Deuterated aminothiazole compounds as antiviral compounds

Abstract

The present invention relates to novel deuterated compounds of formula (I), to processes for their preparation and to their use as medicines, in particular as antiviral agents. [Formula 1] TIFF2023552274000073.tif36170

Description

[Technical Field]

[0001] The present invention relates to novel deuterated helicase primase inhibitors, methods for preparing them, and their use as pharmaceuticals, particularly as antiviral agents. [Background technology]

[0002] [Introduction] Viral infections have plagued humankind since ancient times, causing skin and mucous membrane infections such as oral herpes and genital herpes. Disease symptoms often interfere with daily activities, and sometimes HSV infection can be life-threatening (encephalitis) or cause vision loss (keratitis), particularly in immunocompromised populations such as newborns, the elderly, transplant recipients, cancer patients, or those with hereditary immunodeficiency syndromes or diseases. After infection, alphaherpesviridae survive in a latent state within the host's neurons, periodically reactivating and often causing significant psychosocial distress to the patient. Currently, there is no cure.

[0003] To date, vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators, and small molecule drugs with specific or nonspecific mechanisms of action have lacked either the efficacy or the necessary safety profile to replace the nucleoside drugs acyclovir, valacyclovir, and famciclovir as first-line treatment.

[0004] Known aminothiazoles (e.g., pritelivir) are the most promising drugs in development today. These antivirals act by inhibiting herpesvirus helicase primase and show lower resistance rates in vitro and superior efficacy in animal models compared to nucleoside drugs, but their development is hindered by off-target carbonic anhydrase activity and abnormal pharmacokinetic profiles.

[0005] There is a need to develop novel antiviral therapies targeting HSV-1 and / or HSV-2. In particular, there is a need to develop antiviral drugs with improved pharmacokinetic properties. Covalent CH bonds are weaker than otherwise identical CD bonds due to dynamic isotope effects. Cleavage of CH bonds is a common feature of drug metabolism, and cleavage of similar CD bonds may be more difficult, thus slowing the metabolic rate. Substituting H with D in small molecules can significantly reduce metabolism, beneficially altering the biological effects of the drug. Substitution may also have the effect of reducing toxicity by reducing the formation of toxic metabolites (Non-Patent Literature 1). Deuterated analogs share beneficial mechanisms of action, but are expected to be metabolized more slowly and exhibit less inter-patient variability compared to non-deuterated matched pairs. Differentiated pharmacokinetic profiles are generally considered to enable potentially improved efficacy, less frequent dosing, improved tolerability, reduced inter-patient variability in drug metabolism, and reduced drug-drug interactions.

[0006] This patent application discloses a novel antiviral deuterated aminothiazole compound having a more suitable pharmacokinetic profile (e.g., due to improved microsomal stability) for use as a pharmaceutical agent.

[0007] [Conventional technology] [ka] Aminothiazoles of general formula (A) for use as antiviral compounds are known from the prior art.

[0008] In particular, Patent Document 1 discloses an aminothiazole (A) in which X is a sulfonamide moiety.

[0009] Patent Document 2 describes an aminothiazole of formula (A) in which X is not a primary sulfonamide, but X can be selected from sulfanimine, sulfinimidoamide, sulfoximine, or sulfoxiimidoamide.

[0010] Patent document 3 describes the enantiomers (enantiomers) of the compound described in Patent document 2.

[0011] Patent document 4 describes a novel use of aminothiazole compounds according to Patent documents 2 and 3 in combination therapy with oncolytic viruses for the treatment of cancer.

[0012] None of these prior art documents refer to any general isotope or deuterium in particular, nor to any deuterated compound having the structure of formula (I) as described herein.

[0013] Non-patent document 2 is a chapter from the book series "Advances in Drug Research," and describes the effects of deuterium isotopes on drug metabolism, stating that replacing deuterium with one or more hydrogen atoms results in a small structural change with negligible steric effects. The document further states in Chapter 8, "Conclusion," that the scope of use of deuterium isotope effects in drug design is very limited, and that no drugs containing deuterium in their molecules are on the market. The authors of the document also conclude that drugs intended for human use incur additional costs associated with preclinical toxicology and clinical trials, and that drug regulatory authorities are highly unlikely to consider deuterated drugs designed to have significantly different biological activity from their protium-based forms as anything other than novel drugs.

[0014] The use of deuterated aminothiazole compounds and their antiviral properties is not described. [Prior art documents] [Patent Documents]

[0015] [Patent Document 1] WO2001 / 047904 [Patent Document 2] WO2017 / 174640 [Patent Document 3] WO2019 / 068817 [Patent Document 4] WO2020 / 109389 [Non-patent literature]

[0016] [Non-Patent Document 1] J. Med. Chem. 2019;62:5276 [Non-Patent Document 2] Foster AB “Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design”; Advances in Drug Research, Vol. 14, pages 1 to 40, 1985 [Non-Patent Document 3] Foster in Trends Pharmacol. Sci. 1984:5;524 [Non-Patent Document 4] Comp. Biochem. Physiol. 1998;119A:725. [Non-Patent Document 5] A. Michelotti and M. Roche, Synthesis 2019;51:1319 [Non-Patent Document 6] J. Atzrodt et al. Angew. Chem. Int. Ed. 2018;57:3022 [Modes for carrying out the invention]

[0017] The present invention relates to an aminothiazole derivative of general formula (I): [ka] or their enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts, where in formula (I), X is selected from the following two formulas: [ka] Or X is a group represented by the following formula,

Chemical formula

[0018] In this patent application, "C 1-6 "-alkyl" refers to a saturated alkyl chain having 1 to 6 carbon atoms, which may be a straight or branched chain. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and hexyl. Therefore, "C 1-4 The "-alkyl" group represents a saturated alkyl chain having 1, 2, 3, or 4 carbon atoms, and may be a straight or branched chain. 1-4 -alkyl is preferred, and C such as methyl, ethyl, propyl and isopropyl is preferred. 1-3 Alkyl is more preferred, and methyl is most preferred.

[0019] "Fluoro-C 1-4 -alkyl" or "Fluoro-C 3-4 -Cycloalkyl or O-Fluoro-C 1-4 The term "-alkyl" means that one or more hydrogen atoms in the alkyl chain or ring are replaced by one or more fluoro atoms. A preferred example is the formation of the -CF3 group.

[0020] C 3-4 -Cycloalkyl group refers to a cyclopropyl or cyclobutyl group. Cyclopropyl is preferred.

