EA049475B1 - DEUTERATED DHODH INHIBITORS - Google Patents

Abstract

The invention relates to new deuterated compounds of formula (I) and their use as medicinal products.

Description

Field of technology to which the invention relates

The invention relates to new deuterated dihydroorotate dehydrogenase (DHODH) inhibitors, pharmaceutical preparations containing them, a method for their preparation and their use as a medicinal product, alone or in combination with one or more additional agents, for the treatment of various diseases in which inhibition of DHODH is desirable.

State of the art

Vidofludimus calcium salt (IMU-838) is a selective and active second-generation orally administered dihydroorotate dehydrogenase (DHODH) immunomodulator developed for the treatment of certain chronic inflammatory diseases, including relapsing-remitting multiple sclerosis (rrMS):

vidofludymus

The mechanism of action of vidofludimus calcium, a small molecule selective immunomodulator, is inhibition of intracellular metabolism of activated immune T and B cells by blocking the enzyme DHODH. Inhibition of the enzyme DHODH results in metabolic stress of metabolically activated lymphocytes, leading to a decrease in the amount of proinflammatory cytokines and then to apoptosis of activated immune cells. Blockade of the enzyme DHODH has a selective effect on metabolically activated immune cells, on malignant cells and on virus-infected cells. Thus, inhibition of DHODH does not result in general antiproliferative effects on other cells. IMU-838 as a second-generation inhibitor of DHODH is designed to separate the desired immunomodulatory effects from the undesirable side effect profile due to off-target effects such as neutropenia, alopecia and diarrhea. An additional benefit of DHODH inhibitors such as IMU-838 is their direct antiviral action. Reactivation of latent viruses has been observed during long-term treatment with immunosuppressive drugs. This can lead to severe infections such as progressive multifocal leukoencephalopathy, which can be fatal.

PP-001 is another DHODH inhibitor of the same structural class for the treatment of retinal diseases such as uveitis, diabetic macular edema and retinal vein occlusion, which is currently undergoing clinical trials. Animal models have already shown high efficacy in the treatment of dry keratitis and viral conjunctivitis.

There is a need to develop new DHODH inhibitors. In particular, there is a need to develop DHODH inhibitors with improved pharmacokinetic properties. The C-H covalent bond is generally weaker than the C-D bond due to the kinetic isotope effect. Breakage of C-H bonds is a general feature of drug metabolism and breaking of the analogous C-D bond may be more difficult and therefore decrease the rate of metabolism. Substitution of H to D in small molecules can result in a significant decrease in metabolism, leading to favorable changes in the biological effects of drugs. The substitution may also result in decreased toxicity due to decreased formation of a toxic metabolite (J. Med. Chem. 2019;62:5276). Deuterated analogs contribute to the favorable mechanism of action, but are expected to be metabolized more slowly and lead to less interpatient variation compared to the non-deuterated matched pair. It is generally believed that an altered pharmacokinetic profile may provide potential improved efficacy, less frequent dosing, improved tolerability, less interpatient variation in drug metabolism, and reduced drug interactions.

Prior art

Non-deuterated compounds of formula (I) are described in WO2004/056746, WO2004/056747, WO2004/056797, WO2010/052027, WO2010/128050, WO2012/001148, WO2012/001151, WO2015/169944, WO2015/154820, WO2019/170848, WO2019/101888, WO2019/175396, and in Bioorg. Med. Chem. Lett. 2004; 14:55, Bioorg. Med. Chem. Lett. 2005; 15:4854, Bioorg. Med. Chem. Lett. 2006;16:267 and J. Med. Chem. 2006;49:1239. Deuterated compounds of formula (I) have not been previously described.

Brief description of the drawings

Fig. 1 shows a typical result from an experiment in which the compound of Example 9 was combined with the nucleoside analogue EIDD-1931 (CAS: 3258-02-4). These data demonstrate the synergistic

- 1 049475 antiviral effect on SARS-CoV-2 at different doses.

The essence of the invention

The invention relates to compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, X, R ¹ and R ² are defined as in claim 1, provided that at least one hydrogen in A, B, C, R ² and/or X is replaced by deuterium, and provided that the degree of incorporation of deuterium in each substituent designated as deuterium is at least 52.5%.

The compounds of the present invention have similar or greater inhibitory activity towards DHODH compared to known DHODH inhibitors. In addition, the compounds of the present invention have favorable stability or pharmacokinetic profile when used as a drug due to the replacement of hydrogen with deuterium.

Thus, the present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient. Furthermore, the present invention also relates to a pharmaceutical composition further comprising one or more additional therapeutic agents selected from antiviral agents, anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

The present invention also relates to the use of compounds of formula (I) for the prevention and/or treatment of diseases, disorders or pathological conditions treatable with DHODH inhibitors, wherein the disease, disorder or pathological condition is selected from the group consisting of rheumatism, acute immunological disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused in humans and animals by protozoan infections, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy. More preferably, the disease, disorder or condition is selected from the group consisting of the following: graft versus host and host versus graft diseases, 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.

Detailed description of the invention

The compound 2-((3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid, also known as vidofludimus, is an orally administered DHODH inhibitor. The calcium salt of vidofludimus is known as IMU-838. IMU-838 is currently in a phase 2 clinical trial for the treatment of rrMS, ulcerative colitis, primary sclerosing cholangitis, and COVID-19.

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. PP001 is currently undergoing clinical trials for the treatment of keratoconjunctivitis and non-infectious uveitis.

Vidofludimus, IMU-838 and PP-001 were generally well tolerated in several clinical studies. Despite the potential beneficial activity of vidofludimus, IMU-838 and PP001, there remains a continuing need for new compounds for the treatment of the abovementioned diseases and conditions that exhibit improved drug metabolism and pharmacokinetic (DMPK) properties. Improved DMPK properties may result in positive changes in the safety, efficacy and tolerability profile of the compounds.

Certain embodiments of the present invention are described in detail below, examples of which are illustrated by the accompanying structures and claims. Although the present invention has been described in conjunction with numbered embodiments, it should be understood that they are not intended to limit the present invention to these embodiments. On the contrary, the present invention includes all alternatives, modifications and equivalents that may fall within the scope of the present invention as defined by the claims. The present invention is not limited

- 2 049475 is not limited to the methods and materials described in the present invention, but includes any methods and materials similar or equivalent to those described in the present invention that can be used in practicing the present invention. In the event that one or more of the incorporated literature references, patents, or similar materials differ from or contradict this application, including, but not limited to, defined terms, use of a term, described techniques, etc., the present description controls.

The desired characteristics of a DHODH inhibitor can be provided by compounds that have a structure described by formula (I):

or a pharmaceutically acceptable salt thereof, where

R ² means H;

provided that at least one hydrogen in A, B, C, ^R2 and/or X is replaced by deuterium;

provided that the degree of incorporation of deuterium in each substituent designated as deuterium is not less than 52.5%.

In a more preferred embodiment, in combination with any of the above or below embodiments, the compound is described by formula (I), wherein

selected from

- 3 049475

in combination with any of

In a similar preferred embodiment of the above or below embodiments, the compound is described by formula (I), wherein

from the following:

- 4 049475

or a pharmaceutically acceptable salt thereof.

The present invention also relates to the invention as a medicinal product.

The present invention also relates to the use of a compound according to the present invention, the use of a compound according to the present invention, for the prevention and/or treatment of diseases, disorders or pathological conditions treatable with DHODH inhibitors, wherein the disease, disorder or pathological condition is selected from the group consisting of rheumatism, acute immunological disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused in humans and animals by protozoan infections, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy.

More preferably, the present invention relates to the use of a compound according to the present invention, wherein the disease, disorder or pathological condition is selected from the group consisting of graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

Also provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient.

Also provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient and further comprising one or more additional therapeutic agents selected from antiviral agents, anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

More specifically, the present invention relates to a compound of formula (I) described in the following paragraphs:

1. Compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

selected from

D

-NR2B selected from

and where the -NR ² residue in ring B is in the 1,4-orientation relative to ring C, |-©-x is chosen

- 5 049475

from

R ¹ means H;

R ² means H;

provided that at least one hydrogen in A, B, C, ^R2 and/or X is replaced by deuterium;

provided that the degree of incorporation of deuterium in each substituent designated as deuterium is not less than 52.5%.

2. The compound of formula (I) according to paragraph 1, where

selected

4. A compound of formula (I) according to paragraph 1, which is selected from

selected from

3. A compound of formula (I) according to paragraph 1 or 2, wherein is selected from

-NR2B selected

- 6 049475

or a pharmaceutically acceptable salt thereof.

5. The use of a compound according to any of the preceding paragraphs as a medicinal product.

6. The use of a compound according to any of paragraphs 1-4 for the prevention and/or treatment of diseases, disorders or pathological conditions treatable with DHODH inhibitors, wherein the disease, disorder or pathological condition is selected from the group consisting of rheumatism, acute immunological disorders, autoimmune diseases, diseases caused by the proliferation of malignant cells, inflammatory diseases, diseases caused in humans and animals by protozoan infections, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy.

7. The use of paragraph 6, wherein the disease, disorder or pathological condition is selected from the group consisting of graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

8. A pharmaceutical composition comprising a compound according to any one of paragraphs 1-4 and a pharmaceutically acceptable carrier or excipient.

9. The pharmaceutical composition according to paragraph 8, further comprising one or more additional therapeutic agents selected from antiviral agents, anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

In preferred embodiments, when used in the present invention, when any of R ¹ and R ² is deuterium, the degree of incorporation of deuterium in each of R ¹ and R ² designated as deuterium 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%; when any of R ³ , R ⁴ , R ⁵ and R ⁶ is deuterium, the degree of incorporation of deuterium in each of R ³ , R ⁴ , R ⁵ and R ⁶ designated as deuterium 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%; if any of ^R7 , ^R8 , ^R9 and ^R10 is deuterium, the degree of incorporation of deuterium in each of ^R7 , ^R8 , ^R9 and ^R10 is not less than 52.5%, not less than 75%, not less than 82.5%, not less than 90%, not less than 95%, not less than 97%, not less than 98% or not less than 99%; if any residue in ^R11 contains one or more deuteriums, the degree of incorporation of deuterium at each position in ^R11 is not less than 52.5%, not less than 75%, not less than 82.5%, not less than 90%, not less than 95%, not less than 97%, not less than 98% or not less than 99%; if any residue in ring A contains one or more deuteriums, the degree of incorporation of deuterium at each position in ring A is not less than 52.5%, not less than 75%, not less than 82.5%, not less than 90%, not less than 95%, not less than 97%, not less than 98%, or not less than 99%; if any of R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ is deuterium, the degree of incorporation of deuterium in each of R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ is not less than 52.5%, not less than 75%, not less than 82.5%, not less than 90%, not less than 95%, not less than 97%, not less than 98%, or not less than 99%.

Quantitative analysis of specific deuterated compounds can be achieved by a variety of conventional techniques such as mass spectroscopy (peak area) or by quantifying the residual 1H-NMR signals of a specific deuterated position compared to signals of internal standards or signals of other non-deuterated 1H compounds.

- 7 049475

In preferred embodiments, the degree of deuterium incorporation for each substituent designated as deuterium is at least 52.5%. More preferably, the degree of deuterium incorporation for each substituent designated as deuterium is at least 90%. Even more preferably, the degree of deuterium incorporation for each substituent designated as deuterium is at least 98%.

