and then a solution of compound 4a (150 mg, 0.73 mmol) in dry THF (1 mL) was added at 0° C. After the addition, the mixture was stirred at this temperature for 30 min, then warmed to room temperature and stirred for 1 h. Water (1 mL) was then added and stirring was continued for 1 h. The resulting mixture was then concentrated and purified by reverse phase chromatography (C18) (0.1% TFA in H2O / MeCN=9:1 to 0:1 as gradient) to give compound 4 as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ12.11 (br s, 1H), 11.35 (s, 1H), 7.94 (d, J = 5.2 Hz, 1 H), 7.71 (s, 1 H), 7.44 (d, J = 5.2 Hz, 1 H). LCMS(ESI):m / z483.1(M+H) + , 505.1(M+Na) + .

[0235] Example 4 / 1: The following examples were prepared similarly as described for Example 4 above, using the appropriate components indicated below. [Table 3] Example 5: Step 1: 1-Bromo-3-(difluoromethoxy-d)benzene (5a). [ka] To a solution of 3-bromophenol (560 mg, 3.25 mmol) in dry THF (10 mL) was added NaH (1.3 g, 60% w / w, 33 mmol) at 0° C., the mixture was stirred at 0° C. for 30 min, then D2O (6.5 mL) was added dropwise at 0° C. for 10 min. After adding diethyl (bromodifluoromethyl)phosphonate (1.7 g, 6.5 mmol), the mixture was stirred at room temperature for 30 min. The mixture was extracted with EA (3×20 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated and purified by FCC (PE:EA=40:1) to give compound 5a as a colorless oil.

[0236] Step 2: 3'-(Difluoromethoxy-d)-3-fluoro-[1,1'-biphenyl]-4-amine (5b). [ka] To a solution of compound 5a (250 mg, 1.12 mmol) in 1,4-dioxane (6 mL) and HO (0.6 mL) was added compound 1a (265 mg, 1.12 mmol), NaCO (356 mg, 3.36 mmol) and Pd(dppf)Cl (41 mg, 0.06 mmol). The mixture was heated at 90° C. for 2 h and cooled. The organic layer was separated, concentrated and purified by FCC (PE:EA=10:1) to give compound 5b as a colorless oil.

[0237] Step 3: 2-((3'-(difluoromethoxy-d-3-fluoro-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (5). [ka] To a solution of compound 5b (70 mg, 0.28 mmol) in DCM (2.5 mL) was added 1-cyclopentene-1,2-dicarboxylic anhydride (39 mg, 0.28 mmol), and the mixture was then heated at 40° C. for 4 h. The mixture was cooled to room temperature, filtered, and the filter cake was washed with MeCN (2×2 mL). The solid was dried in vacuum to give compound 5 as a pale yellow solid. 1H-NMR(500MHz,DMSO-d6)δ13.04(br s,1H),10.70(s,1H),8.12(t,J=8.0Hz,1H),7.68(d,J=12.5Hz,1H),7.60-7.50(m,4H),7.18(d,J=7.0,1H),2.80(br s,2H),2.70(br s,2H),1.92-1.86(q,J=2.5Hz,2H). LCMS(ESI):m / z393.3(M+H) + .

[0238] Example 6: Step 1: 4-Bromo-2-fluorobenzene-6-d-amine (6a). [ka] A solution of 4-bromo-2-fluoroaniline (2.0 g, 10.6 mmol) in 15 mL of DCl (35% in D2O) in an autoclave was heated at 105° C. for 7 days. The solution was cooled to room temperature, adjusted to pH=8 with 6N NaOH, and extracted with EA (3×20 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated, and purified by FCC (PE:EA=10:1) to give compound 6a as an oil.

[0239] Step 2: 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-6-d-amine (6b). [ka] To a solution of compound 6a (1.0 g, 5.3 mmol) in 1,4-dioxane (12 mL) was added bis(pinacolato)diborane (1.3 g, 5.3 mmol), KOAc (1.56 g, 15.9 mmol), and Pd(dppf)Cl2 (190 mg, 0.26 mmol). The mixture was heated at 90° C. for 1 h, cooled to room temperature, filtered, concentrated, and purified by FCC (PEEA=10:1) to give compound 6b as a white solid.