[0021] C 1-4 - The acyl group (also called "alkanoyl") contains a double-bonded oxygen atom [R-(C=O)-]. 1-4 - This signifies an alkyl group, where R represents H or a C1-C3-alkyl group.

[0022] The halogen is selected from fluorine, chlorine, bromine, and iodine, with fluorine and chlorine being preferred, and fluorine being the most preferred.

[0023] In the sense of this specification, “deuterated,” “deuterium-labeled,” “deuterium-substituted,” or “deuterated” means that one or more hydrogen atoms in the compound of formula (I) are deuterium (represented by “D”). 2 This means that it will be replaced by H).

[0024] The compound of formula (I) contains 1 to n deuterium atoms that substitute for 1 to n hydrogen atoms bonded to a carbon atom, where n is the number of hydrogen atoms in the molecule. Surprisingly, such deuterated aminothiazole compounds have been found to exhibit increased resistance to metabolism when administered to mammals, such as humans, compared to their respective non-deuterated compounds, and are therefore useful in increasing the half-life of the compound of formula (I). See, for example, Non-Patent Document 3. Such deuterated aminothiazole compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens are substituted with deuterium (see Experiments section for details).

[0025] The deuterium-labeled or substituted therapeutic compounds disclosed in this patent application have been found to exhibit surprisingly improved DMPK (drug metabolism and pharmacokinetic) properties related to absorption, distribution, metabolism, and excretion (ADME). Deuterium substitution has been found to result in specific therapeutic benefits as a result of higher metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index.

[0026] The concentration of deuterium may be defined by the isotopic enrichment factor. In the compounds disclosed in this patent application, any atom not specifically designated as a particular isotope is meant to represent any stable or radioactive isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition (approximately 99.98% hydrogen).

[0027] Therefore, in the compounds disclosed in this patent application, any atom specifically designated as deuterium (D) means that it represents deuterium having an isotopic purity of at least 50%, preferably at least 95%, and more preferably at least 99%.

[0028] The proportion of deuterium incorporation can be determined by quantitative analysis using numerous conventional methods such as mass spectrometry (peak area), or by internal standards or other deuterated materials in the compound. 1 Compared to the signal from the H signal, the remaining specific deuterated site 1 This can be obtained by quantifying the H-NMR signal.

[0029] It will be recognized that some variation in the natural isotopic abundances will occur in synthesized compounds, depending on the origin of the chemicals used in the synthesis. Therefore, preparations of non-deuterated analogs of the compounds of the present invention essentially contain small amounts of deuterated isotope substitutions. The concentrations of naturally abundant and stable hydrogen and carbon isotopes, despite this variation, are small and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Non-Patent Document 4.

[0030] The term "isotope enrichment factor" at a particular location typically occupied by hydrogen refers to the ratio between the abundance of deuterium at that location and its natural abundance at that location. For example, an isotope enrichment factor of 3500 means that the amount of deuterium at a particular location is 3500 times its natural abundance, or that 52.5% of a compound contains deuterium at that location (i.e., 52.5% deuterium uptake at a given location). The abundance of deuterium in the Earth's oceans is approximately 1 atom for every 6500 hydrogen atoms (about 154 ppm). Therefore, deuterium accounts for about 0.015% (0.030% by weight) of all natural hydrogen atoms in the Earth's oceans, and its abundance varies slightly from one type of natural water to another.

[0031] The deuterated compounds according to the disclosure of this patent application are preferably characterized by an isotopic enrichment factor of at least 6300 or a degree of deuteration of at least 95%, more preferably characterized by an isotopic enrichment factor of at least 6500 or a degree of deuteration of at least 98%.

[0032] Any formula or structure shown herein is also intended to represent deuterated compounds containing additional isotopically labeled atoms. Examples of additional isotopes that can be incorporated into the compounds according to the disclosure of this patent application include isotopes of hydrogen as well as isotopes of carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, but not limited to, 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. The disclosure of this patent application 3 H, 13 C and 14 C, further includes various isotopically labeled compounds incorporated with radioisotopes such as these. Such isotopically labeled compounds can be useful in metabolic studies, kinetic studies, detection or imaging techniques, for example, positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or radioactive treatment of patients. The isotopically labeled compounds and their prodrugs according to the disclosure of this patent application can generally be prepared by using readily available isotopically labeled reagents in place of non-isotopically labeled reagents and by carrying out the procedures disclosed in the schemes or examples and preparations described below.

[0033] If the list of alternative substituents includes members that cannot be used to substitute a particular group for their valence requirements or for other reasons, it will be understood by those skilled in the art that the list is intended to be read as containing only members suitable for substituting a particular group.

[0034] The compounds used in the present invention may be in the form of pharmaceutically acceptable salts or solvates. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including organic and inorganic bases or acids. If the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes the corresponding pharmaceutically or toxicologically acceptable salts thereof, in particular the pharmaceutically usable salts thereof. Accordingly, compounds of the present invention containing acidic groups can be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids. Compounds of the present invention containing one or more basic groups, i.e., protonable groups, can be used according to the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. When the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes intramolecular salts or betaines (amphoteric ions) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention, which, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0035] Furthermore, the compounds disclosed in this patent application may exist in the form of solvates, e.g., solvated water, or pharmaceutically acceptable solvates, e.g., alcohols, particularly ethanol. The stoichiometric or non-stoichiometric amounts of the solvent are bonded by non-covalent intermolecular forces. When the solvent is water, the “solvate” is a “hydrate.” It is understood that a “pharmaceutically acceptable salt” may optionally further contain a “solvate.”

[0036] Depending on the substitution pattern, the compounds according to the present invention may exist in stereoisomeric forms, which may behave as enantiomers or not as diastereomers. The present invention relates to both enantiomers or diastereomers and mixtures thereof. Similar to diastereomers, racemates can be separated into stereoisomerically homogeneous components by known methods. The term “diastereomer” means stereoisomers that are not mirror images of each other and cannot be superimposed on each other. The term “enantiomer” means an individual optically active form of the compound of the present invention, which has an optical purity or enantiomer excess (determined by conventional methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, more preferably at least 98%.

[0037] The term "effective dose" means an amount of a compound that, when administered, is sufficient to prevent or, to some extent, alleviate the onset of one or more symptoms of the disorder, disease, or physical condition being treated. The term "effective dose" also refers to an amount of a compound sufficient to elicit a biological or medical response in a cell, tissue, system, animal, or human, as determined by a researcher, veterinarian, physician, or clinician.