In preferred embodiments, when used in the present invention, ring A is

It is most preferable if ring A is

In preferred embodiments of the present invention, -NR2B is selected from the group consisting of the following:

In even more preferred embodiments of the present invention, -NR2B is selected from the group consisting of the following:

In the most preferred embodiments of the present invention, -NR2B is selected from the group consisting of the following:

selected from

In preferred embodiments of the present invention, the group consisting of the following:

- 8 049475

It is most preferable if

represents

selected from

In preferred embodiments of the present invention, the group consisting of the following:

if selected from the group consisting of the following:

More preferably,

It is more preferable if

In preferred embodiments of the present invention, R ¹ is H and R ² is H;

represents

- 9 049475

selected from the group consisting of the following:

In more preferred embodiments of the present invention, R ¹ is H and R ² is H;

-NR2B is selected from the group consisting of the following:

selected from the group consisting of the following:

selected from the group consisting of the following:

In the most preferred embodiments of the present invention, R ¹ is H and R ² is H;

-NR2B is selected from the group consisting of the following:

selected from the group consisting of the following:

selected from the group consisting of the following:

- 10 049475

-NR2B is selected from the group consisting of the following:

selected from the group consisting of the following:

Preferred compounds according to the present invention are the compounds given in the examples of the present invention below, more preferably the compounds of the following examples 1, 2 and 6.

the compounds proposed in the present invention are selected from the group, preferably consisting of the following:

or a pharmaceutically acceptable salt thereof.

the compounds proposed in the present invention are selected from

The most preferred groups consist of the following:

or a pharmaceutically acceptable salt thereof.

The present invention also relates to the use of the compounds of the present invention for the prevention and/or treatment of diseases, disorders or pathological conditions as described in the present invention, in particular a disease or pathological condition in which inhibition of DHODH is beneficial, more preferably where the disease or pathological condition is selected from the group consisting of the following: rheumatism, acute immunological disorders, autoimmune diseases, diseases caused by the proliferation of malignant

- 11 049475 cells, inflammatory diseases, diseases caused in humans and animals by protozoan infections, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy.

The present invention also relates to the use of the compounds of the present invention for the prevention and/or treatment of diseases, disorders or pathological conditions as described in the present invention, in particular a disease or pathological condition in which inhibition of DHODH is beneficial, more preferably where the disease, disorder or pathological condition is selected from the group consisting of graft versus host and host versus graft diseases, 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.

The present invention also relates to pharmaceutical compositions containing the compounds of the present invention.

The present invention also relates to the use of the compounds of the present invention for the preparation of pharmaceutical compositions that are used for the treatment and/or prevention of the diseases, disorders, disorders and/or pathological conditions referred to in the present invention.

The present invention also relates to the medical uses described in the present invention, including the pharmaceutical compositions described in the present invention.

The pharmaceutical compositions described in the present invention comprise one or more compounds of the present invention and a pharmaceutically acceptable carrier or excipient.

The pharmaceutical compositions described in the present invention comprise one or more compounds of the present invention and a pharmaceutically acceptable carrier or excipient, and further comprise one or more additional therapeutic agents selected from the group consisting of the following: antiviral agents, anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

The pharmaceutical compositions according to the present invention are prepared according to methods which are generally known and familiar to the person skilled in the art. As pharmaceutical compositions, the compounds according to the present invention (=active compounds) are used alone or, in particular, in combination with suitable pharmaceutical auxiliary substances and/or excipients, for example in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. in the form of TTS), emulsions, suspensions, gels or solutions, the content of the active compound is preferably from 0.1 to 95% and, with a suitable choice of auxiliary substances and/or excipients, the pharmaceutical form to be administered (e.g. delayed-release form or enteric-coated form) is excellent for the active substance and/or for ensuring the onset of action.

The person skilled in the art knows auxiliary substances, carriers, excipients, diluents, vehicles or auxiliary components, which, according to his expert training, are suitable for the sought pharmaceutical preparations, preparations or compositions. In addition to solvents, gelling agents, ointment bases and other active compound excipients can be used, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers, dyes, complexing agents or permeation promoters.

Depending on the particular disease being treated or prevented, additional therapeutically active agents that are typically administered to treat or prevent that disease may optionally be co-administered with the compounds of the present invention. When used in the present invention, additional therapeutic agents that are typically administered to treat or prevent a particular disease are known to be appropriate for the disease being treated.

In another aspect of the present invention, the compounds of the present invention, or salts or solvates of said compounds of formula (I), can be combined with standard therapeutic agents that are commonly used to treat the pathological conditions described in the present invention.

The person skilled in the art, according to his expert training, knows the total daily dose(s) and the form(s) to be administered of the additional therapeutic agent(s) to be administered together. Said total daily dose(s) may vary over a wide range. In practicing the present invention and depending on the details, characteristics or purpose specified above, the compounds of the present invention may be administered in combination therapy separately, sequentially, simultaneously or alternately (e.g., as combined single dosage forms, as separate single dosage forms, or as separate single dosage forms).

- 12 049475 bath forms or sequential single dosage forms, in the form of fixed or non-fixed combinations, in the form of a set of components or in the form of mixtures) with one or more standard medicinal products, in particular chemotherapeutic or targeted anti-cancer agents known in the art, such as those mentioned above.

Thus, another object 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 pharmaceutically acceptable salt or solvate thereof, a second active ingredient which is a standard drug known in the art for the pathological conditions described in the present invention, and optionally a pharmacologically acceptable carrier, diluent and/or excipient for separate, sequential, simultaneous or alternate use in therapy in any order, for example for the treatment, prevention or alleviation of the pathological conditions described in the present invention in a patient. In this context, the present invention also 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 drug known in the art for the pathological conditions described in the present invention, for use separately, sequentially, simultaneously or alternately in therapy, for example in the therapy of the diseases indicated in the present invention.

The term combination in the present invention may mean a fixed combination, a non-fixed combination or a set of components. A fixed combination is defined as a combination where said first active ingredient and said second active ingredient are contained together in a single dosage form or in a single entity. One example of a fixed combination is a pharmaceutical composition where said first active ingredient and said second active ingredient are contained in a mixture for simultaneous administration, such as in a preparation. Another example of a fixed combination is a pharmaceutical combination where said first active ingredient and said second active ingredient are contained in a single unit without mixing.

A kit of components is defined as a combination wherein said first active ingredient and said second active ingredient are contained in more than one unit. One example of a kit of components is a combination wherein said first active ingredient and said second active ingredient are contained separately. The components of a kit of components may be administered separately, sequentially, simultaneously, or alternately.

The first and second active ingredients of the combination or kit of parts according to the invention may be presented as separate preparations (i.e., independently of each other), which are then combined for use separately, sequentially, simultaneously or alternately in combination therapy; or packaged and provided together as separate package components of a combination for use separately, sequentially, simultaneously or alternately in combination therapy. The pharmaceutical preparation types 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 are prepared as separate tablets or capsules, or may be different, i.e., suitable for different administration forms, such as, for example, when one active ingredient is prepared as a tablet or capsule and the other is prepared, for example, for intravenous administration. The amounts of the first and second active ingredients of the combinations, compositions or kits according to the invention may together constitute a therapeutically effective amount for the treatment, prevention or amelioration of the pathological condition described in the invention.

To obtain pharmaceutical compositions, the compounds according to the present invention (=active compounds) are individually mixed with suitable pharmaceutical excipients 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 generally known methods.

The doses of the active compounds are used in the usual amounts. Thus, forms for topical application (such as ointments) contain the active compounds in a concentration of, for example, 0.1 to 99%. The usual dose in the case of systemic therapy (oral administration) is 0.3 to 30 mg/kg per day, with intravenous administration 0.3 to 30 mg kg/h. The choice of the optimal mode of administration and the duration of treatment, in particular the optimal dose and type 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 expert training.

The class of compounds provided by the present invention is useful for the development of drugs suitable for the treatment of autoimmune or viral diseases and chronic inflammation or, more commonly, for the treatment of diseases in which inhibition of DHODH is beneficial. The compounds

- 13 049475 the invention is also applicable to the treatment of diseases such as rheumatism, acute immunological disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused in humans and animals by protozoan infections, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy. More preferably, the disease is selected from the group consisting of the following: graft-versus-host and host-versus-graft reactions, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis.

The class of compounds according to the present invention is useful for the treatment of viral diseases, especially acute viral infections selected from the group consisting of the following: coronavirus infections, COVID-19, SARS, influenza/flu (and avian flu), HIV/Aids, chickenpox, cytomegalovirus, dengue fever, rubella, hand-foot-and-mouth disease, hantavirus infections, all forms of hepatitis, Lassa fever, Marburg disease infections, measles, meningitis, MERS-CoV, mumps, norovirus infections, herpes simplex virus infections, smallpox, rotavirus infections, Ebola virus infections, poliovirus infections, rhinovirus infections, parainfluenza infections, RSV infections, HCMV infections and Banna virus infections. The most relevant are COVID-19, influenza/flu, and rhinovirus infections, with COVID-19 being the most relevant. It should be understood that these also include mutated forms of viruses (e.g. SARS-CoV-2).

It should be understood that, depending on the nature of the chemical materials used in the synthesis, some variation in the isotopic composition of the synthesized compounds occurs. Thus, the resulting vidofludimus (and other compounds of formula (I) specifically substituted with deuterium) will naturally contain small amounts of deuterated isotopologues. The concentration of naturally occurring stable isotopes of hydrogen and carbon is small and insignificant compared to the degree of substitution of stable isotopes in the compounds of the present invention. See, e.g., Coll. Biochem. Physiol. 1998; 119A:725.

The term isotopic enrichment factor at a particular position normally occupied by hydrogen means the ratio of the abundance of deuterium at that position to the natural abundance of deuterium at that position. For example, an isotopic enrichment factor of 3500 means that the amount of deuterium at a particular position is 3500 times greater than the natural abundance of deuterium, or that 52.5% of the compounds contain deuterium at a particular position (i.e., 52.5% of the deuterium is incorporated into that position).

The abundance of deuterium in the world's oceans is approximately one atom per 6,500 hydrogen atoms (approximately 154 parts per million (ppm)). Thus, deuterium makes up approximately 0.015% (0.030 wt%) of all the hydrogen atoms in the world's oceans; the abundance varies slightly from one type of natural water to another.

When a particular position in a compound of the present invention (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) is indicated in the name or structure as containing hydrogen or deuterium, it is understood that that position may contain hydrogen at natural abundance or may be enriched in deuterium with an isotopic enrichment factor of, for example, at least 835 (12.5% deuterium incorporation), at least 1670 (25% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (inclusion of 95% deuterium), not less than 6466.7 (inclusion of 97% deuterium), not less than 6600 (inclusion of 99% deuterium) or not less than 6633.3 (inclusion of 99.5% deuterium).

When a particular position in a compound of the present invention (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) is indicated in the name or structure as containing H or hydrogen, it is understood that hydrogen of natural isotopic composition may be present at that position.