[0240] Step 3: 3-Fluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-5-d-4-amine (6c). [ka] To a solution of compound 6b (380 mg, 1.60 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was added 1-bromo-3-(methoxy-d3)benzene (302 mg, 1.60 mmol), Na2CO3 (0.51 g, 4.8 mmol), and Pd(dppf)Cl2 (58 mg, 0.08 mmol). The mixture was stirred at 90 °C for 2 h and then cooled to room temperature. The organic layer was separated, concentrated, and purified by FCC (PE:EA = 10:1) to give compound 6c as an oil.

[0241] Step 4: 2-((3-fluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl-5-dcarbamoyl)cyclopent-1-ene-1-carboxylic acid (6). [ka] A solution of compound 6c (80 mg, 0.36 mmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (50 mg, 0.36 mmol) in DCM (2.5 mL) was stirred at 40° C. for 4 h, cooled to room temperature, and filtered. The filter cake was washed with MeCN (2×2 mL). The solid was dried in vacuum to give compound 6 as a yellow solid. 1 H-NMR(500MHz,DMSO-d6)δ13.04(br s,1H),10.58(s,1H),7.63(dd,J=12.5,2.0Hz,1H),7.53(d,J=1.5Hz,1H),7.37(t,J=8.0Hz,1H),7.26(d,J=8.5Hz,1H ),7.23-7.22(m,1H),6.94(dd,J=8.3,2.3Hz,1H),2.80(t,J=7.3Hz,2H),2.70(t,J=7.3Hz,2H),1.89(p,J=7.6Hz,2H). LCMS(ESI):m / z360.3(M+H) + .

[0242] Example 7: 2-((3-Fluoro-3'-hydroxy-[1,1'-biphenyl]-4-yl-2',4',5,6'-d4)carbamoyl)cyclopent-1-ene-1-carboxylic acid (7). [ka] By using appropriate building blocks, the routes outlined above were applied to obtain the target compounds. 1 H-NMR(500MHz,DMSO-d6)δ13.03(br s,1H),10.54(s,1H),9.54(s,1H),7.51(dd,J=12.3,1.8Hz,1H),7.44(d,J=1.5Hz,1 H),7.25(s,1H),2.79(t,J=7.0Hz,2H),2.68(t,J=7.0Hz,2H),1.89(p,J=7.0Hz,2H). LCMS(ESI):m / z346.3(M+H) + .

[0243] Example 8: 2-((3-fluoro-3'-hydroxy-[1,1'-biphenyl]-4-yl-2',4',6'-d3)carbamoyl)cyclopent-1-ene-1-carboxylic acid (8). [ka] By using appropriate building blocks, the routes outlined above were applied to obtain the target compounds. 1 H-NMR(500MHz,DMSO-d6)δ10.68(br s,1H),9.55(s,1H),8.06(dd,J=8.0,9.0Hz,1H),7.50(d,J=12.0Hz,1H),7.44(d,J =8.0Hz,1H),7.25(s,1H),2.79-2.78(m,2H),2.69-2.68(m,2H),1.92-1.86(m,2H). LCMS(ESI):m / z345.3(M+H) + .

[0244] Example 9: Step 1: 2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (9a). [ka] To a solution of 4-bromo-2,6-difluoroaniline (10 g, 48 mmol) in 1,4-dioxane (100 mL) was added bis(pinacolato)diborane (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 9a as a yellow solid.

[0245] Step 2: 3,5-Difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-amine (9b). [ka] To a solution of compound 9a (4.5 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 9b as a yellow solid. LCMS (ESI): m / z 239.1 (M+H). + .

[0246] Step 3: 2-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (9). [ka] To a solution of compound 9b (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 reaction mixture was concentrated in vacuo to give compound 9 as a white solid. 1 H-NMR(500MHz,DMSO-d6)δ12.95(br s,1H),10.13(s,1H),7.55(d,J=8.0Hz,2H),7.39(t,J=7.8Hz,1H),7.32-7.28(m,2H), 6.99(dd,J=1.8,8.3Hz,1H),2.81-2.79(m,2H),2.69-2.66(m,2H),1.97-1.89(m,2H). LCMS(ESI):m / z377.3(M+H) + .

[0247] Example 10: 4-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)-2,5-dihydro-thiophene-3-carboxylic acid (10). [ka] The target molecule 10 was obtained by reacting with 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) in the same manner as above. 1 H-NMR(400MHz,DMSO-d6)δ13.01(br s,1H),10.20(s,1H),7.54(d,J=9.2Hz,2H),7.39(t,J=7.8Hz,1H),7.32-2.2 8(m,2H),6.99(dd,J=2.4,8.0Hz,1H),4.15-4.11(m,2H),4.03-4.00(m,2H). LCMS(ESI):m / z395.2(M+H) + .