[0038] The scope of the present invention includes compounds (so-called prodrugs) that, once ingested, are converted solely into the actual active compound of formula (I).

[0039] The present invention relates particularly to the following embodiments: In a preferred embodiment combined with any one of the above or below embodiments, R 1 is selected from C 1-4 -alkyl and fluoro-C 1-4 -alkyl, the C 1-4 -alkyl has one or more hydrogen atoms optionally substituted by deuterium, preferably, R 1 is selected from CH3 and CD3, and most preferably, R 1 is CD3.

[0040] In a preferred embodiment combined with any one of the above or below embodiments, R 2 is selected from H, -CN, C 1-4 -alkyl, fluoro-C 1-4 -alkyl and C 1-4 -acyl, the C 1-4 -alkyl or C 1-4 -acyl has one or more hydrogen atoms optionally substituted by deuterium, preferably, R 2 is selected from H, CH3 and CD3, and most preferably, R 2 is H.

[0041] In a preferred embodiment combined with any one of the above or below embodiments, R 3 is selected from H and C 1-4 -alkyl and fluoro-C 1-4 -alkyl, the C 1-4 -alkyl has one or more hydrogen atoms optionally substituted by deuterium, and most preferably R 3 is H.

[0042] In a preferred embodiment combined with any one of the above or below embodiments, R 4 is selected from H and C 1-6 -alkyl, the C 1-6 -alkyl has one or more hydrogen atoms optionally substituted by deuterium, preferably, R 4is selected from CH3 and CD3, and most preferably R 4 It is CH3.

[0043] In a preferred embodiment combined with either of the above or below embodiments, R 5 and R 6 These are H, D and C independently. 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, preferably R 5 and R 6 Both are H or both are D, and most preferably R 5 and R 6 Both are H.

[0044] In a preferred embodiment combined with either of the above or below embodiments, R 8 H, -CN, -NO2,C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally replaced by deuterium, and most preferably R 8 H is H.

[0045] In a preferred embodiment combined with either of the above or below embodiments, R 9 C 1-4 -alkyl, fluoro-C 1-4 -alkyl, C 3-4 -Cycloalkyl and fluoro-C 3-4 - Selected from cycloalkyl, the C 1-4 -Alkyl or C 3-4 - The cycloalkyl group has one or more hydrogen atoms optionally replaced by deuterium, preferably R 9 is selected from CH3, CD3 and cyclopropyl, and most preferably R 9 It is CH3.

[0046] Particularly preferred embodiments of the present invention relate to a compound of formula (I) as defined above, wherein, R1 The channel is selected from CH3 and CD3; R 4 It is CH3; R 2 ,R 3 ,R 5 ,R 6 and R 8 is H; R 9 The compound is selected from methyl and cyclopropyl.

[0047] In a more preferred embodiment combined with either of the above or below embodiments, Y is a group represented by the following formula: [ka] During the ceremony, R 11 H, D, halogen, CN, C 1-4 -alkyl and fluoro-C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally replaced by deuterium, preferably R 11 is selected from H, D, and F, more preferably R 11 is selected from H and F, most preferably R 11 is H; R 12 H, D, halogen, CN, C 1-4 -alkyl and fluoro-C 1-4 Selected from alkyl groups, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, most preferably R 12 is H; R 13 H, D, halogen, CN, C 1-4 -alkyl and fluoro-C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, most preferably R 13 is H; R 14 H, D, halogen, CN, C1-4 -alkyl and fluoro-C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, most preferably R 14 is H; R 21 H, D, halogen, CN, C 1-4 -alkyl, OC 1-4 -alkyl, fluoro-C 1-4 -alkyl and O-fluoro-C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, preferably R 21 is selected from H, D, F and OCD3, more preferably R 21 is selected from H and F, most preferably R 21 is F; R 22 H, D, halogen, CN, C 1-4 -alkyl, OC 1-4 -alkyl, fluoro-C 1-4 -alkyl and O-fluoro-C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, preferably R 22 is selected from H, D, and F, more preferably R 22 is selected from H and D, most preferably R 22 is H; R 23 H, D, halogen, CN, C 1-4 -alkyl, OC 1-4 -alkyl, fluoro-C 1-4 -alkyl and O-fluoro-C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, preferably R 23 is selected from H, D, and F, more preferably R 23 is selected from H and D, most preferably R 23 is H; R 24 H, D, halogen, CN, C 1-4 -alkyl, OC 1-4 -alkyl, fluoro-C 1-4 -alkyl and O-fluoro-C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, preferably R 24 is selected from H, D, F and OCD3, more preferably R 24 is selected from H and F, most preferably R 24 is F; R 25 H, D, halogen, CN, C 1-4 -alkyl, OC 1-4 -alkyl, fluoro-C 1-4 -alkyl and O-fluoro-C 1-4 -Selected from alkyl, the C 1-4 -Alkyl has one or more hydrogen atoms optionally substituted with deuterium, preferably R 25 is selected from H, D, and F, more preferably R 25 is selected from H and D, most preferably R 25 H is H.

[0048] In a more preferred embodiment, combined with either of the above or below embodiments, Y is selected from the group consisting of the following formulas. [ka] Preferably, Y is selected from the following: [ka] More preferably, Y is selected from the following: [ka] Most preferably, Y is as follows: [ka]

[0049] In yet another preferred embodiment, combined with either of the above or below embodiments of formula (I), base R 1 It is CD3.

[0050] In yet another preferred embodiment, combined with either of the above or below embodiments of formula (I), base X is as follows: [ka]

[0051] In yet another preferred embodiment, combined with either of the above or below embodiments of formula (I), base X is as follows: [ka]

[0052] In yet another preferred embodiment, combined with either of the above or below embodiments of formula (I), base X is as follows: [ka] Preferably, base X is as follows: [ka] Most preferably, base X is as follows: [ka]

[0053] In yet another preferred embodiment, combined with either of the above or below embodiments of formula (I), base X is as follows: [ka] Preferably, base X is as follows: [ka]

[0054] Particularly preferred compounds of the present invention are compounds represented by the following formula, or their solvates or pharmaceutically acceptable salts. [ka]

[0055] Particularly preferred compounds of the present invention are compounds represented by one of the following formulas, or their solvates or pharmaceutically acceptable salts. [ka]

[0056] Particularly preferred compounds of the present invention are compounds represented by the following formula, or their solvates or pharmaceutically acceptable salts. [ka]

[0057] In yet another alternative preferred embodiment combined with any of the above or below embodiments in formula (I), base X is as follows: [ka] Preferably, base X is as follows: [ka]

[0058] Particularly alternative preferred compounds of the present invention are compounds represented by the following formula, or their solvates or pharmaceutically acceptable salts. [ka]

[0059] A particularly alternative and more preferred compound of the present invention is a compound represented by the following formula, or a solvate or pharmaceutically acceptable salt thereof. [ka]

[0060] The most preferred alternative compounds of the present invention are compounds represented by the following formula, or their solvates or pharmaceutically acceptable salts. [ka]

[0061] Further aspects of the present invention relate to pharmaceutical formulations comprising one or more compounds of any of the embodiments described above.