When a particular position in a compound of the present invention (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) is indicated in the name or structure as containing D or deuterium, it is understood that deuterium may be present at that position in an amount that is at least 3,340 times the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3,500 times the natural abundance of deuterium (52.5% deuterium incorporation), at least 4,500 times the natural abundance of deuterium (67.5% deuterium incorporation), at least 5,000 times (75% deuterium incorporation), at least 5,500 times the natural abundance of deuterium (82.5% deuterium incorporation), at least 6000 times the natural content of deuterium (inclusion of 90% deuterium), not less than 6333.3 times the natural content of deuterium (inclusion of 95% deuterium), not less than 6466.7 times the natural content of deuterium (inclusion of 97% deuterium), not less than

- 14 049475

6600 times the natural abundance of deuterium (99% deuterium inclusion) or at least 6633.3 times the natural abundance of deuterium (99.5% deuterium inclusion).

The degree of deuterium incorporation can be determined by quantitative analysis using a variety of conventional techniques such as mass spectroscopy (peak area) or by quantifying the residual 'H-NMR signals of a particular deuterated position compared to signals from internal standards or signals from other non-deuterated 'H compounds.

Unless a chemical name or structure indicates that a particular position in a compound normally occupied by hydrogen is isotopically enriched, it is understood that the particular position is occupied by hydrogen at its natural abundance. For example, the term phenyl or

without any additional indication of isotopic enrichment, it shows that all hydrogen atoms are present at their natural abundance.

If ring A is a partially saturated ring, the double bond in ring A is in iso

in fermented position:

In case the ring A is a 5-membered heteroaryl ring, then the double bond is part of a delocalized π-system, and it can exist in mesomeric forms. An example are the following mesomeric forms of thiophene:

In addition, the compounds of the present invention may partially exhibit tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group at the carbon atom adjacent to the nitrogen atom, the following tautomerism may be observed:

The term 1,4-orientation (such as that indicated for ring B) means a specific relative position of two substituents in one ring and that in the ring for the substituents there is at least one possibility that between two substituents in the ring attached to the ring system there are 4 atoms:

The term "compound" when referring to any compound of the present invention, including a compound of formula (I) or a pharmaceutically acceptable salt thereof, means a set of molecules having the same chemical structures, except that the isotopic composition of the hydrogen atoms that make up the molecules may differ. The relative isotopic abundances of a compound of the present invention depend on a number of factors, including the isotopic purity of the deuterated reactants used to prepare the compound and the efficiency of deuterium incorporation at the various synthetic steps used to prepare the compound.

D and d both stand for deuterium. H stands for hydrogen.

Deuterium substitution means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

Any formula or structure described in the present invention also describes deuterated compounds containing an additional number of isotopically labeled atoms. Examples of additional isotopes that can be included in the compounds of the present invention include additional isotopes of hydrogen (i.e., tritium or ³ H), as well as isotopes of carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such ^as , but not limited to, 11C, ^13C , ^14C , ^15N , ^18F , ^31P , ^32P , 35S, ^36Cl and ^125I . The present invention further includes various isotopically labeled compounds in which radioactive isotopes such as ^3H , ^13C and ^14C are included. Such isotopically labeled compounds can be used in studies of metabolism, reaction kinetics, detection or imaging techniques such as positron emission tomography (PET) or single photon emission

- 15 049475 computed tomography (SPECT), including analyses of drug or substrate tissue distribution or radioactive treatment of patients.

The halogen is selected from the group consisting of fluorine, chlorine, bromine and iodine, more preferably fluorine or chlorine and most preferably fluorine.

In the context of the present invention, C _1-4 -alkyl means a preferably saturated hydrocarbon chain containing from 1 to 4 carbon atoms, which may have a linear or branched chain. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Preferred is C _1-3 -alkyl, such as methyl, ethyl, propyl and isopropyl, most preferred is methyl. The term alkyl by itself or as part of another substituent, for example halo-C _1-4 -alkyl, unless otherwise specified, also includes derivatives of alkyl, defined in more detail below as unsaturated alkyl. An unsaturated alkyl group is one comprising one or more double bonds or triple bonds. Preferred unsaturated alkyl substituents are vinyl, 2-propenyl or prop-2-yn-1-yl.

In the context of the present invention, the term C _1-4 -alkyl containing in the alkyl one or more hydrogen atoms optionally substituted with deuterium includes, but is not limited to, the following residues: -CD3, -CH ₂ D, -CHD2, CD ₃ CH ₂ (CH ₂ )n-, CD ₃ CH ₂ (CHD) _n -, CD ₃ CH ₂ (CD ₂ ) _n -,

CH ₂ DCH ₂ (CHD) _n -, CD3CHD(CH2)n-, CH2DCHD(CD2)n-,

CH2DCH2(CD2)n-, CD3CHD(CHD)n-, CHD2CHD(CH2)n-,

CHDCH2(CH2)n-, CHD2CH2(CD2)n-, CH ₂ DCHD(CHD) _n -,

CHD2CH2(CH2)n-, CD3CHD(CD2)n-, CHD2CHD(CHD)n-,

CHD2CH2(CHD)n

CH2DCHD(CH2)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-, CHD ₂ CD ₂ (CD ₂ ) _n -, CH ₃ CD ₂ (CH ₂ ) _n -, CH ₃ CD ₂ (CHD) _n -, CH ₃ CD ₂ (CD ₂ ) _n -, where n is an integer from 0 to 2, and CH ₃ CH ₂ (CHD)m-, CH ₃ CH ₂ (CD ₂ )m-, where m is an integer from 1 to 2, as well as -CD( _CD3 ) ₂ , -CH( _CD3 ) ₂ and -C( _CD3 ) ₃ . Preferred _C1-2 -alkyls containing deuterium are -CD3 and -CD3CD2, the most preferred is -CD3.

Co-6-alkylene indicates that the corresponding group is divalent and connects the attached residue to the rest of the molecule. Furthermore, in the context of the present invention, C ₀ -alkylene means a bond, and C 1 -alkylene means a methylene bridge, C ₂ -alkylene means an ethylene bridge or a methyl-substituted methylene bridge, etc. In the context of the present invention, C _0-6 -alkylene preferably means a bond, a methylene group, an ethylene group or a propylene group. The term alkylene, unless otherwise specified, also includes an unsaturated divalent chain, if appropriate (i.e., possibly C _2-6 -alkylene). A typical example of unsaturated C ₄ -alkylene is -CH ₂ -CH=CH-CH ₂ -.

The term fluoro-C _1-4 -alkyl or O-fluoro-C _1-4 -alkyl respectively means that one or more hydrogen atoms in the alkyl chain are replaced by one or more fluorine atoms. Preferred are CHF2, CF3, CH2CF3 and CF2CF3. A more preferred example thereof is the formation of the -CF3 group.

The same applies to halo-C _1-4 -alkyl or O-halo-C _1-4 -alkyl, which means that one or more hydrogen atoms in the alkyl chain are replaced by one or more halogen atoms independently selected from the group consisting of fluorine, chlorine, bromine and iodine.

In the context of the present invention, the term fluoro-C _1-4 -alkyl containing in the alkyl one or more hydrogen atoms optionally substituted by deuterium means that in the fluoro-C 1-4 -alkyl containing one or more hydrogen atoms, one or more hydrogen atoms may be replaced by a fluorine atom(s) and form what is described above by the term C _1-4 -alkyl containing in the alkyl one or more hydrogen atoms optionally substituted by deuterium. It should be understood that fluoro-C 1-4 -alkyl may also be fully fluorinated. Preferred are fluoro-C 1-2 -alkyl containing deuterium, such as CDF2, CD2CF3 and CD ₂ CF ₂ D. Most preferred is CDF ₂ .

A 3- to 10-membered cycloalkyl group means a saturated or partially unsaturated mono-, bi-, spiro-, or polycyclic ring system containing from 3 to 10 carbon atoms, wherein 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 ^2.5 .0 ^3.8 .0 ^4.7 ]octyl. Therefore, a 3- to 6-membered cycloalkyl group means a saturated or partially unsaturated mono-, bi-, or spirocyclic ring system containing from 3 to 6 carbon atoms, and a 5- to 8-membered cycloalkyl group means a saturated or partially unsaturated mono-, bi-, or spirocyclic ring system containing from 5 to 8 carbon atoms.

The term 3- to 6-membered cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, and spiro[2,3]hexanyl. More preferred is cyclopropyl or cyclobutyl.

The term C _3-4 -cycloalkyl containing one or more hydrogen atoms in the alkyl, is not

- 16 049475 necessarily substituted by deuterium includes, but is not limited to, the following residues:

A cycloalkyl or heterocyclyl group may be attached by a bond or spirocyclically, for example if cyclohexane is substituted with a heterocycloalkyl group by oxetane, the following structures are possible:

3-10 membered heterocycloalkyl, a group containing from 1 to 4 heteroatoms independently selected from the group consisting of: N, O and S is a saturated or partially unsaturated 3-10 membered carbon mono-, bi-, spiro- or polycyclic ring, wherein 1, 2, 3 or 4 carbon atoms are replaced by 1, 2, 3 or 4 heteroatoms, respectively, wherein the heteroatoms are independently selected from the group consisting of: N, O or S. The sulfur heteroatom in the ring can also be oxidized to S=O or _SO2 . The carbon atom 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. A heterocycloalkyl group may be attached to the rest of the molecule through a carbon, nitrogen (e.g., in morpholine or piperidine), or sulfur atom. An example of an S atom attached to a heterocycloalkyl group is

terocycloalkyl is a cyclic sulfonimidamide ·

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, etc.

6- or 10-membered aryl means phenyl or naphthyl.

5-10 membered heteroaryl containing from 1 to 6 heteroatoms independently selected from the group consisting of N, O and S means a 5-10 membered mono- or bicyclic heteroaromatic ring system (also referred to herein as heteroaryl) containing up to 6 heteroatoms independently selected from the group consisting of 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 also means a bicyclic ring system wherein the heteroatom(s) may be contained in one or both rings, including bridging atoms. Examples thereof include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl-1,5-naphthyridinyl, 1,7-naphthyridinyl and pyrazolo[1,5-a]pyrimidinyl. The nitrogen or sulfur atom of the heteroaryl system may also be optionally oxidized to form the corresponding N-oxide, Soxide or S,S-dioxide.

5-Membered heteroaryl means a monocyclic aromatic ring system containing up to 3 heteroatoms independently selected from the group consisting of 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.

A 5-membered heterocyclopentenyl group means a partially unsaturated 5-membered carbon monocyclic ring wherein 1 or 2 carbon atoms are replaced by 1 or 2 heteroatoms, respectively, wherein the heteroatoms are independently selected from the group consisting of N, O and S. Examples thereof include 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl or 2,5-dihydro1H-pyrrole. The sulfur heteroatom in the ring can also be oxidized to S=O or SO2.

The compounds according to the present invention may exist in tautomeric or stereoisomeric forms (enantiomers, diastereomers), depending on their structure. The present invention therefore also includes tautomers, enantiomers or diastereomers and corresponding mixtures thereof. Stereoisomerically homogeneous components can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.