[0248] Example 11: Step 1: 4,6-Dihydro-1H,3H-furo[3,4-c]furan-1,3-dione. [ka] To a solution of 4,6-dihydro-1H,3H-thieno[3,4-c]furan-1,3-dione (400 mg, 2.23 mmol) (synthesis described in Bioorg. Med. Chem. Lett. 2005;15:4854) in toluene (5 mL) was added ACCl (385 mg, 4.92 mmol), and the mixture was then stirred at 110° C. for 4 h, cooled to room temperature, and concentrated in vacuo to give compound 11a as a yellow solid, which was used in the next step without purification. LCMS (ESI): m / z=140.1 (M+H). + .

[0249] Step 2: 4-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)-2,5-dihydrofuran-3-carboxylic acid (11). [ka] Compound 11a was reacted in the same manner as above to give the target molecule 11 as a white solid. 1 H-NMR(500MHz,DMSO-d6)δ10.89(br s,1H),7.58(d,J=9.5Hz,2H),7.39(t,J=7.8Hz,1H),7.33-2.28(m,2H),6.99 (dd,J=2.3,8.3Hz,1H),4.97(t,J=5.3Hz,2H),4.89(t,J=5.0Hz,2H),3.43(br s,1H). LCMS(ESI):m / z379.2(M+H) + .

[0250] Example 12 (reverse coupling procedure): Step 1: 3-Fluoro-5-(3-(methoxy-d3)phenyl)pyridin-2-amine (12a). [ka] To a solution of 5-bromo-3-fluoropyridin-2-amine (400 mg, 2.09 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was added (3-(methoxy-d3)phenyl)boronic acid (389 mg, 2.51 mmol), Cs2Co3 (2.4 g, 6.27 mmol), and Pd(dppf)Cl2 (40 mg, 0.11 mmol). The mixture was stirred at 90 °C under N2 for 2 h and cooled to room temperature. The organic layer was separated, concentrated, and purified by FCC (PE:EA = 10:1) to give compound 12a as a yellow solid. LCMS (ESI): m / z 222.0 (M+H). + .

[0251] Step 2: 2-((3-fluoro-5-(3-(methoxy-d3)phenyl)pyridin-2-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (12) [ka] Compound 12a was reacted according to the method described in Step 4 of Example 6 to obtain target molecule 12. 1 H-NMR(500MHz,MeOD)δ8.50(br s,1H),7.99(d,J=9.0Hz,1H),7.41(t,J=8.0Hz,1H),7.25-7.21(m,2H),6.99(d d,J=8.5,2.0Hz,1H),2.97-2.93(m,2H),2.86-2.83(m,2H),2.03-1.97(m,2H). LCMS(ESI):m / z360.1(M+H) + .

[0252] Example 12 / 1 to 12 / 6: The following examples were prepared similarly as described for Example 12 above, using the appropriate components as indicated below. [Table 4] Example 13: Step 1: Di-tert-butyl (3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)iminodicarbonate (13a). [ka] The target compound 13a was prepared by treating compound 9b with di-tert-butyl dicarbonate in DMF and DMAP as catalyst, similarly as described in WO 2008 / 018426.

[0253] Step 2: tert-Butyl (3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamate (13b). [ka] The target compound 13b was prepared by treating compound 13a with trifluoroacetic acid in CH2Cl2 at 0 °C as described in Chem. Commun. 2018;54:4589.

[0254] Step 3: tert-Butyl (3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)(methyl)carbamate (13c) [ka] The target compound 13c was prepared by treating compound 13b with lithium bis(trimethylsilyl)amide and MeI similarly as described in J. Am. Chem. Soc. 2002;124:8206.

[0255] Step 4: 3,5-difluoro-3'-(methoxy-d3)-N-methyl-[1,1'-biphenyl]-4-amine (13d) [ka] Compound 13c was deprotected with 4N HCl in dioxane to prepare the target compound 13d after work-up under basic conditions.

[0256] Step 5: 2-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)(methyl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (13) [ka] The target compound 13 was prepared by coupling compound 13d with 1-cyclopentene-1,2-dicarboxylic anhydride as described above. LCMS (ESI): m / z 391.1 (M+H). + .