[0062] Further aspects of the present invention relate to any of the compounds of the above embodiments for use as pharmaceuticals.

[0063] In particular, the present invention relates to the above-mentioned compounds for use in the treatment or prevention of diseases or disorders related to viral infections.

[0064] More specifically, the present invention relates to the above-mentioned compounds for use in the treatment or prevention of diseases or disorders associated with viral infections caused by herpes viruses, particularly herpes simplex viruses.

[0065] In a further embodiment, the present invention relates to the above-mentioned compounds for use in the treatment or prevention of neurodegenerative diseases caused by viruses, such as Alzheimer's disease caused by viruses, and especially neurodegenerative diseases caused by herpes simplex virus.

[0066] In further embodiments, the present invention relates to the use in the treatment and prevention of herpes simplex infection in patients presenting with herpes infections, particularly oral herpes, genital herpes and herpes-associated keratitis, Alzheimer's disease, encephalitis, pneumonia, and hepatitis; use in patients with a suppressed immune system, such as AIDS patients, cancer patients, patients with genetic immunodeficiency, and transplant patients; use in neonates and infants; use in herpes-positive patients, particularly herpes simplex-positive patients, and patients undergoing relapse suppression (suppressive therapy); or use in patients resistant to nucleoside antiviral therapies such as acyclovir, penciclovir, famciclovir, ganciclovir, and valacyclovir, particularly in herpes-positive patients, particularly herpes simplex-positive patients.

[0067] In a further embodiment, the present invention relates to ICs with a molecular weight of preferably less than 100 μM, more preferably less than 10 μM. 50 , and very particularly preferred ICs with a minimum particle size of 1 μM. 50 IC in an in vitro activity-selective assay for Vero cells in HSV-1, as described in the embodiments of the present invention. 50 This relates to the above compound characterized by its valency (HSV-1 / bero).

[0068] In a further embodiment, the present invention provides an ED in the in vivo animal model described in the embodiments of the present invention, preferably less than 10 mg / kg relative to HSV-1, more preferably less than 5 mg / kg relative to HSV-1, and very preferably less than 2 mg / kg relative to HSV-1. 50 ED 50 This relates to the above-mentioned compound characterized by its valency.

[0069] The compounds according to the present invention are being investigated for use in the prevention and treatment of disorders and diseases in humans and animals, respectively.

[0070] Accordingly, the present invention relates to the use of the compounds described herein for the preparation of pharmaceuticals.

[0071] Furthermore, the present invention relates to a method for treating a disease or disorder associated with viral infection, such as a disease or disorder associated with a viral infection caused by a herpes virus, for example, particularly herpes simplex virus, and a method for treating a neurodegenerative disease caused by a virus, for example, particularly Alzheimer's disease, the method comprising administering an effective amount of an effective amount of a compound described herein or a composition containing such compound to a human or animal in need.

[0072] In practical use, the compounds used in the present invention can be combined as active ingredients in a tight mixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier can take a wide variety of forms depending on the desired form of the preparation for administration, e.g., orally or parenterally (including intravenously). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used, such as water, glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., in the case of oral liquid formulations such as suspensions, elixirs, and solutions; or, in the case of oral solid formulations such as powders, hard and soft capsules, and tablets, starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc., with solid oral formulations being preferred over liquid formulations.

[0073] For ease of administration, tablets and capsules offer the most advantageous oral unit dosage forms, in which case solid drug carriers are obviously used. If necessary, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can, of course, be varied and, conveniently, may range from about 2.0 percent to about 60.0 percent of the unit weight. The amount of the active compound in such therapeutically useful compositions is such that an effective dose is obtained. The active compound may also be administered intranasally, for example, as droplets or sprays, or as eye drops.

[0074] Tablets, pills, capsules, etc., may also contain binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. If the unit dosage form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the above-mentioned materials.

[0075] Various other materials can be used as coatings or to alter the physical shape of the dosage unit. For example, tablets can be coated with shellac, sugar, or both. In addition to the active ingredient, syrups or elixirs may contain sucrose as a sweetener, methylparaben and propylparaben as preservatives, colorants, and flavorings such as cherry or orange.

[0076] The compounds used in this invention may also be administered parenterally. Solutions or suspensions of these active compounds may be prepared in water appropriately mixed with a surfactant such as hydroxypropyl cellulose. Dispersants may also be prepared in glycerin, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0077] Suitable drug forms for injection include sterile aqueous solutions or dispersions and sterile powders for immediate preparation of sterile injection solutions or dispersions. In all cases, the drug form must be sterile and liquid enough to be easily injected. It must be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0078] To provide an effective dose of the compound of the present invention to mammals, particularly humans, any suitable route of administration can be used. For example, it can be administered orally, rectally, topically, parenterally (including intravenously), orally, in the lungs, or nasally. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compound of the present invention is administered orally or as eye drops, and more preferably, the compound of the present invention is administered orally.

[0079] The effective dose of the active ingredient used may vary depending on the specific compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such doses can be readily determined by those skilled in the art.

[0080] The compounds of the present invention may also be present in combination with further active ingredients, in particular one or more active ingredients that exhibit a favorable effect in the treatment of any of the disorders or diseases described herein. More particularly, the compounds of the present invention are present in a composition in combination with at least one further active substance that is effective in treating diseases or disorders associated with viral infection (antiviral active compound), preferably by herpesviruses, particularly herpes simplex virus, and thus diseases or disorders associated with so-called combination therapy. The at least one further active substance that is effective in treating diseases or disorders associated with viral infection (antiviral active compound) is preferably selected from the group consisting of nucleoside drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir and trifluridine, and compounds such as foscarnet and cidofovir.