The term pharmaceutically acceptable salts means salts derived from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Thus, the compounds of the present invention that contain acidic groups can form these salts and can be used in the context of the present invention, for example, in the form of an alkali metal salt, an alkaline earth metal salt or an ammonium salt. Specific examples are

- 17 049 475 such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The corresponding salts can be prepared by conventional methods known to those skilled in the art, for example by reacting them with an organic or inorganic base in a solvent or dispersant, or by cation exchange with other salts. The present invention also includes all salts of the compounds according to the invention which, due to low physiological compatibility, are not directly suitable for use in pharmaceuticals, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

It should be understood that pharmaceutically acceptable salts may optionally further include a solvate.

The term polymorph as used herein means a crystalline form of a compound or its salt, hydrate or solvate in a particular crystal packing. All polymorphs have the same elemental composition. The term crystalline as used herein means a solid-state form that consists of ordered structural units. Different crystalline forms of the same compound or its salt, hydrate or solvate are formed due to different packing of molecules in the solid state, which leads to crystals with different symmetries and/or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical characteristics, stabilities and solubilities.

The term effective amount includes an amount of a compound that, when administered, is sufficient to prevent the development of, or to some extent alleviate, one or more symptoms of the disorder, disease, or pathological condition being treated. The term effective amount also means an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or clinician.

As used herein, the term subject means any member of the animal kingdom, including humans. In some embodiments, a subject means a human at any stage of development. In some embodiments, a subject means a human patient. In some embodiments, a subject means non-human animals. In some embodiments, a non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, or pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, a subject may be a transgenic animal, a genetically engineered animal, or a clone.

It has been surprisingly found that the deuterated compounds detailed in the present invention have greater stability in microsomes and improved pharmacokinetic properties in rats and mice. Further details are provided in the following examples section.

Experimental part

The compounds of the present invention can be prepared as described in WO2003/006425 and WO2004/056797 (and literature cited therein) by using suitable deuterated building blocks or by hydrogen-deuterium exchange (e.g. Synthesis 2019; 51:1319 or Angew. Chem. Int. Ed. 2018; 57:3022).

Abbreviations.

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene,

DMSO: dimethyl sulfoxide, dppf: 1,1'-bis(diphenylphosphino)ferrocene,

EA: ethyl acetate,

FCC: silica gel flash chromatography,

PE: petroleum ether, rt: room temperature (20±4°C).

Experimental section.

Example of obtaining P1.

Step 1. 5-Bromo-1-fluoro-3-(methoxy^3)-2-nitrobenzene (P1a).

- 18 049475

5-Bromo-1,3-difluoro-2-nitrobenzene can be treated with CD ₃ OD in KOH in a similar manner as described in WO2018/059314 to afford the desired compound P1a.

Step 2. 4-Bromo-2-fluoro-6-(methoxy^3)aniline (P1).

.Вг н ₂ ,Д/ < ^₽1 >

OCDg

Compound P1a can be treated with hydrazine hydrate and Raney nickel as a catalyst in a similar manner as described in WO2018/059314 to yield the desired compound P1.

Example of obtaining P2. 1-(3/. ⁶ -Propoxy^9)-3-bromobenzene (P2).

OCDjiCDgCDnDg _ΒΓ ώ (RF

Compound P2 can be obtained by the reaction of 1-iodo-3/.6 ^- propane-1.1.2.2.3.3.3,3,3^9 with 3-bromophenol and potassium carbonate in DMF.

An example of obtaining P3. 2,6-Difluoro-4-(morpholino^8)aniline (P3).

By the reaction of tert-butyl (4-bromo-2,6-difluorophenyl)carbamate with morpholine-2,2,3,3,5,5,6,6^8 using palladium diacetate, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and potassium tert-butoxide in toluene for 14 h at 60°C similarly to that described in WO2008/018426, the desired compound P3 can be obtained after removal of the Boc protecting group with 4 N HCl in dioxane and aqueous workup in alkaline medium.

Example of obtaining P4.

Step 1. 1-(1,3-dioxoisoindolin-2-yl)-4-methyl bicyclo[2.2.2]octane-1,4-dicarboxylate (P4a).

Οχ /Ά ⁰ rw o

4-(Methoxycarbonyl)bicyclo _[ 2.2.2]octane-1-carboxylic acid was coupled with phthalimide using dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine as a catalyst in _CH2Cl2 at RT.

Step 2. Methyl 4-(3-methoxyphenyl)bicyclo[2.2.2]octane-1-carboxylate (P4b).

Compound P4a was coupled with bis(3-methoxyphenyl)zinc using 1,2-bis(diphenylphosphino)benzene and iron(III) acetylacetonate (iron(III) acetylacetonate) (acac) ₃ ) as a catalyst similarly to that described in J. Am. Chem. Soc. 2016; 138:11132 to afford the desired compound P4b.

Step 3. Methyl 4-(3-hydroxyphenyl)bicyclo[2.2.2]octane-1-carboxylate (P4c).

- 19 049475

Compound P4b was treated with _BBr3 in _CH2Cl2 at temperatures from _-78 °C to rt to give the desired compound P4c.

Step 4. Methyl 4-(3-(methoxy^3)phenyl)bicyclo[2.2.2]octane-1-carboxylate (P4d).

Compound P4c was alkylated with CD3I in a similar manner as described in Example 2, step 2, to yield the desired compound P4d.

Step 5. 4-(3-(Methoxy^3)phenyl)bicyclo[2.2.2]octane-1-carboxylic acid (P4e).

Compound P4d was saponified to obtain the desired compound P4e.

Step 6. tert-Butyl (4-(3-(methoxy^3)phenyl)bicyclo[2.2.2]octan-1-yl)carbamate (P4f).

Compound P4e was treated with diphenylphosphoryl azide, Boc ₂ O and NEt ₃ in tert-butanol at reflux for 16 h in a similar manner as described in WO2016/045587 to give the desired compound P4f.

Step 7. 4-(3-(Methoxy^3)phenyl)bicyclo[2.2.2]octan-1-amine (P4).

Compound P4e was treated with 4 N HCl in dioxane to give P4 after aqueous workup in alkaline medium.

Example 1.

Step 1. 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1a).

To a solution of 4-bromo-2-fluoroaniline (4.00 g, 21.1 mmol) in 1,4-dioxane (30 mL) were 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), then the mixture was heated at 90 °C for 1 h, cooled to rt, filtered, concentrated and purified by FCC (PE:EA=8:1) to give compound 1a as a white solid.

Step 2. 3-Fluoro-3'-(methoxy^3)-[1,G-biphenyl]-4-amine (1b).

- 20 049475

To a solution of compound 1a (800 mg, 3.37 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) were added 1-bromo-3-(methoxy-3)benzene (638 mg, 3.36 mmol), _Na2CO3 (1.07 g, 10.1 mmol) and Pd(dppf) _Cl2 (124 mg, 0.17 mmol), and then the mixture was heated at 90 °C for 2 h, cooled to rt, filtered, concentrated and purified by FCC (PE:EA=10:1) to give compound 1b as an oil.

Step 3. 2-((3-Fluoro-3'-(methoxy^3)-[1,G-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (1).

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 x 2 mL). The solid was dried in vacuo to give compound 1 as a pale yellow solid. ¹ H-NMR (400 MHz, DMSC-d ₆ ): 13.04 (br s, 1H), 10.58 (s, 1H), 8.07 (t, J=8.4 Hz, 1H), 7.63 (d, J=12.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.27-7.23 (m, 2H), 6.94 (dd, J=8.0, 2.0 Hz, 1H), 2.80 (br s, 2H), 2.69 (br s, 2H), 1.93-1.85 (m, 2H). LCMS (ESI): m/z 359.0 (M+H)+.

Examples 1/1-1/13.

The following examples were prepared in a manner similar to that described above in Example 1, using the appropriate building block given below.

- 21 049475

(ESI): m/z 413.1 (M+H) ⁺ 1/3 OCD^CDg p|| F^x-^,Βγ Br jl JJ ΗίΝ'γ F OCD2CD3 ”ΝΝ ^ώ Vft F 'H-NMR (400 MHz, DMSO-t/6) δ 12.95 (br s, 1H), 10.12 (s, 1H), 7.54 (t, J=9.2 Hz, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.30-7.26 (m, 2H), 6.97 (dd, J=2.8, 8.0 Hz, 1H), 2.80 (t, J=7.2 Hz, 2H), 2.68 (t, J=7.2 Hz, 2H), 1.96-1.89 (m, 2H). LCMS (ESI): m/z 393.3 (M+H) ⁺ 1/4 R q Ш CD 'ft- QJ X ABOUT C^iO t i )=° IZ -η \ / ABOUT \7 'H-NMR (400 MHz, DMSO-t/6) δ 10.09 (s, 1H), 7.42-7.39 (m, 2H), 7.28 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.0 Hz, 1H), 7.07-7.02 (m, 1H), 2.822.78 (m, 2H), 2.70-2.65 (m, 2H), 1.97-1.88 (m, 2H). LCMS (ESI): m/z 377.3 (M+H) ⁺ 1/5 X PJ Z ϋ ο—о о \_/ о )---( С ш 0CD ₃ CD ₃ 'H-NMR (400 MHz, DMSO-t/6) δ 13.14 (br s, 1H), 9.91 (s, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.17 (t, J=2.0 Hz, 1H), 6.93-6.89 (m, 1H), 2.82 (t, J=7.4 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H), 1.96-1.88 (m, 2H). LCMS (ESI): m/z 361.1 (M+H) ⁺ 1/6 ocd _z cd ₂ cd ₂ d ₃ Г?| ^F '^\x ^Br Βι·-^^ X Ji (P2) ^h sN γ F D ₃ C(D ₂ C) ₃ O ⁰ + ^0H ° ^F YfY Λγ 'Ν-γ \ η 1 ⁴ ' F 'H-NMR (400 MHz, DMSO-t/6) δ 12.96 (br s, 1H), 10.13 (s, 1H), 7.55 (d, J=9.2 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 7.31-7.27 (m, 2H), 6.97 (dd, J=l.8, 7.8 Hz, 1H), 2.82-2.78 (m, 2H), 2.70-2.65 (m, 2H), 1.97-1.88 (m, 2H). LCMS (ESI): m/z 425.3 (M+H) ⁺ 1/7 F ft 1 F _x Br ^Br g ^D G T ^D H ₂ N^\^ F 0 0 s. X A° iz -n ^σ о—AjC—-Π □ a 'H-NMR (500 MHz, CD3OD) δ 7.38 (d, J=9.5 Hz, 2H), 2.96-2.91 (m, 2H), 2.87-2.82 (m, 2H), 2.04-1.96 (m, 2H). LCMS (ESI): m/z 366.1