[0257] Example 14: Step 1: Methyl (3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)glycinate (14a) [ka] The target compound 14a can be prepared by treating compound 9b with methyl 2-bromoacetate.

[0258] 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 (14). [ka] The target compound 14 can be prepared by coupling compound 14a with 1-cyclopentene-1,2-pentene-1,2-dicarboxylic anhydride.

[0259] Example 15: 2-((3,5-difluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)(2-hydroxyethyl)carbamoyl)cyclopent-1-ene-1-carboxylic acid 15). [ka] The target compound 15 can be prepared by reduction of compound 14a, for example with lithium borohydride.

[0260] Example 99: 2-((3-fluoro-3'-(methoxy-d3)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid-3,3,4,4,5,5-d6 acid. [ka] Hexandioic acid-d8 acid (CAS number: 52089-65-3) can be bis-esterified with MeOH to give dimethyl hexanedioate-d8. This bis-ester can be cyclized as described in WO 2009 / 140279 to give methyl 2-hydroxycyclopent-1-ene-1-carboxylate-3,3,4,4,5,5-d6, the corresponding triflate of which can be prepared. A palladium-catalyzed reaction with sodium formate as described in Heterocycles 2009;77:179 gives the monoacid cyclopent-1-ene-1,2-dicarboxylic acid d6 acid, which can be coupled with compound 1b to give the target molecule.

[0261] Examples 100 / 1 to 100 / 13: The following examples can be prepared similarly as described for the above examples using the appropriate components shown below. [Table 5-1] [Table 5-2] Examples 101 / 1 to 101 / 16: The following examples can be prepared similarly as described for the above examples using the appropriate components shown below. [Table 6-1] [Table 6-2] Example 200: Human DHODH Inhibition Assay In vitro inhibition of hDHODH was measured using N-terminally truncated recombinant hDHODH as described in J. Med. Chem. 2006;49:1239. Briefly, hDHODH concentrations were adjusted so that an average slope of approximately 0.2 AU / min served as a positive control (e.g., no inhibitor). The standard assay mixture contained 60 μM 2,6-dichloroindophenol, 50 μM decylubiquinone, and 100 μM dihydroorotate. At least six different concentrations of hDHODH were added with or without compounds, and measurements were performed in 50 mM TrisHCl, 150 mM KCl, and 0.1% Triton® X-100 at pH 8.0 and 30° C. The reaction was started by adding dihydroorotate, and the absorbance at 600 nm was measured for 2 min. IC 50 Each data point was recorded three times to determine the value of the inhibition constant K i For the determination of M Compounds were then tested at their IC 50 The dilutions were made according to the IC value. 50 , 1 / 4×IC 50 , 1 / 2×IC 50 , 1 x IC 50 , 2×I.C. 50 , 4×I.C. 50 In addition, the substrate concentrations of DHO and decylubiquinone were adjusted to 1 / 4×K in further dilution steps with separate measurements of DHO and decylubiquinone. M , 1 / 2×K M , 1×K M , 2×KM , 4×K M Each data point was recorded twice.

[0262] Example K of the present invention i The values ​​were within the range of the undeuterated counterpart (Example C26 of WO 2003 / 006425). [ka] [Table 7] [Table 8] IC for the human DHODH assay described herein 50 Range: +++: <100nM; ++: 100nM ~ <1μM; +: 1μM ~ <10μM; 0: ≥ 10μM.

[0263] As shown above, DHODH inhibition of the deuterated analogs (i.e., 1, 2, and 6) is unaffected compared to the non-deuterated matched pairs (Example C26 of WO 2003 / 006425). The same is true for Example 4, where the non-deuterated matched pairs have reported ICs of 7 nM. 50 (Bioorg. Med. Chem. Lett. 2005;15:4854).

[0264] Example 201: Microsomal Stability Examples 1 and 2 and the non-deuterated counterpart (Example C26 of WO 2003 / 006425) were incubated for 60 min with three different batches of pooled male rat liver microsomes (RLM) and human liver microsomes (HLM), respectively. Conversion to metabolites was monitored by HPLC-MS / MS. Verapamil served as a positive control. Intrinsic clearance was calculated (in duplicate) from the remaining compound values ​​measured at 0, 10, 30 and 60 min. The 60 min data points are as follows: [Table 9] Deuteration can reduce the intrinsic clearance of compounds of the invention in rat and human microsomes compared to their non-deuterated counterparts, as illustrated in Examples 1 and 2. Reduced intrinsic clearance is beneficial as it extends the residence time of the drug in the body.