[0081] Accordingly, the present invention further relates to a pharmaceutical composition effective for treating diseases or disorders associated with viral infections (antiviral active compounds), comprising one or more of the compounds described herein and at least one pharmaceutically acceptable carrier and / or excipient and / or at least one further active substance.

[0082] A further aspect of the present invention relates to the use of the deuterated compound described herein, wherein the deuterated compound acts as a deuterated helicase primase inhibitor in combination therapy with oncolytic viruses for the treatment of tumors, cancer, or abnormal proliferation.

[0083] Further embodiments of this additional aspect of the present invention relate to a pharmaceutical composition for use as an antidote in combination therapy with oncolytic viruses for the treatment of cancer, comprising at least one deuterated helicase primase inhibitor as defined in any embodiment described herein, acting to control, modulate, inhibit or block the activity of oncolytic viruses sensitive to the inhibitor used in cancer treatment, and may further comprising at least one pharmaceutically acceptable carrier and / or excipient and / or at least one further active substance such as an antiviral or immunomodulatory compound, and comprising a checkpoint inhibitor, and being effective in treating diseases or disorders associated with oncolytic virus infection used in cancer treatment.

[0084] Further embodiments of this additional aspect of the present invention relate to deuterated helicase primase inhibitors or pharmaceutical compositions for use in combination therapy with oncolytic viruses described herein, wherein the cancer treated herein is a solid tumor, and preferably the cancerous disease is selected from liver cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, brain cancer, melanoma, and glioblastoma.

[0085] Further embodiments of this additional aspect of the present invention relate to deuterated helicase primase inhibitors or pharmaceutical compositions for use in combination therapy with oncolytic viruses as described herein, wherein the oncolytic virus is an oncolytic herpesvirus.

[0086] Further embodiments of this additional aspect of the present invention relate to deuterated helicase primese inhibitors or pharmaceutical compositions for use in combination therapy with oncolytic viruses as described herein, wherein the cancer therapy includes infusion, injection, intratumoral injection, or topical or transdermal application of oncolytic viruses or oncolytic virus-infected cells and / or helicase primese inhibitors or pharmaceutical compositions comprising the same.

[0087] Further embodiments of this additional aspect of the present invention relate to deuterated helicase primase inhibitors or pharmaceutical compositions for use in combination therapy with oncolytic viruses as described herein, wherein the oncolytic virus or oncolytic virus-infected cells are selected from oncolytic wild-type, clinical isolates or experimental herpesvirus strains or genetically engineered or polymutated, and optionally attenuated or booster-immunized oncolytic herpesviruses.

[0088] Further embodiments of this additional aspect of the present invention relate to a kit comprising at least one deuterated helicase primase inhibitor or pharmaceutical composition for use in combination therapy with oncolytic viruses as described herein, and at least one oncolytic virus selected from wild-type, laboratory strains, clinical isolates, and genetically modified or polymutant oncolytic viruses.

[0089] Further embodiments of this additional aspect of the present invention relate to the kit for use in the treatment of cancer as defined herein.

[0090] The deuterated helicase primemase inhibitors, pharmaceutical compositions, or kits described herein for use in combination therapy with oncolytic viruses may be applied to one or more of the following patient groups: infants; herpes-positive patients, particularly oncolytic herpes simplex-positive patients, for the suppression of recurrent or oncolytic virus shedding; and patients resistant to nucleoside antiviral therapies such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir, and / or foscarnet or cidofovir, particularly herpes-positive patients, particularly oncolytic herpes simplex-positive patients.

[0091] The deuterated compounds detailed herein were unexpectedly found to exhibit higher microsomal stability and improved in vivo behavior in rodents. Further details are provided in the following examples. [Examples]

[0092] <Experiment Department> The compounds of the present invention can be prepared by using appropriate deuterated units or by hydrogen-deuterium exchange, as outlined in Patent Documents 1, 2, and 3 (for example, Non-Patent Document 5; Non-Patent Document 6).

[0093] <abbreviation> DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) dppf 1,1'-bis(diphenylphosphin)ferrocene EA ethyl acetate EDCI·HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Flash chromatography of FCC silica gel HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate PE (Petroleum Ether) rt Room temperature (20±4℃) THF (Tetrahydrofuran)

[0094] <Experimental Section> (Preparation Example P1): [Step 1]: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)methyl acetate (P1a) [ka] To an aqueous solution of (4-bromophenyl)-methyl acetate (120 g, 524 mmol) in 1,4-dioxane (1.5 L) and H2O (150 mL), 2,5-difluorophenylboronic acid (99.4 g, 629 mmol), Pd(dppf)Cl2 (12.0 g, 16.4 mmol), and Na2CO3 (167 g, 1.57 mol) were added. This mixture was heated at 100 °C for 1 hour and then cooled to room temperature. The organic layer was separated, concentrated, and purified by FCC (PE:EA = 15:1) to obtain compound P1a as a yellow oily substance.

[0095] [Step 2]: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)acetic acid (P1) [ka] To a solution of compound P1a (120 g, 458 mmol) in MeOH (800 mL) and THF (200 mL), 5N NaOH (100 mL) was added. This mixture was stirred at room temperature for 30 minutes, concentrated under vacuum, and the pH was adjusted to <7 with 2N HCl. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven (45°C) to obtain compound P1 as a white solid.

[0096] (Preparation Examples P2 / 1~P2 / 6): The following examples can be prepared in the same manner as described for Preparation Example 1, using the appropriate constituent units shown below.

[0097] [Table 1]

[0098] (Example 1)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide: [Step 1]: 1-bromopropan-2-one-1,1,3,3,3-d5(1a) [ka] Br2 (2.5g, 15 mmol) was added to propan-2-one-d6 (2.0g, 31 mmol) at room temperature, stirred for 2 hours, and then immediately used in the next step.

[0099] [Step 2]: N-methyl-4-(methyl-d3)thiazole-2-amine (1b) [ka] To a solution of compound 1a in EtOH (20 mL), 1-methylthiourea (1.4 g, 15 mmol) was added at 75°C, and after stirring for 2 hours, saturated NaHCO3 solution was added. This mixture was extracted with EA (2 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated, and then purified by FCC (EA:PE = 1:1) to obtain compound 1b.