- 22 049475

(M+H) ⁺ 1/8 OCD ₃ vL ^l xj h ₂ n γ F C9 □ O../Y 1J xx IL ZT 0=/ ΞΕ\___ τη □ ¹ H-NMR (400 MHz, CD3OD) δ 7.587.53 (m, 2H), 7.34 (s, 1H), 2.96-2.90 (m, 2H), 2.87-2.81 (m, 2H), 2.041.96 (m, 2H). LCMS (ESI): m/z 384.1 (M+H) ⁺ 1/9 F-^x\Br LJ OCD ₃ Η ₂ Ν γ 1 ^F JO ¹ Br'^^ OCD ₃ YXA '— ¹ F 'H-NMR (500 MHz, DMSO-t/6) δ 12.90 (br s, 1H), 10.21 (s, 1H), 8.25 (d, J=5.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.40 (d, J=5.5 Hz, 1H), 7.23 (s, 1H), 2.81-2.77 (m, 2H), 2.69-2.65 (m, 2H), 1.96-1.89 (m, 2H). LCMS (ESI): m/z 378.1 (M+H) ⁺ 1/10 I M z m οα / b-f ABOUT L/o\I )=o ΞΕΖ -η fVo \_/a '—c 'H-NMR (500 MHz, DMSO-t/6) δ 12.98 (br s, 1H), 10.19 (s, 1H), 7.91 (d, J=9.5 Hz, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 2.82-2.77 (m, 2H), 2.69-2.65 (m, 2H), 1.96-1.89 (m, 2H). LCMS (ESI): m/z 378.2 (M+H) ⁺ 1/11 d ^D v ^D D-y'O jL Jj DD ^D NgM'u F (P3) DV Ο^Ά) O^ ^OH n ^F \bV ^N \A ^D 1l XJ □ □ ^D \η 1 F 'H-NMR (400 MHz, CD3OD) δ 6.646.59 (m, 2H), 2.96-2.89 (m, 2H), 2.87-2.79 (m, 2H), 2.03-1.94 (m, 2H). LCMS (ESI): m/z 361.2 (M+H) ⁺ 1/12 _OCD3H2 \( _P4 ) OCD ₃ n ' ^0H As J ΛΑν-'' \__j H 'H-NMR (400 MHz, DMSO-t/6) δ 8.83 (br s, 1H), 7.18 (t, J=8.0 Hz, 1H), 6.89 (dd, J=l.2, 8.8 Hz, 1H), 6.83 (t, J=2.2 Hz, 1H), 6.73-6.71 (m, 1H), 2.65-2.57 (m, 4H), 1.97-1.93 (m, 6H), 1.85-1.80 (m, 6H), 1.781.67 (m, 2H). LCMS (ESI): m/z 373.3 (M+H) ⁺

- 23 049475

Example 2.

Stage 1. 3-Bromophenol-2,4,6^3-ol (2a).

'H-NMR (400 MHz, DMSO-76) δ 12.84 (br s, 1H), 10.63 (br s, 1H), 7.55-7.50 (m, 1H), 7.39 (d, J=6.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.10 (t, J=7.2 Hz, 1H), 2.80 (t, J=7.4 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 1.99-1.91 (m, 2H). LCMS (ESI): m/z 413.0 (M+H) ⁺

A solution of 1-bromo-3-(methoxy-3)benzene (800 mg, 4.21 mmol) in 20 mL DCl (35% in D ₂ O) was heated in an autoclave at 105 °C for 2 days, cooled and diluted with Et ₂ O. The organic layer was separated, dried over Na ₂ SO ₄ , concentrated and purified by FCC (PE:EA = 100:1 to 1:100) to give compound 2a as an oil.

Step 2. 1-Bromo-3-(methoxy^3)benzene-2,4,6^ ₃ (2b).

_To a solution of 2a (300 mg, 1.70 mmol) in MeCN (10 mL) was added iodomethaneM3 (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 rt, filtered, concentrated and purified by FCC (PE:EA=20:1) to give compound 2b as an oil.

Step 3. 3-Fluoro-3'-(methoxy^3)-[1,1'-biphenyl]-2',4',6'^3-4-amine (2c).

To a solution of compound 1a (237 mg, 1.00 mmol) in 1,4-dioxane (5 mL) and _H2O (0.5 mL) was added compound 2b (192 mg, 994 μmol), _Na2CO3 (0.32 g, 3.0 mmol) and Pd(dppf) _Cl2 (36 mg, 49 μmol), and then the mixture was heated at 90°C for 2 _h , cooled to rt, filtered, concentrated and purified by FCC (PE:EA=10:1) to give compound 2c as an oil.

Step 4. 2-((3-Fluoro-3'-(methoxy^3)-[1,1'-biphenyl]-4-yl-2',4',6'^3)carbamoyl)cyclopent-1-ene-1carboxylic acid (2).

A solution of 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 x 2 mL). The solid was dried in vacuo to afford 1b as a yellow solid. ¹ H-NMR (500 MHz, DMSC-d ₆ ) δ 13.04 (br s, 1H), 10.57 (s, 1H), 8.07 (t,

- 24 049475

J=7.8 Hz, 1H), 7.63 (d, J=12.5 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 2.80 (br s, 2H), 2.69 (br s, 2H), 1.93-1.85 (m, 2H). LCMS (ESI): m/z 362.0 (M+H)+.

Examples 2/1-2/2.

The following examples were prepared in a manner similar to that described above in Example 1 and 2 using the appropriate building blocks given below.

No. structural block structure analytic data 2/1 χζχ,Βtu h ₂ n F □ Сo > _о IZ -п ^//( о □—Ч-о \_/ о --\ о □ “ Ή-NMR (400 MHz, DMSO-t76) δ 12.94 (br s, 1H), 10.15 (s, 1H), 7.55 (d, J=9.2 Hz, 2H), 7.39 (s, 1H), 2.83-2.77 (m, 2H), 2.70-2.64 (m, 2H), 1.97-1.89 (m, 2H). LCMS (ESI): m/z 380.2 (M+H) ⁺ 2/2 F F^J^Br tu HaN^y^F F a SU o t° ΙΖ -P (UCH -p o—o \_/ o —\ o a ^and Ή-NMR (400 MHz, DMSO-t76) δ 12.86 (br s, 1H), 10.63 (br s, 1H), 7.46 (s, 1H), 2.82-2.76 (m, 2H), 2.70-2.64 (m, 2H), 1.98-1.91 (m, 2H). LCMS (ESI): m/z 380.2 (M+H) ⁺

Example 3.

Step 1. Ethyl 2-(3-bromophenoxy-2,4,6^3)-2,2-difluoroacetate (3a).

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 slowly added ethyl 2-bromo-2,2-difluoroacetate (5.8 g, 28.6 mmol) at RT. The mixture was stirred at RT for 16 h under nitrogen, poured into water (50 mL) and extracted with EA (3x100 _mL ). The combined organic layer was dried over _Na2SO4 , concentrated and purified by FCC (PE:EA=10:1) to give compound 3a as a colourless oil.

Step 2. 2-(3-Bromophenoxy-2,4,6^3)-2,2-difluoroacetic acid (3b).

To a solution of compound 3a (2.8 g, 9.4 mmol) in MeOH (20 mL) and THF (5 mL) was added 3 M aqueous NaOH (5 mL). The mixture was stirred at RT for 30 min, acidified to pH 1, _concentrated and purified by reverse phase (C18) chromatography (0.1% _NH4HCO3 in _H2O /MeCN=9:1 to 0:1 gradient) to afford compound 3b as an oil. LCMS (ESI): m/z 268.1 (M-H) ^- .

Stage 3. 1-Bromo-3-(trifluoromethoxy)benzene-2,4,6^3 (3c).

To a solution of compound 3b (2.4 g, 8.9 mmol) in CDCl ₃ (25 mL) was added XeF ₂ (1.5 g, 8.8 mmol). The mixture was stirred at RT for 10 min, concentrated and purified by FCC (PE:EA = 40:1) to give compound 3c as a colorless oil.

Step 4. (3-(Trifluoromethoxy)phenyl-2,4,6^3)boronic acid (3d).

- 25 049475

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, maintaining the temperature at about -78 °C. After the addition, the mixture was stirred for 30 min at this temperature, then allowed to warm to rt over 1 h. With stirring, 2 N HCl was added. HCl (3.1 mL) and the resulting mixture was concentrated and purified by reverse phase (C18) chromatography (0.1% TFA in _H2O /MeCN=9:1 to 0:1 gradient) to afford compound 3d as a white solid. LCMS (ESI): m/z 208.2 (M-H) ^- .

Step 5. 2,3,5,6-Tetrafluoro-3'-(trifluoromethoxy)-[1,G-biphenyl]-2',4',6'D3-4-amine (3e).

To a solution of compound 3d (150 mg, 0.72 mmol) in 1,2-dimethoxyethane (3 mL) and H ₂ O (0.6 mL) were added 4-bromo-2,3,5,6-tetrafluoroaniline (174 mg, 0.71 mmol), Cs ₂ CO ₃ (702 mg, 2.15 mmol) and Pd(PPh ₃ ) 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 Na ₂ SO ₄ , concentrated and purified by FCC (PE:EA = 8:1) to give compound 3 as a colorless oil. LCMS (ESI): m/z 329.2 (M+H)+.

Step 6. 2-((2,3,5,6-Tetrafluoro-3'-(trifluoromethoxy)-[1,D-biphenyl]-4-yl-2',4',6'D3)carbamoyl)cyclopent-1-ene-1-carboxylic acid (3).

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 (C18) chromatography (0.1% NH4HCO3 in _H2O /MeCN=9:1 to 0:1 gradient) to give compound 3 as a white solid. ¹ H-NMR (500 MHz, CD3OD) δ 7.63 (s, 1H), 2.94-2.89 (m, 2H), 2.87-2.83 (m, 2H), 2.03-1.97. LCMS (ESI): m/z 467.1 (M+H)+, 489.2 (M+Na)+.

Example 4.

Step 1. Methyl 3-(chlorocarbonyl)thiophene-2-carboxylate (4a).

To a solution of 2-(methoxycarbonyl)thiophene-3-carboxylic acid (200 mg, 1.07 mmol) in dry DCM (8 mL) was added SOCl ₂ (152 mg, 1.28 mmol). The reaction mixture was stirred at RT for 2 h and concentrated to give compound 4a as a yellow solid, which was used in the next step without further purification.

Step 2. 3-((2,3,5,6-Tetrafluoro-3'-(trifluoromethoxy)-[1,G-biphenyl]-4-yl-2',4',6'D3)carbamoyl)thiophene-2-carboxylic acid (4).

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 for 1 h at this temperature, then a solution of compound 4a (150 mg, 0.73 mmol) in dry THF (1 ml) was added dropwise at 0 °C. After the addition, the mixture was stirred for 30 min at this temperature, then allowed to warm to rt and stirred for

- 26 049475 1 h. Then water (1 mL) was added and stirring was continued for 1 h. Then the resulting mixture was concentrated and purified by reverse phase (C18) chromatography (0.1% TFA in H ₂ O/MeCN=9:1 to 0:1 gradient) to give compound 4 as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.11 (br s, 1H), 11.35 (s, 1H), 7.94 (d, J=5.2 Hz, 1H), 7.71 (s, 1H), 7.44 (d, J=5.2 Hz, 1H). LCMS (ESI): m/z 483.1 (M+H)+, 505.1 (M+Na)+.

Example 4/1.

The compound of the following example was prepared in a similar manner as described above in Example 4, using the appropriate building block given below.

Example 5.

Step 1. 1-Bromo-3-(difluoromethoxy^)benzene (5a).

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 and the mixture was stirred at 0 °C for 30 min, then D2O (6.5 mL) was added dropwise at 0 °C over 10 min. After addition of diethyl (bromodifluoromethyl)phosphonate (1.7 g, 6.5 mmol), the mixture was stirred at RT for 30 min. The mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , concentrated and purified by FCC (PE:EA = 40:1) to give compound 5a as a colorless oil.