[0265] Examples 1 and 2 and the non-deuterated counterpart (Example C26 of WO 2003 / 006425) were incubated for 60 min (twice, i.e., first and second measurement) using three identical different batches of rat liver microsomes (RLM) and human liver microsomes (HLM). The conversion of the parent to the demethylated metabolite was monitored and quantified by HPLC-MS / MS (peak area of ​​the mass peak) to obtain the percentage of the deMe metabolite related to the original parent (% of the original parent). The data was used to calculate the mean with the standard deviation (SD).

[0266] [Table 10] As illustrated in Examples 1 and 2, selective deuteration can reduce the cleavage of the methoxy group to form hydroxy metabolites in rat microsomes compared to the non-deuterated counterpart (Example C26).

[0267] [Table 11] As illustrated in Examples 1 and 2, by selective deuteration, cleavage of the methoxy group to form hydroxy metabolites can also be reduced in human microsomes compared to the non-deuterated counterpart (Example C26).

[0268] Example 202: Pharmacokinetics in rats The pharmacokinetics of the deuterated compounds of the invention were evaluated in 3 male and 3 female rats (Han Wistar strain, 8 weeks old) after oral or intravenous cassette administration to evaluate oral bioavailability. Rats were catheterized in the jugular vein (2-3 days prior to blood collection). At each designated time point (0, 1, 2, 4, 8 and 24 hours after administration), 100 μL of blood was collected in Li-heparin tubes and stored on ice until centrifugation (3000 g, 4° C. for 10 minutes), and plasma was prepared within 45 minutes after collection, frozen at −20° C., and stored at this temperature until processed for LC-MS analysis. The data obtained are as follows: [Table 12] The non-deuterated compound Bidofludimus (Comparative Example C26) itself already has very good bioavailability. Selective deuteration (Example 2) can further improve this bioavailability, which can be attributed to reduced metabolism.

[0269] Example 203: Mouse Pharmacokinetics 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 cassette administration. The dose was 5 mg / kg, the administration volume was 5 mL / kg, and the vehicle was 5% Solutol, 95% NaCl solution (0.9% saline concentration). At each designated time point (0, 0.25, 0.5, 1, 2, 4, 8 hours after administration), 20 μL of whole blood was collected from the tail vein into Li-heparin tubes, frozen on dry ice within 1-2 minutes of sampling, and stored at -20°C until processed for LC-MS analysis. The data obtained are as follows: [Table 13] Again, the non-deuterated comparative example C26 has a lower C max and AUC values, which can be dramatically improved by selective deuteration (Example 1).

[0270] Example 204: Antiviral activity against SARS-CoV-2 Viral replication (YFP) and cell viability assays are generally described in Pathogens 2021;10:1076 and were applied to the compounds of the present invention with the following results: [Table 14] EC for the SARS-CoV-2 assays described herein 50 Range: +++: <10 μM; ++: 10 μM ~ <25 μM; +: 25 μM ~ <50 μM; 0: ≥ 50 μM.

[0271] Example 205: Synergistic antiviral activity with nucleoside analogues against SARS-CoV-2 The synergistic potential of Example 9 together with the nucleoside analog EIDD-1931 (CAS: 3258-02-4) was evaluated.

[0272] A method for evaluating drug combinations by viral replication inhibition assay is published in Pathogens 2021;10:1076. Caco-2 cells were cultured in 96-well plates at 25,000 cells / well, infected with SARS-CoV-2 d6-YFP at an MOI of 0.003, and treated with Example 9, EIDD-1931 or drug combinations at 4 × EC of each of the single compounds. 50 Concentrations were initiated at 100 mg / mL. Viral replication was determined as 30 hours post-infection (pi) by quantitative fluorescent detection of virally-driven YFP expression in fixed cells. The inhibition profile of viral replication measured via virally-encoded YFP reporter expression is shown in bar graphs of quadruplicate measurements (mean ± SD). Combination drug evaluation was calculated by using the CompuSyn algorithm described in Int. J. Mol. Sci. 2021;22:575.