[0100] [Step 3]: 5-bromo-N-methyl-4-(methyl-d3)thiazole-2-amine (1c) [ka] To a solution of compound 1b (400 mg, 3.0 mmol) in CHCl3 (4 mL), Br2 (740 mg, 4.7 mmol) was added at room temperature, and the mixture was stirred overnight. Then, water (10 mL) was added. The pH was adjusted to 8 with saturated NaHCO3 solution. This mixture was extracted with CHCl3 (2 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain compound 1c as a solid.

[0101] [Step 4]: N-methyl-4-(methyl-d3)-5-(methylthio)thiazole-2-amine(1d) [ka] To a solution of compound 1c (350 mg, 1.6 mmol) in 1,4-dioxane (4 mL), MeSNa (230 mg, 3.2 mmol) was added at room temperature. After stirring overnight, the mixture was evaporated to obtain an oily substance, which was then purified by FCC (EA:PE = 1:1) to obtain compound 1d as a yellow solid.

[0102] [Step 5]: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(methylthio)thiazole-2-yl)acetamide(1e) [ka] Compound 1d (100 mg, 0.56 mmol) was added at room temperature to a solution of compound P1 (140 mg, 0.56 mmol), HATU (322 mg, 0.85 mmol), and Et3N (171 mg, 0.85 mmol) in CH2Cl2 (2.0 mL). After stirring overnight, the mixture was washed with water (2 × 2.5 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified in FCC (PE:EA = 2:1) to obtain compound 1e as a white solid.

[0103] [Step 6]: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(methylsulfinyl)thiazole-2-yl)acetamide(1f) [ka] To a solution of compound 1e (180 mg, 0.44 mmol) in CH2Cl2 (1 mL), metachloroperoxybenzoic acid (76 mg, 85% purity) was added. This mixture was stirred at room temperature for 20 minutes and then partitioned between CH2Cl2 and a 5% sodium carbonate solution. The organic phase was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by FCC (PE:EA = 1:2) to obtain compound 1f as a white solid.

[0104] [Step 7]: tert-butyl((2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methylacetamide)-4-(methyl-d3)thiazole-5-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (1g) [ka] MgO (57 mg, 1.40 mmol), tert-butyl carbamate (83 mg, 0.70 mmol), Rh2(OAc)4 (15 mg, 33 μmol), and (diacetoxy)iodobenzene (171 mg, 0.52 mmol) were added to a solution of compound 1f (150 mg, 0.35 mmol) in CH2Cl2 (2.5 mL). The mixture was stirred overnight at 40°C, cooled to room temperature, and filtered through a Celite pad. The solvent was removed under vacuum, and the crude product was purified by FCC (PE:EA = 1:1) to obtain 1 g of the compound as a white solid.

[0105] [Step 8]: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide(1) [ka] At ambient temperature, 1 g (150 mg, 0.28 mmol) of compound was added to a stirred solution of trifluoroacetic acid (2 mL) in CH2Cl2 (8 mL). Stirring was continued for 1 hour, then the mixture was concentrated, decomposed in CH2Cl2, washed with saturated NaHCO3 (2 × 20 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain compound 1 as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:7.57(d,J=7.2Hz,2H),7.46-7.35(m,4H),7.31-7. 24(m,1H),4.69(s,1H),4.23(s,2H),3.72(s,3H),3.14(s,3H).MS:439.1[M+1] + .

[0106] (Example 2)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-(methyl-d3)-sulfonimidoyl)thiazole-2-yl)acetamide: [ka] By applying the route outlined in Example 1, the target compound can be obtained by using propan-2-one instead of propan-2-one-d6 (Step 1) and CD3SNa instead of MeSNa (Step 4). CD3SNa can be optionally prepared from commercially available methane-d3-thiol (CAS: 73142-81-1) or methanethiol-d4 (CAS: 65871-23-0).

[0107] (Example 3)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-(methyl-d3)-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide: [ka] By applying the route outlined in Example 1, the target compound can be obtained by using propan-2-one instead of propan-2-one-d6 (Step 1) and 1-(methyl-d3)thiourea instead of 1-methylthiourea (Step 2).

[0108] (Example 4 / 1~4 / 22): By applying the pathway outlined above using appropriate structural units, the following target compounds, which can be separated into their enantiomers, can be obtained, as described in Patent Document 3.

[0109] [Table 2] TIFF0007876206000040.tif133170

[0110] (Example 5)-2-([1,1'-biphenyl]-4-yl-2',3',4',5',6'-d5)-N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)acetamide: [Step 1]: 2-(4-bromophenyl)-N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)acetamide (5a) [ka] To a mixture of 2-(4-bromophenyl)acetic acid (5.00 g, 23.3 mmol) in DMF (50 mL), 4-methyl-2-(methylamino)thiazole-5-sulfonamide (4.80 g, 23.2 mmol), HOBt (3.50 g, 25.7 mmol), and EDCI·HCl (4.90 g, 25.7 mmol) were added. This mixture was stirred at room temperature for 3 hours, poured into water (500 mL), and filtered. The filtered cake was dried to obtain intermediate 5a as a white solid.

[0111] [Step 2]: 2-([1,1'-biphenyl]-4-yl-2',3',4',5',6'-d5)-N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)acetamide(5) [ka] A mixture of compound 5a (202 mg, 0.50 mmol) in dioxane / H2O (5 mL / 0.5 mL) was mixed with (phenyl-d5)boronic acid (64 mg, 0.50 mmol), Pd(dppf)Cl2 (18 mg), and K2CO3 (138 mg, 1.00 mmol). The mixture was stirred at 90°C for 4 hours, cooled to room temperature, poured into water (50 mL), and extracted with EA (3 × 30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to obtain compound 5 as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:7.65(d,J=7.6Hz,4H),7.36(d,J=8.4Hz,2H),4.20(s,2H),3.71(s,3H),2.48(s,3H).MS:407.1[M+1] + .

[0112] (Examples 5 / 1~5 / 2): The following examples were prepared using appropriate structural units, in the same manner as described for Example 5.

[0113] [Table 3]

[0114] (Example 6)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-sulfamoylthiazol-2-yl)acetamide: [Step 1]: 4-(methyl-d3)thiazole-2-amine (6a) [ka] Br2 (7.0 g, 44 mmol) was added to propan-2-one-d6 (10 mL) at room temperature and stirred for 5 hours. This solution was diluted with EtOH (50 mL) and heated to 75°C. Then, thiourea (3.30 g, 43.4 mmol) was added, and the mixture was stirred for 2 hours, diluted with saturated NaHCO3 solution, and extracted twice with EA (50 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated, and purified by FCC (PE:EA = 1:1) to obtain compound 6a as a yellow oily substance.