Step 2. 3'-(Difluoromethoxy-^)-3-fluoro-[1,G-biphenyl]-4-amine (5b).

To a solution of compound 5a (250 mg, 1.12 mmol) in 1,4-dioxane (6 mL) and _H2O (0.6 mL) was added compound 1a (265 mg, 1.12 mmol), _Na2CO3 (356 mg, 3.36 mmol) and Pd(dppf) _Cl2 (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.

Step 3. 2-((3'-(Difluoromethoxy-^)-3-fluoro-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (5).

To a solution of 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 rt, filtered and the filter cake was washed with MeCN (2 x 2 mL). The solid was dried in vacuo to give 5 as a light yellow solid. 1H-NMR (500

- 27 049475

MHz, DMSO-de) δ 13.04 (br s, 1H), 10.70 (s, 1H), 8.12 (t, J=8.0 Hz, 1H), 7.68 (d, J=12.5 Hz, 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=2.5 Hz, 2H). LCMS (ESI): m/z 393.3 (M+H)+.

Example 6.

Step 1. 4-Bromo-2-fluorobenzene-6L-amine (6a).

D (ba)

A solution of 4-bromo-2-fluoroaniline (2.0 g, 10.6 mmol) in 15 mL DCl (35% in D2O) was heated at 105 °C in an autoclave for 7 days. The solution was cooled to rt, adjusted to pH 8 with 6 N NaOH and extracted with EA (3x20 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.

Step 2. 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-6^-amine (6b).

XI (6b) η ₂ ν

D

To a solution of compound 6a (1.0 g, 5.3 mmol) in 1,4-dioxane (12 mL) were added bis(pinacolato)diboron (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 rt, (filtered, concentrated and purified by FCC (PE:EA=10:1) to give compound 6b as a white solid.

Step 3. 3-Fluoro-3'-(methoxy^3)-[1,G-biphenyl]-5^-4-amine (6c).

OCD ₃

X J (6s)

N _g M u^

F

To a solution of compound 6b (380 mg, 1.60 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) were added 1-bromo-3-(methoxy-3)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 rt. The organic layer was separated, concentrated and purified by FCC (PE:EA=10:1) to give compound 6c as an oil.

Step 4. 2-((3-Fluoro-3'-(methoxy^3)-[1,G-biphenyl]-4-yl-5^)carbamoyl)cyclopent-1-ene-1carboxylic acid (6).

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 rt and filtered. The filter cake was washed with MeCN (2 x 2 mL). The solid was dried in vacuo to give compound 6 as a yellow solid. 1H-NMR (500 MHz, DMSO-d ₆ ) δ 13.04 (br s, 1H), 10.58 (s, 1H), 7.63 (dd, J=12.5, 2.0 Hz, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 7.237.22 (m, 1H), 6.94 (dd, J=8.3, 2.3 Hz, 1H), 2.80 (t, J=7.3 Hz, 2H), 2.70 (t, J=7.3 Hz, 2H), 1.89 (p, J=7.6 Hz, 2H). LCMS (ESI): m/z 360.3 (M+H)+.

Example 7. 2-((3-Fluoro-3'-hydroxy-[1,G-biphenyl]-4-yl-2',4',5,6'^4)carbamoyl)cyclopent-1-ene-1carboxylic acid (7).

- 28 049475

The desired compound was obtained by the above-described route using suitable building blocks. 1H-NMR (500 MHz, DMSO-d6) δ 13.03 (br s, 1H), 10.54 (s, 1H), 9.54 (s, 1H), 7.51 (dd, J=12.3, 1.8 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.25 (s, 1H), 2.79 (t, J=7.0 Hz, 2H), 2.68 (t, J=7.0 Hz, 2H), 1.89 (p, J=7.0 Hz, 2H). LCMS (ESI): m/z 346.3 (M+H)+.

Example 8. 2-((3-Fluoro-3'-hydroxy-[1,G-biphenyl]-4-yl-2',4',6'^3)carbamoyl)cyclopent-1-ene-1carboxylic acid (8).

The desired compound was obtained by the above-described route using suitable building blocks. 1H-NMR (500 MHz, DMSO-d _b ) δ 10.68 (br s, 1H), 9.55 (s, 1H), 8.06 (dd, J=8.0, 9.0 Hz, 1H), 7.50 (d, J=12.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 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/z 345.3 (M+H)+.

Example 9.

Step 1. 2,6-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (9a).

To a solution of 4-bromo-2,6-difluoroaniline (10 g, 48 mmol) in 1,4-dioxane (100 mL) were added bis(pinacolato)diboron (12.8 g, 50.4 mmol), _CH3COOK (14.1 g, 144 mmol) and Pd(dppf) _Cl2 (1.0 g, 2.40 mmol). The mixture was stirred at 90 °C under N2 for 2 h, cooled to rt, concentrated and purified by FCC (PE:EA=10:1) to give compound 9a as a yellow solid.

Step 2. 3,5-Difluoro-3'-(methoxy^3)-[1,G-biphenyl]-4-amine (9b).

To a solution of compound 9a (4.5 g, 13.3 mmol) in 1,4-dioxane (50 mL) and _H2O (5 mL) were added 1-bromo3-(methoxy-3)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 rt, 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) ⁺ .

Step 3. 2-((3,5-Difluoro-3'-(methoxy^3)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1carboxylic acid (9).

To a solution of compound 9b (3.40 g, 14.3 mmol) in DCM (20 mL) was added 1-cyclopentene-1,2

- 29 049475 dicarboxylic anhydride (1.90 g, 14.3 mmol) and then the mixture was stirred at RT for 2 h. The mixture was filtered and the filter cake was washed with MeCN. The solid was dried in vacuo to give compound 9 as a white solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 12.95 (br s, 1H), 10.13 (s, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.32-7.28 (m, 2H), 6.99 (dd, J=1.8, 8.3 Hz, 1H), 2.81-2.79 (m, 2H), 2.69-2.66 (m, 2H), 1.97-1.89 (m, 2H). LCMS (ESI): m/z 377.3 (M+H)+.

Example 10. 4-((3,5-Difluoro-3'-(methoxy^3)-[1,G-biphenyl]-4-yl)carbamoyl)-2,5-dihydrothiophene-3-carboxylic acid (10).

The reaction of 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) similarly to that described above gave the desired molecule 10. ¹ HNMR (400 MHz, DMSO-d6) δ 13.01 (br s, 1H), 10.20 (s, 1H), 7.54 (d, J=9.2 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.32-2.28 (m, 2H), 6.99 (dd, J=2.4, 8.0 Hz, 1H), 4.15-4.11 (m, 2H), 4.03-4.00 (m, 2H). LCMS (ESI): m/z 395.2 (M+H)+.

Example 11.

Step 1. 4,6-Dihydro-1H,3H-furo[3,4-c]furan-1,3-dione.

(11 a)

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 then the mixture was stirred at 110 °C for 4 h, cooled to rt 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)+.

Step 2. 4-((3,5-Difluoro-3'-(methoxy-3)-[1,G-biphenyl]-4-yl)carbamoyl)-2,5-dihydrofuran-3-carboxylic acid (11).

Compound 11a was reacted similarly to that described above to afford the desired molecule 11 as a white solid. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 10.89 (br s, 1H), 7.58 (d, J=9.5 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H), 7.33-2.28 (m, 2H), 6.99 (dd, J=2.3, 8.3 Hz, 1H), 4.97 (t, J=5.3 Hz, 2H), 4.89 (t, J=5.0 Hz, 2H), 3.43 (br s, 1H). LCMS (ESI): m/z 379.2 (M+H)+.

Example 12 (reverse combination method).

Step 1. 3-Fluoro-5-(3-(methoxy^3)phenyl)pyridin-2-amine (12a).

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) were added (3-(methoxy-^3)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 rt. 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)+.

Step 2. 2-((3-Fluoro-5-(3-(methoxy^3)phenyl)pyridin-2-yl)carbamoyl)cyclopent-1-ene-1carboxylic acid (12).

- 30 049475

The reaction of compound 12a as described in Example 6, step 4, gave the desired molecule 12.1HNMR (500 MHz, MeOD) δ 8.50 (br s, 1H), 7.99 (d, J=9.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.25-7.21 (m, 2H), 6.99 (dd, J=8.5, 2.0 Hz, 1H), 2.97-2.93 (m, 2H), 2.86-2.83 (m, 2H), 2.03-1.97 (m, 2H). LCMS (ESI): m/z 360.1 (M+H)+.

Examples 12/1-12/6.

The following examples were prepared in a manner similar to that described above in Example 12, using the appropriate building blocks given below.

No. structural block structure analytic data 12/1 (D. Bg T Ϊ σ> ZI O=( t X__, °л o 'H-NMR (500 MHz, DMSO-76) δ 13.11 (brs, 1H), 10.11 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.96 (t, J=l.8 Hz, 1H), 6.90 (dd, J=8.0, 2.0 Hz, 1H), 2.96-2.87 (m, 4H), 2.83-2.80 (m, 2H), 2.72-2.68 (m, 2H), 2.00-1.86 (m, 4H). LCMS (ESI): m/z 381.3 (M+H) ⁺

- 31 049475

12/2 Vy ^Br OCD ₃ □η ηυό θγ 0 ^N |]^ /AA' _N 'AA \Α ⁿ Ή-NMR (400 MHz, CD3OD) δ 8.65 (d, J=l,6 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.98 (d, J=9.6 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.08-6.99 (m, 3H), 2.76 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.4 Hz, 2H), 2.03-1.95 (m, 2H). LCMS (ESI): m/z 381.2 (M+H) ⁺ 12/3 N'U X U OCD _{3 0} , _he χΧχό-ΐ Tl u__/ n Ή-NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.69 (s, 1H), 8.56 (d, J=4.0 Hz, 1H), 7.97-7.88 (m, 3H), 7.49 (t, J=8.0 Hz, 1H), 7.10-7.06 (m, 3H), 2.90 (br s, 2H), 2.73 (br s, 2H), 2.021.96 (m, 2H). LCMS (ESI): m/z 392.2 (M+H) ⁺ 12/4 Ck-Br x g OCD _{3 o} ph CX Xj A/ n^- \__/ H Ή-NMR (500 MHz, DMSO-d6) δ 13.11 (brs, 1H), 10.49 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.57-7.43 (m, 4H), 7.05-7.00 (m, 3H), 2.92-2.89 (m, 2H), 2.75-2.71 (m, 2H), 2.00-1.93 (m, 2H). LCMS (ESI): m/z 391.2 (M+H) ⁺ 12/5 tu ^H = ^N qr (P1) OCD ₃ OCD ₃ •uh/ A ^H OCD ₃ Ή-NMR (400 MHz, DMSO-d6) δ 13.48 (br s, 1H), 9.92 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.27 (d, J=6.4 Hz, 1H), 7.21-7.16 (m, 2H), 6.98 (dd, J=2.2, 8.2 Hz, 1H), 2.842.80 (m, 2H), 2.73-2.68 (m, 2H), 1.931.85 (m, 2H). LCMS (ESI): m/z 392.1 (M+H) ⁺ 12/6 XJ H ₂ N^Y CN OCD ₃ Ayr ⁰ ' ^H CN LCMS (ESI): m/z 384.1 (M+H) ⁺

Example 13.