[0273] A representative experiment is shown in Figure 1. The compound of Example 9 exhibits synergistic antiviral effects against SARS-CoV-2 when combined with the nucleoside analog EIDD-1931 (CAS:3258-02-4).

Claims

1. Compounds according to formula (I): 【Chemistry 1】 or an enantiomer, diastereomer, tautomer, prodrug, solvate, or pharma- ceutically acceptable salt thereof, wherein A is selected from 5-membered heteroaryl, cyclopentenyl, and heterocyclopentenyl, having one or more hydrogen atoms optionally replaced with deuterium; The A is unsubstituted or is halogen, CN, NO ２ , oxo, OH, C １～４ -alkyl, O-C １～４ -alkyl, fluoro-C １～４ -alkyl, O-fluoro-C １～４ -Alkyl, CO ２ H, and SO ３ H, with one or more hydrogen atoms in the alkyl optionally replaced with deuterium; B is selected from the group consisting of 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5-10 membered heteroaryl containing 1-6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with halogen, —CN, —NO ２ Oxo, C １～４ -Alkyl, C ０～６ -Alkylene-OR ２７ , 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 ２９ ) ｍ R ２７ , C ０～６ -Alkylene-NR ２７ S (=O) ｘ (=NR ２９ ) ｙ R ２７ , C ０～６ -Alkylene-S(=O) ｘ (=NR ２９ ) ｙ N.R. ２７ R ２８ , C ０～６ -Alkylene-NR ２７ S (=O) ｘ (=NR ２９ ) ｙ N.R. ２７ R ２８ , C ０～６ -Alkylene-CO ２ R ２７ , C ０～６ -Alkylene-O-COR ２７ , C ０～６ -Alkylene-CONR ２７ R ２８ , C ０～６ -Alkylene-NR ２７ -COR ２７ , C ０～６ -Alkylene-NR ２７ -CONR ２７ R ２８ , C ０～６ -alkylene-O-CONR ２７ R ２８ , C ０～６ -Alkylene-NR ２７ -CO ２ R ２７ , C ０～６ -Alkylene-NR ２７ R ２８ and is substituted with 1 to 4 substituents 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 halogen, —CN, oxo, —OH, C １～４ -Alkyl, halo-C １～４ -alkyl, -O-C １～４ -Alkyl and -O-halo-C １～４ -substituted with 1 to 6 substituents independently selected from alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing 1-3 heteroatoms independently selected from O, S, or N; The additional ring may be a halogen, —CN, oxo, —OH, C １～４ -Alkyl, halo-C １～４ -alkyl, -O-C １～４ -alkyl, and -O-halo-C １～４ -alkyl; Residue on Ring B -NR ２ is in a 1,4-orientation relative to ring C; Ring B or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium; C is selected from the group consisting of 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1-4 heteroatoms independently selected from N, O, and S, 6- or 10-membered aryl, and 5-10 membered heteroaryl containing 1-6 heteroatoms independently selected from N, O, and S; Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 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 N.R. ３１ R ３２ , C ０～６ -Alkylene-NR ３１ S (=O) ｘ (=NR ３３ ) ｙ N.R. 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 and is substituted with 1 to 4 substituents 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 halogen, —CN, oxo, —OH, C １～４ -Alkyl, halo-C １～４ -alkyl, -O-C １～４ -Alkyl and -O-halo-C １～４ -substituted with 1 to 6 substituents independently selected from alkyl, optionally, two adjacent substituents on an aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring, optionally containing 1-3 heteroatoms independently selected from O, S, or N; The additional ring may be a halogen, —CN, oxo, —OH, C １～４ -Alkyl, halo-C １～４ -alkyl, -O-C １～４ -alkyl, and -O-halo-C １～４ -alkyl; Ring C or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium; X is H, D, halogen, -CN, -NO ２ , C １～６ -alkyl, -O-C １～６ -alkyl, O-halo-C １～６ -Alkyl, C ０～６ -Alkylene-OR 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 N.R. ４１ R ４２ , C ０～６ -Alkylene-NR ４１ S (=O) ｘ (=NR ４３ ) ｙ N.R. 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 halogen, —CN, oxo, —OH, C １～４ -Alkyl, halo-C １～４ -alkyl, -O-C １～４ -alkyl, and -O-halo-C １～４ -substituted with 1 to 6 substituents independently selected from alkyl, X or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium; R １ is selected from H and D; R ２ is H and C １～６ alkyl, Alkyl is unsubstituted or substituted with 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, -O-C １～４ -alkyl, and -O-halo-C １～４ -substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R ２ or its substituents have one or more hydrogen atoms optionally replaced with deuterium; R ２７ , R ２８ , R ３１ , R ３２ , R ４１ , R ４２ is H, C １～６ - independently selected from alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; The alkyl, cycloalkyl, or heterocycloalkyl may be unsubstituted or may be substituted with 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, -O-C １～４ -alkyl, and -O-halo-C １～４ -substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R ２７ and / or R ２８ and / or R ３１ and / or R ３２ and / or R ４１ and / or R ４２ or each of its substituents has one or more hydrogen atoms optionally replaced with deuterium; Or R ２７ and R ２８ , R ３１ and R ３２ , R ４１ , and R ４２ each together with the nitrogen to which they are attached complete a 3- to 6-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S, or N; The ring is unsubstituted or substituted with 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, -O-C １～４ -alkyl, and -O-halo-C １～４ -substituted with 1 to 3 substituents independently selected from alkyl, R ２７ and / or R ２８ and / or R ３１ and / or R ３２ and / or R ４１ and / or R ４２ or each of its substituents has one or more hydrogen atoms optionally replaced with deuterium; R ２９ , R ３３ , R ４３ is H, -CN, -NO ２ , C １～６ -Alkyl, -CO-O-C １～６ - independently selected from alkyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl; The alkyl, cycloalkyl, or heterocycloalkyl may be unsubstituted or may be substituted with 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, -O-C １～４ -alkyl, and -O-halo-C １～４ -substituted with 1 to 3 substituents independently selected from alkyl, heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S; R ２９ and / or R ３３ and / or R ４３ or each of its substituents 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 attached to the same sulfur atom is independently selected from 0 to 2; provided that the sum of integers x and y for residues bound to the same sulfur atom is independently selected from 1 or 2; However, A, B, C, R ２ , R ２７ , R ２８ , R ２９ , R ３１ , R ３２ , R ３３ , R ４１ , R ４２ , R ４３ and / or at least one hydrogen in X is replaced with deuterium; with the proviso that the level of deuterium incorporation at each substituent designated as deuterium is at least 52.5%, or an enantiomer, diastereomer, tautomer, prodrug, solvate, or pharma- ceutically acceptable salt thereof.