[0115] [Step 2]: 2-Chloro-4-(methyl-d3)thiazole (6b) [ka] Isoamyl nitrite (2.40 g, 20.5 mmol) was added at 0°C to a solution of compound 6a (1.60 g, 13.7 mmol) and copper(II) chloride dihydrate (2.30 g, 13.5 mmol) in MeCN (10 mL). The mixture was stirred at room temperature for 16 hours, concentrated under vacuum, redissolved in CHCl3, and filtered through Celite. The filtrate was concentrated and purified by FCC (PE:EA = 15:1) to obtain compound 6b as a yellow oily substance.

[0116] [Step 3]: 2-Chloro-4-(methyl-d3)thiazole-5-sulfonyl chloride (6c) [ka] To compound 6b (0.80 mg, 5.86 mmol), solutions of thionyl chloride (1.1 mL, 15 mmol) and chlorosulfonic acid (3.9 mL, 59 mmol) were added dropwise. The mixture was stirred overnight at 120°C, cooled to room temperature, rapidly cooled in ice water, and extracted with CH2Cl2 (3 × 30 mL). The combined organic layer was dried over Na2SO4, filtered, concentrated, and purified in FCC (PE:EA = 10:1) to obtain compound 6c as a yellow oily substance.

[0117] [Step 4]: 2-Chloro-4-(methyl-d3)thiazole-5-sulfonamide(6d)

Chem.

[0118] [Step 5]: 4-(Methyl-d3)-2-(methylamino)thiazole-5-sulfonamide (6e)

Chem.

[0119] [Step 6]: 2-(2’,5’-Difluoro-[1,1’-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-sulfamoylthiazol-2-yl)acetamide (6)

Chem.

[0120] (Example 6 / 1 - 6 / 2): The following examples were prepared in the same manner as described for Example 6 using appropriate structural units.

[0121]

Table 4

[0122] (Comparative Example 6 / 3): By applying the route as outlined above for Example 6 using appropriate structural units, the following target compounds can be obtained.

[0123]

Table 5

[0124] (Example 7) - 2-(2’,5’-Difluoro-[1,1’-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(N-(methyl-d3)sulfamoyl)thiazol-2-yl)acetamide:

Chemical Structure

[0125] (Example 8) - 2-(2’,5’-Difluoro-[1,1’-biphenyl]-4-yl)-N-(methyl-d3)-N-(4-methyl-5-sulfamoylthiazol-2-yl)acetamide:<00009​[Chemistry] By applying the route outlined in Example 6, the target compound can be obtained by using (methyl-d3)amine (CAS: 5581-55-5) instead of H2NMe (step 5).

[0126] (Examples 9 / 1 - 9 / 2): By applying the route as outlined above using appropriate structural units, the following target compounds can be obtained.

[0127] [Table 6]

[0128] (Example 10) - 2-(2’,5’-Difluoro-[1,1’-biphenyl]-4-yl)-N-(methyl-d3)-N-(4-methyl-5-sulfamoylthiazol-2-yl)acetamide: [Chemistry] By applying the route outlined in Patent Document 2 (Example 3) using appropriate structural units, the target compound can be obtained.

[0129] (Chromatographic separation of Example 1 and isolation of two isomers): The crude product (300 mg) of Example Compound 1 was separated by chiral-HPLC, and enantiomer 4 / 2 and enantiomer 4 / 1 were obtained as white solids, respectively, by using the following column and conditions: Equipment: SFC-150 (Thar, Waters) Column: OJ 20 * 250 mm, 10 μm (Daicel) Column temperature: 35 °C Mobile phase: CO2 / 2-propanol (55:45) Flow rate: 100 g / min Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 3.7 minutes Sample solution: 300 mg dissolved in 40 mL of methanol Injection volume: 1.0 mL

[0130] Example 4 / 2 is the first enantiomer to elute. This enantiomer is [α] 19.8 Hg365nm It is further characterized by a negative specific rotation of -22.8±0.3° (c=0.434g / 100mL, MeOH). 1 H-NMR(DMSO-d6,400MHz)δ:δ7.57(dd,J=8.0,1.6Hz,2H),7.45-7.35(m,4H),7.30-7. 24(m,1H),4.70(brs,1H),4.24(s,2H),3.72(s,3H),3.14(s,3H).MS actual value: 439.1[M+H] + .

[0131] Example 4 / 1 is a second elution enantiomer. This enantiomer is [α] 19.8 Hg365nm It is further characterized by its positive specific rotation, and 1 The 1H-NMR and MS results are the same as in Example 4 / 2.

[0132] <In vitro activity> (Viruses and cells): The in vitro activity of (HSV-1 infected tongue), (HSV-2 infected tongue), and (HSV-1 (ACV resistant) infected tongue) was tested as outlined in Patent Documents 2 and 3. The results for several compounds are summarized in Table 1 (Table 7) below. For comparison, a non-deuterated matched pair was tested for Example 1 of this patent application. This test is referred to below as Comparative Example C7 and corresponds to Example 7 of Patent Document 2.

[0133] (Comparative Example C7) / Patent Document 2 (Non-deuterated) Example 7: [ka]

[0134] [Table 7]

[0135] (Microsomal stability): Example 1 and the non-deuterated matched pair (Comparative Example C7 / Example 7 of Patent Document 2) were incubated for 60 minutes using three different batches of human liver microsomes (HLMs). Conversion to hydroxylated metabolites was monitored by LC-MS.

[0136] [Table 8]

[0137] By deuterating the metabolic weakness (which directs 4-methyl in the thiazole core to 4-methyl-d3), the conversion to hydroxylated metabolites was reduced by a coefficient of ~27 to 0.11 ± 0.03%, compared to 3.07 ± 1.00% for the non-deuterated matched pair (Comparative Example C7).

[0138] (Further stability of microsomes): The formation of hydroxy metabolites was quantified by the peak area ratio to the corresponding non-deuterated matched pair after incubation for 60 minutes in rat microsomes (SD rat, male) or human microsomes (sex mixed) using an Admesscope. The peak signal (positive mode) was quantified using Waters Acquity UPLC + Thermo Q-Exactive Focus Orbitrap MS on a Phenomenex Kinetex Biphenyl (2.1 × 50 mm, 1.7 μm particle size 10 Å) column. The data are as follows.