Step 1. Di-tert-buty.l-('3,5-difluoro-3'-('methoxy^3)-[1,1'-bipheni.l|-4-i.l)iminodicarbonate (13a).

- 32 049475

By treating compound 9b with di-tert-butyl dicarbonate in DMF and using DMAP as a catalyst in a similar manner as described in WO2008/018426, the title compound 13a was obtained.

Step 2. tert-Butyl (3,5-difluoro-3'-(methoxy-3)-[1,G-biphenyl]-4-yl)carbamate (13b).

By treating compound 13a with trifluoroacetic acid in _CH2Cl2 at 0°C similarly to that described in Chem. Commun. 2018;54:4589 _, the desired compound 13b was obtained.

Step 3. tert-Butyl-(3,5-difluoro-3'-(methoxy^3)-[1,G-biphenyl]-4-yl)(methyl)carbamate (13c).

OCD ₃

BocN O Zs) ¹ F

By treating compound 13b with lithium bis(trimethylsilyl)amide and MeI similarly as described in J. Am. Chem. Soc. 2002; 124:8206, the title compound 13c was obtained.

Step 4. 3,5-Difluoro-3'-(methoxy^3)-N-methyl-[1,N-biphenyl]-4-amine (13d).

OCD ₃

Fx^xjO^ _hn AJ (13d)

F

By removing the protecting group from compound 13c with 4 N HCl in dioxane, the desired compound 13d was obtained after treatment in an alkaline medium.

Step 5. 2-((3,5-Difluoro-3'-(methoxy-3)-[1,G-biphenyl]-4-yl)(methyl)carbamoyl)cyclopent-1-ene-1carboxylic acid (13).

By coupling compound 13d with 1-cyclopentene-1,2-dicarboxylic anhydride in a manner similar to that described above, the desired compound 13 was obtained. LCMS (ESI): m/z 391.1 (M+H)+.

Example 14.

Step 1. Methyl (3,5-difluoro-3'-(methoxy-3)-[1,G-biphenyl]-4-yl)glycinate (14a).

By treating compound 9b with methyl 2-bromoacetate, the desired compound 14a can be obtained.

Step 2. 2-((3,5-Difluoro-3'-(methoxy^3)-[1,G-biphenyl]-4-yl)(2-methoxy-2-oxoethyl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (14).

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By coupling compound 14a with 1-cyclopentene-1,2-dicarboxylic anhydride in a manner similar to that described above, the desired compound 14 can be obtained.

Example 15. 2-((3,5-Difluoro-3'-(methoxyD3)-[1,1'-biphenyl]-4-yl)(2-hydroxyethyl)carbamoyl)cyclopent-1-ene-1-carboxylic acid (15).

By reducing compound 14a, for example, with lithium borohydride, the desired compound 15 can be obtained.

Example 99. 2-((3-Fluoro-3'-(methoxyD3)-[1,1'-biphenyl]-4-yl)carbamoyl)cyclopent-1-ene-1-carboxylic-3,3,4,4,5,5D6 acid.

By bis-esterification of hexanedioic acid (CAS number: 52089-65-3) with MeOH, dimethyl hexanedioate D6 can be obtained. This bis-ester can be cyclized as described in WO2009/140279 to give methyl 2-hydroxycyclopent-1-ene-1-carboxylate-3,3,4,4,5,5D6, from which the corresponding triflate can be obtained. By palladium-catalyzed reaction with sodium formate as described in Heterocycles 2009; 77:179, cyclopent-1-ene-1,2-dicarboxylic monoacid can be obtained, which can be coupled with compound 1b to give the desired molecule.

Examples 100/1-100/13.

The compounds of the following examples can be prepared in a similar manner to that described in the examples above, using the appropriate building blocks given below.

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No. structural block structure 100/1 _O .CD ₃ □νχ,ο t X D CAS number: 1109219-40-0 OCD ₃ ^D 'X ⁴ V' ^D _n .on XI X ίι Γιι ^D AAV ^d \ J η I ' F 100/2 D LI Η ₂ Ν'η^Ό F CAS number; 646502-91-2 “4 Q \___ o / A °dA /—X ^Q Q 5—( Q ZT o =/ o 100/3 D X T F CAS number: 646502-91-2 OCD ₃ 100/4 ^F x^X.Br X g H ₂ NX^ F CAS number: 67567-26-4 OCD ₃ ^d xAy- ^d ΛΛν-U ^d \ I η I O'- ³ F

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100/5 .Вг I Г Η ₂ Ν'η ^/ F CAS number: 67567-26-4 OCD ₃ O; s ,OH 0 0^4. D LJ Jd N H F 100/6 F F OCD D LI H ₂ Nyx O- OH 0. F _v . π jf F CAS number: 1998-66-9 b i\r H F II F D 100/7 F % J-^Rr F D OCD 3 ,D T G HaN'y^'F 0 _Z OH 0 F.._. if F CAS number: 1998-66-9 s ZT ⁴ N ^X H F II ' T D 100/8 CD ₃ D CD ₃ ° D D T g Ό Oi ,OH O |Γ X D D CAS number: 1643544-03-9 IT H F JJ D 100/9 CD ₃ CD ₃ O. I ] 0 z ^OH 0 J CAS number: 892397-56-7 'N' H F 100/10 CD ₃ D CkJ-^D CD _a □ D X 1 Br y-'T 0= ,OH 0 4 ¢1 D D CAS number: 1643544-03-9 H Ji D 100/11 CD ₃ CD ₃ °V T J Br^'''' O; ,OH O F. π E CAS number: 892397-56-7 0 I< H F 100/12 5 0-0 \__/ σ о о 0. _Z OH ABOUT R F CD ₃ P D 3 ,D 'D D CAS number: 1643544-03-9 in H F II ^F D 100/13 CD ₃ T ] Br^=>^ 0 OH 0 F-, ς CD ₃ r E CAS number: 892397-56-7 u F

Examples 101/1-101/16.

The compounds of the following examples can be prepared in a similar manner to that described in the examples above, using the appropriate building blocks given below.

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No. structural block structure 101/1 R.<x.Br Σ G F CAS number: 67567-26-4 Q o \=\ □ /=\ o=( 0 101/2 alkylation of compound 2a /К °<г° □ /=\ St. o=( V.O. !G p 0 101/3 alkylation of compound 2a rt Q O O CM 1 Q \___ Q / \ ⁰ / \ ⁰ a /=\ l/ zi o=( fT tn 0 101/4 OCD2CD3 ..Ό CAS number; 1185312-30-4 OCD2CD3 oLuU ¹ 101/5 alkylation of compound 2a nQ 0 ^=X a /=\ Ο ΖΞΕ Oh =( %Zo if ϋ} ABOUT 101/6 connection 6b o У° ξγζ σ ( O _h \=/ O

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101/7 1-bromo-3-(methoxy-73)benzene ABOUT )=o ΞΖ O -nXX Xa-o \_/ c '- O w 101/8 1-bromo-3-(methoxy-73)benzene OCD ₃ n X, J V ^H J 101/9 alkylation of compound 2a π О О \=\ ^ъ о /=\ ΖΙ О=( θΧ<ι // с/у О 101/10 „.CD, o ³ IT □ CAS number: 1109219-40-0 OCD ₃ f ΥΤ° \A _n XA d \J n ι 101/11 connection 5 a _o -CDF ₂ 101/12 alkylation of compound 2a ο ω and Ιγο )=Ο ο—ςΐ—(□ \=< ο Kommersant? Ρΰ 101/13 CD ₃ D XI Br^y^DD CAS number: 1043544-03-9 ρ ΙΧίο χ° =ΕΖ Π ^=( 0-0 \__/σ >---( ω ο—Ο Ο □ 101/14 CD ₃ I 5 Br CAS number: 892397-56-7 f ο )=ο ιζ -π \=( 0-0 \__/Ο \/

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Example 200. Assay for inhibition of human DHODH.

In vitro inhibition of hDHODH was studied using an N-terminal truncated recombinant hDHODH enzyme as described in J. Med. Chem. 2006; 49:1239. Briefly, the concentration of hDHODH was adjusted to yield an average slope of approximately 0.2 AU/min as a positive control (i.e., no inhibitor). The standard assay mixture contained 60 μM 2,6-dichloroindophenol, 50 μM decylubiquinone, and 100 μM dihydroorotate. hDHODH enzyme was added without and with compounds at least at six different concentrations 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 initiated by adding dihydroorotate and the absorbance was measured at 600 nm for 2 min. To determine the IC ₅₀ values, each data point was recorded in triplicate. To determine the inhibition constant _Ki, the KM values for DHO and decylubiquinone were determined. The compounds were then serially diluted in DMSO based on their IC ₅₀ values. The following dilutions were prepared: 0xIC ₅₀ , ¹ /4xIC50, ¹ /2xIC ₅₀ , 1xIC ₅₀ , 2xIC ₅₀ , 4xIC ₅₀ . In addition, the substrate concentration for DHO and decylubiquinone was varied ¹ /4xKM, ¹ /2xK _M , 1xK _M , 2xK _M , 4xK _M in further dilution series with separate measurement of DHO and decylubiquinone. All data were recorded in duplicate.

The K _i values for the example compounds proposed in the present invention ranged from the non-deuterated matched pair (example C26 in WO2003/006425):

ABOUT''

(C26)

Example No. K _; (DHO) [nM] Ki (decyl ubiquinone) [nM] C26 592 245 1 521 234 2 524 273 4 3.7 1,2 5 1820 839 6 570 257

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IC ₅₀ ranges for the human DHODH assay described in the present invention: +++:

<100 nM; ++: 100 nM to <1 μM; +: 1 μM to <10 μM; 0: >10 μM.

As shown above, the inhibition of DHODH by the deuterated analogues (i.e. 1, 2 and 6) compared to the undeuterated matched pair (example C26 in WO2003/006425) was not altered. This is also true for example 4, for which an IC ₅₀ value of 7 nM is reported for the undeuterated matched pair (Bioorg. Med. Chem. Lett. 2005; 15:4854).

Example 201. Stability in microsomes.

Compounds of Example 1 and 2 and the non-deuterated matched pair (Example C26 in WO2003/006425) were incubated with three different lots of pooled male rat liver microsomes (RLM) and human liver microsomes (HLM), respectively, for 60 min. Metabolite conversion was monitored by HPLC-MS/MS. Verapamil served as a positive control. Intrinsic clearance was calculated from the measured values for the remaining compound (in duplicate) at 0, 10, 30 and 60 min. The values for 60 min are as follows:_________________

Clint (µl/min/mg protein) batch of rat liver microsomes a batch of human liver microsomes 4085002 (Corning) 9078001 (Coming) 1910100 (Xenotech) 38296 Mixed Floors, 150 Donor Pool (Corning) 1210270 male, pool for 10 donors (Xenotech) 1210079 women, pool for 10 donors (Xenotech) Example C26 8.48 9.81 11.23 2.27 12.61 6.58 Example 1 13.45 8.43 9.75 0.96 7.69 5.02 Example 2 3.17 5.48 7.77 0.74 7.67 5.80 Verapamil 200.4 222.9 238.2 173.5 158.8 124,0

As follows, for example, from Example 1 and 2, by deuteration, its own clearance in microsomes

- 40 049475 rat and human for the compounds of the present invention can be reduced compared to the non-deuterated matched pair. The reduced intrinsic clearance is advantageous because it increases the residence time of the drug in the body.