2. R １ is H, and R ２ is H, or a solvate or pharma- ceutically acceptable salt thereof. 【Request 3】 【Chemistry 2】 teeth, 【Chemistry 3】 3. The compound of formula (I) according to claim 1 or 2, selected from:

4. -NR ２ B is, 【Chemistry 4】 3. The compound of formula (I) according to claim 1 or 2, selected from:

5. C is phenyl, pyridyl, or thiazolyl; Phenyl, pyridyl, or thiazolyl is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of D and F; X is D, F, Cl, -CN, OH, C １～４ -alkyl, O-C １～４ -alkyl, fluoro-C １～４ -alkyl, O-fluoro-C １～４ -alkyl, having one or more hydrogen atoms optionally replaced with deuterium. 【Request 6】 【Chemical 5】 teeth, 【Chemistry 6】 3. The compound of formula (I) according to claim 1 or 2, selected from: 【Request 7】 【Chemical 7】 teeth, 【Chemistry 8】 3. The compound of formula (I) according to claim 1 or 2, selected from:

8. R １ is H, and R ２ is H, 【Chemistry 9】 teeth, 【Chemistry 10】 is selected from -NR ２ B is, 【Chemistry 11】 is selected from 【Chemistry 12】 teeth, 【Chemistry 13】 3. The compound of formula (I) according to claim 1 or 2, selected from:

9. 【Chemical 14】 【Chemistry 15】 Compounds of formula (I) according to claim 1 or 2, selected from Or a solvate or a pharma- ceutically acceptable salt thereof.

10. 3. A compound according to claim 1 or 2 for use as a medicament.

11. 3. A compound according to claim 1 or 2 for use in the prevention and / or treatment of a disease, disorder, therapeutic indication or medical condition suitable for treatment with a DHODH inhibitor.

12. The compound for use according to claim 11, wherein the disease, disorder, therapeutic indication or medical condition is selected from the group comprising rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections 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 claim 1 or 2 and a pharma- ceutically acceptable carrier.

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

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