[0139] [Table 9]

[0140] The detection of the hydroxylated metabolite of the deuterated eutomeric enantiomer Example 4 / 2 and the non-deuterated matched pair (Comparative Example C4 / 2 / Example 7(-) of Patent Document 2) again demonstrated a dramatic improvement in the microsomal stability of the deuterated analogue toward oxidation of the metabolic weak point (4-methyl in the thiazole core), similar to that shown in the racemic mixture (Example 1 vs. Comparative Example C7) above. A similar trend can be observed for Example 6 compared to the non-deuterated matched pair (Comparative Example C6).

[0141] (Pharmacokinetics in mice): The pharmacokinetics of the deuterated compound of the present invention, Example 4 / 2, were evaluated in three male mice (strain C57Bl / 6N, body weight 21-26g) after oral or intravenous cassette administration. Oral bioavailability was evaluated in comparison with a non-deuterated matched pair (Comparative Example C4 / 2 / Example 7(-) of Patent Document 2), also known as IM-250 (see Sci. Transl. Med. 2021; 13: eabf8668). The compound was formulated in 5% DMSO and 95% aqueous solution, with HPMC (0.5%) used for po (oral administration) and 10% DMSO and 90% serum used for ip (intraperitoneal administration). Plasma from the retroocular venous plexus was analyzed by LC-MS at each specified time point (0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration for po; 0.083, 0.25, 0.5, 1, 4, 8, and 24 hours post-administration for iv (intravenous injection)). The data obtained is as follows (NC = Uncalculable):

[0142] [Table 10]

[0143] The non-deuterated compound according to Comparative Example C4 / 2 already possesses very good bioavailability and AUC. Selective deuteration (Example 4 / 2) can further improve this bioavailability and AUC, which may be due to a decrease in metabolism, as shown with the decrease in clearance (CL) for Example 4 / 2. This surprisingly provides a compound with improved stability, including improved bioavailability, improved AUC, and improved metabolic stability. The improved stability is beneficial and more convenient for suppressive therapy, as it allows for longer dosing intervals (e.g., once a week) or enables the use of lower doses to provide similar therapeutic benefits compared to the non-deuterated derivative.

[0144] Bioavailability exceeding 100% is a common phenomenon. The F% exceeding 100% is for intravenous administration, assuming linear and unchanging clearance after intravenous and oral administration. Elimination rates are controlled by absorption rates, and possible reasons include sustained drug release, delayed compound clearance, or re-entry into the systemic circulation.

[0145] (Brain exposure and brain-to-plasma ratio in mice): Brain and plasma exposure for Example 6, Example 4 / 2, and their non-deuterated matched pairs (Comparative Example C4 / 2 / Example 7(-) of Patent Document 2) was evaluated in three mice (strain C57Bl / 6N, body weight 21-26g) after oral cassette administration at a dose of 10 mg / kg, 4 hours later. The compounds were formulated in 5% DMSO and 95% aqueous HPMC (0.5%). All animals exhibited normal behavior, and no clinical signs were observed after administration. Plasma from the posterior venous plexus was analyzed by LC-MS. The obtained data are as follows.

[0146] [Table 11]

[0147] As previously shown in pharmacokinetic experiments, after 4 hours, plasma and brain exposure in deuterated Example 4 / 2 was improved by more than 50% compared to the non-deuterated matched pair (Comparative Example C4 / 2 / Example 7(-) of Patent Document 2). Example 6, which contains a primary sulfonamide, showed brain exposure, which can be further improved by replacing the primary sulfonamide with a methylated sulfoximine moiety, as in Example 4 / 2. High brain exposure is beneficial, for example, in the treatment of herpes encephalitis and Alzheimer's disease.

Claims

1. A compound that is a compound of the following formula (I), or an enantiomer, diastereomer, tautomer, solvate, or pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the above formula (I), X is the base shown by the following two equations. 【Chemistry 2】 Selected from, In each of the above formulas, R １ CD ３ And; R ２ H is; R ３ H is; R ４ CH ３ And; R ５ and R ６ H is; R ８ is H; R ９ CH ３ And; Y is selected from the bases shown in the following six formulas. 【Transformation 3】

2. The compound according to claim 1, wherein Y is selected from the group represented by the following three formulas. 【Chemistry 4】

3. The compound according to claim 1, wherein X is one of the two groups represented by the following formulas. 【Transformation 5】

4. The compound according to claim 1, which is a compound selected from the following four formulas, or a solvate or pharmaceutically acceptable salt thereof. 【Transformation 6】

5. The compound according to claim 1, which is a compound of the following formula, or a solvate or pharmaceutically acceptable salt thereof. 【Transformation 7】

6. A compound according to any one of claims 1 to 5, for use as a pharmaceutical agent.

7. A compound according to any one of claims 1 to 5, for use in the treatment or prevention of herpes infection.

8. The compound according to claim 7, wherein the herpes infection is herpes simplex infection.

9. A compound according to any one of claims 1 to 5, for use in the treatment or prevention of neurodegenerative diseases caused by herpesviruses.

10. A compound according to any one of claims 1 to 5, for use in the treatment or prevention of neurodegenerative diseases such as Alzheimer's disease, caused by the herpes simplex virus.

11. In patients presenting with oral herpes, genital herpes, or herpes-associated keratitis, in patients with Alzheimer's disease, encephalitis, pneumonia, or hepatitis, in patients with AIDS, cancer, genetic immunodeficiency, or transplantation, in patients with a suppressed immune system, in neonates or infants, in herpes-positive patients for relapse prevention, or in herpes-positive patients resistant to nucleoside antiviral therapy with acyclovir, penciclovir, famciclovir, ganciclovir, or valacyclovir, A compound according to any one of claims 1 to 5, for use in the treatment or prevention of herpes infection.

12. In patients presenting with oral herpes, genital herpes, or herpes-associated keratitis, in patients with Alzheimer's disease, encephalitis, pneumonia, or hepatitis, in patients with AIDS, cancer, genetic immunodeficiency, or transplantation, in patients with a suppressed immune system, in neonates or infants, in herpes-positive patients for relapse prevention, or in herpes-positive patients resistant to nucleoside antiviral therapy with acyclovir, penciclovir, famciclovir, ganciclovir, or valacyclovir, A compound according to any one of claims 1 to 5, for use in the treatment or prevention of herpes simplex infection.

13. One or more compounds according to any one of claims 1 to 5, At least one pharmaceutically acceptable carrier and / or excipient and / or at least one further active substance effective in treating herpes infections, A pharmaceutical composition containing the following:

Images