The compounds of Examples 1 and 2 and the non-deuterated matched pair (Example C26 in WO2003/006425) were incubated with the same three different lots of rat liver microsomes (RLM) and human liver microsomes (HLM) for 60 min (twice, i.e. 1st and 2nd dimension). The conversion of the parent compound to the demethylated metabolite was monitored and quantified by HPLC-MS/MS (peak areas) and the percentage of demethylated (deMe) metabolite compared to the parent compound (% of parent compound) was obtained. From these data, the mean values and standard deviations (SD) were calculated.

The compound under study RLM Party Initial compound (peak area) 0 min de-Me metabolite (peak area) 60 min In % of the original compound content Average % for the original compound SD Example C26 4085002 1st 70407854 6464897 9.18 9.6 2,1 2nd 66458354 5565295 8.37 9078001 1st 76921121 5826014 7.57 2nd 75265781 5834629 7.75 1910100 1st 77652247 9489759 12.22 2nd 73068386 9306164 12.74 Example 1 4085002 1st 68383402 3802248 5.56 6.2 2,5 2nd 103585969 3438750 3.32 9078001 1st 74865289 3583020 4.79 2nd 84814771 3520018 4.15 1910100 1st 71968334 7056012 9.80 2nd 73004097 6959900 9.53 Example 2 4085002 1st 67670601 3329296 4.92 6.2 1,8 2nd 60106721 3196275 5.32 9078001 1st 65611921 3100045 4.72 2nd 64106098 3214860 5.01 1910100 1st 74941907 6492165 8.66 2nd 72219324 6353644 8.80

As follows, for example, from Example 1 and 2, by selective deuteration the cleavage of methoxy groups from the hydroxyl-containing metabolite in rat microsomes can be reduced compared to the non-deuterated matched pair (Example C26).

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The compound under study HLM Party Initial compound (peak area) 0 min de-Me metabolite (peak area) 60 min In % of the original compound content Average % for the original compound SD Example C26 38296 1st 71669595 5684466 7.93 6.3 1,3 2nd 72276431 5453339 7.55 1210270 1st 63777868 4351799 6.82 2nd 68505784 4047804 5.91 1210079 1st 62073486 2823678 4.55 2nd 58533090 2831883 4.84 Example 1 38296 1st 70932995 3066405 4.32 3.6 0,7 2nd 71680594 2853522 3.98 1210270 1st 60462120 2365635 3.91 2nd 55159734 2301305 4.17 1210079 1st 54904219 1444490 2.63 2nd 58389962 1583025 2.71 Example 2 38296 1st 70019222 2766098 3.95 3.2 0,6 2nd 70286951 2628411 3.74 1210270 1st 56288300 1908629 3.39 2nd 56222644 1965386 3.50 1210079 1st 57353703 1316183 2.29 2nd 55909814 1331182 2.38

As follows, for example, from Example 1 and 2, by selective deuteration the cleavage of methoxy groups from a hydroxyl-containing metabolite in human microsomes can be reduced compared to a non-deuterated matched pair (Example C26).

Example 202. Pharmacokinetics in rats.

The pharmacokinetics of the deuterated compounds of the present invention were studied in 3 male and 3 female rats (Han Wistar, 8 weeks old) after oral or intravenous administration of the oral bioavailability cassettes. The rats were catheterized in the jugular vein (2-3 days before blood collection). At each indicated time point (0, 1, 2, 4, 8 and 24 h after administration), 100 μl of blood were collected in tubes with Li-heparin, stored on ice until centrifugation (10 min at 3000g, 4°C) and 45 min after collection, plasma was obtained, frozen at -20°C and stored at this temperature until processing for LC-MS analysis. The following data were obtained:

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Floor Males Females The compound under study Comparative example C26 Route of administration ro iv RO iv Carrier PEG 300 Dose (mg/kg) 5 1 5 1 Volume (ml/kg) 5 2 5 2 Stakh (ng/ml) 14936,0 - 21334,3 - CO (ng/ml) - 5787 - 8130 tmax (h) 2.0 - 2.0 - Cz (ng/ml) 1540 421 3620 939 tz( ₄ ) 24 24 24 24 tl/2z (h) 6.4 7.3 9.1 9.7 AUC0-tz(Hrx h/ml) 200498 43239 253138 68625 AiC0-co(ng><h/ml) 205788 47852 297424 82937

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Vz/f (ml/kg) 7 9 16 16 CL/f (ml/(h*kg)) 223 225 222 168 %AUCextra 25 22 17 12 Bioavailability (%) 92.7 - 73.8 -

Floor Males Females The compound under study Example 1 Route of administration ro iv RO iv Carrier PEG 300 Dose (mg/kg) 5 1 5 1 Volume (ml/kg) 5 2 5 2 Stakh (ng/ml) 14588 - 19697 - CO (ng/ml) - 5541 - 7012 tmax (h) 2.0 - 2.0 - Cz (ng/ml) 1525 437 3536 943 tz( ₄ ) 24 24 24 24 tl/2z (h) 6,6 7.9 9.1 9.9 AUC0-tz(Hrx h/ml) 183255 42623 249133 66205 AiC0-co(ng><h/ml) 209643 47879 291424 80697 Vz/f (ml/kg) 8 10 16 17 CL/f (ml/(hxkg)) 229 242 226 176 %AUCextra 24 22 17 13 Bioavailability (%) 86,0 - 75.3 - Floor Males Females The compound under study Example 2 Route of administration RO iv RO iv Carrier PEG 300 Dose (mg/kg) 5 1 5 1 Volume (ml/kg) 5 2 5 2 Stakh (ng/ml) 16050 - 21276 - CO (ng/ml) - 5309 - 7983 tmax (h) 2.0 - 2.0 - Cz (ng/ml) 1657 422 3892 915 tz(n) 24 24 24 24

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tl/2z (h) 6,6 7.6 9.3 10,0 AUC0-tz(Hrx h/ml) 201953 40393 268689 64698 AiC0-oo(ng><h/ml) 232828 45215 319543 79125 Vz/f (ml/kg) 8 10 17 17 CL/f (ml/(hxkg)) 206 247 210 181 %AUCextra 22 23 16 13 Bioavailability (%) 100,0 - 83.1 -

The non-deuterated compound vidofludimus itself (comparative example C26) already had very good bioavailability. By selective deuteration (example 2) this bioavailability can be further improved, which can be attributed to reduced metabolism.

Example 203. Pharmacokinetics in mice.

The pharmacokinetics of the compounds of the present invention were studied in 3 male and 3 female mice (C57BL/6J, 8 weeks old) after oral administration of the cassettes. The dose was 5 mg/kg, the administered volume was 5 ml/kg and the diluent was 5% Solutol, 95% NaCl solution (at a concentration of physiological saline 0.9%). At each indicated time point (0, 0.25, 0.5, 1, 2, 4, 8 h after administration), 20 μl of whole blood was collected from the tail vein into tubes with Li-heparin, frozen with solid carbon dioxide no later than 1-2 min after collection and stored at -20 °C until processing for LC-MS analysis. The following data were obtained:

Example No. with ^shah tl/2 AUC Example C26 789 ng/ml 9,745 ng/ml s? 1.7 h 9 1.7 h <3 1620 nghch/ml 9 1970 nghch/ml Example 1 4110 ng/ml 5 3440 ng/ml L,7 h ? 1,6 h 3 5110 ngkhch/ml $ 5740 ngkhch/ml Abbreviations: ^? = males, $ = females, C _max = peak plasma concentration, ΐ, ₂ = half-life, AUC = area under the curve (integral of concentration-time curve from 0 to 8 h)

In this case, the non-deuterated compound of comparative example C26 had lower C _max and AUC values, which can be dramatically improved by selective deuteration (example 1).

Example 204. Antiviral Activity against SARS-CoV-2. The viral replication (YFP) and cell viability assay described generally in Pathogens 2021; 10:1076 was used using the compounds of the present invention and the following results were obtained:

Example No. EC50 range Range CC50 1 +++ >100

-

Claims (9)

1/2 +++ >100 1/3 +++ >100 1/4 +++ >100 1/6 +++ >100 1/7 +++ >100 1/8 + >100 1/9 + >100 1/10 ++ >100 3 +++ >100 8 + >100 9 ++ >100 10 ++ >100 And 0 >100 12 +++ 76 12/1 +++ >100 12/3 + >100 12/4 ++ >100 The EC50 ranges for the SARS-CoV-2 assay described in the present invention are: +++: <10 μM; ++: 10 μM to <25 μM; +: 25 μM to <50 μM; 0: >50 μM. Example 205. Synergistic antiviral activity against SARS-CoV-2 using a nucleoside analogue. The synergistic potential of the compound of Example 9 together with the nucleoside analogue EIDD-1931 (CAS: 3258-02-4) was evaluated. The methodology for combinatorial drug evaluation using the viral replication inhibition assay is published in Pathogens 2021; 10:1076. Caco-2 cells were grown 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 the drug combination starting at _4xEC50 concentrations of one of the compounds. Viral replication was determined at 30 h post infection (p.i.) by quantitative fluorescence detection of virus-induced YFP expression in fixed cells. Viral replication inhibition profiles based on expression of the virus-encoded YFP reporter are shown as a bar graph of quadruplicate determinations (mean ± SD). Combinatorial drug evaluation was performed using the CompuSyn algorithm as described in Int. J. Mol. Sci. 2021;22:575. A typical experiment is shown in Fig. 1. The compound of Example 9 has a synergistic antiviral effect on SARS-CoV-2 when combined with the nucleoside analogue EIDD-1931 (CAS: 3258-02-4). CLAUSE OF INVENTION 1. Compound of formula (I): -NR2B selected from - 46 049475 and where the -NR ² residue in ring B is in the 1,4-orientation relative to ring C, Ь©-х is selected from R ¹ means H; R ² means H; provided that at least one hydrogen in A, B, C, ^R2 and/or X is replaced by deuterium; provided that the degree of incorporation of deuterium in each substituent designated as deuterium is not less than 52.5%. 2. A compound of formula (I) according to claim 1, wherein -NR2B or 2, where selected from 3. The compound of formula (I) according to claim 1 is selected from selected - 47 049475 selected from 4. A compound of formula (I) according to claim 1, which is selected from or a pharmaceutically acceptable salt thereof. 5. Use of a compound according to any of the preceding paragraphs as a medicinal product. 6. Use of a compound according to any one of claims 1 to 4 for the prevention and/or treatment of diseases, disorders or pathological conditions treatable with DHODH inhibitors, wherein the disease, disorder or pathological condition is selected from the group consisting of rheumatism, acute immunological disorders, autoimmune diseases, diseases caused by the proliferation of malignant cells, inflammatory diseases, diseases caused in humans and animals by protozoan infections, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy. 7. The use according to claim 6, wherein the disease, disorder or pathological condition is selected from the group consisting of graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, COVID-19, influenza, ulcerative colitis, Crohn's disease, primary sclerosing cholangitis and psoriasis. 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient. 9. The pharmaceutical composition according to claim 8, further comprising one or more additional therapeutic agents selected from antiviral agents, anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics and suitable mixtures thereof. -