Solid crystalline forms of helicase-primase inhibitors and process of preparation thereof

Abstract

The present invention provides a solid crystalline form of a compound that can be used as a helicase inducing enzyme inhibitor, its composition, a method of manufacturing the compound, and a method of using the compound to treat herpes simplex virus infection and mediated diseases.

Description

Technical Field

[0001] The present invention provides a solid crystalline form of an antiviral compound that can be used as a helicase inducing enzyme inhibitor, its composition, a method of manufacturing the compound, and a method of using the compound to treat herpes simplex infection and mediated diseases. Prior Technology

[0002] [background]

[0003] Viral pandemics have plagued humanity since ancient times, causing skin and mucous membrane infections such as cold sores and genital herpes. Symptoms often disrupt daily activities, and occasionally, HSV infection can be life-threatening (encephalitis) or cause vision impairment (keratitis), especially in newborns, the elderly, and immunocompromised patients, such as transplant recipients, cancer patients, or those with inherited immunodeficiency syndromes or diseases. Following infection, alpha herpesviruses persist latently in the host's neurons, periodically reactivating and often causing significant psychosocial distress. Currently, there is no cure.

[0004] To date, vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators, and small molecule drugs with specific or non-specific modes of action lack efficacy or the required safety profiles to replace nucleoside drugs acyclovir, valacyclovir, and famciclovir as first-line treatment options.

[0005] Aminothiazoles (such as pritelivir and HN0037) are among the most effective drugs currently under development. These antiviral agents work by inhibiting the helicase initiating enzyme of herpesviruses, exhibiting lower in vitro resistance rates and superior efficacy in animal models compared to nucleoside drugs. However, development is hampered by off-target carbonic anhydrase activity, reduced penetration into neuronal tissue and the brain, and unusual pharmacokinetic profiles.

[0006] Herpesviruses are neurotrophic viruses, meaning they enter and settle in neuronal tissue after infection, causing the virus to persist in the host's neurons in a latent form for life, resulting in permanent neuronal exposure. This permanent neuronal exposure to latent herpesviruses is the cause of the lifelong risk of recurrent, periodic reactivation of herpes infections, often causing severe psychosocial distress. This neuronal herpesvirus exposure can further cause herpesvirus encephalitis (or herpes simplex encephalitis; HSE), which is thought to be caused by the spread of the herpesvirus from the periaqueductal area of ​​the face or neuronal tissue along nerve axons to the brain after HSV-1 reactivation. The virus lies dormant in the trigeminal ganglion or neuronal tissue and enters the brain, causing HSE. Therefore, it is important to provide highly active antiviral drugs to allow for the treatment and elimination of (dormant) herpesviruses in neuronal tissue and nerves, thereby avoiding recurrence and reactivation of herpes infections or even serious consequences like HSE. Known antiviral drugs, such as known aminothiazoles, are not potent enough to enter neuronal tissue or cross the blood-brain barrier to enter the brain, and cannot provide effective and curative treatment for latent or dormant forms of herpesvirus or even HSE.

[0007] This patent application discloses novel solid crystalline forms of antiviral aminothiazole compounds with more suitable pharmacokinetic and stability profiles (e.g., allowing the antiviral drug compound to enter neuronal tissue and the brain to a greater extent due to improved solubility and bioavailability). Furthermore, the novel solid crystalline forms of antiviral aminothiazole compounds are characterized by improved compound stability and improved bioavailability, making them more suitable for drug development and use as pharmaceuticals. [Previous Technology]

[0008] General formula from prior art ( [A]) aminothiazoles It is known to be used as an antiviral compound.

[0009] Specifically, WO2003 / 007946 and WO2001 / 047904 disclose this type of aminothiazole ( [A]), where the X-series sulfonamide moiety is present. Both documents describe compounds with the following structure. It can be prepared by the method described in Example 8 of WO2003 / 007946 and the method described in Example 87 of WO2001 / 047904, and is in the form of a yellow solid with a melting point of 184°C.

[0010] WO2017 / 174640 describes the formula ( [A]) Thiazolyl amides, wherein X-series sulfonamides, sulfinamides, sulfinamides or sulfinamides.

[0011] WO2019 / 068817 describes a mirror isomer of the compound according to WO2017 / 174640.

[0012] WO2020 / 109389 describes novel uses of aminothiazole compounds in combination with oncolytic viruses for the treatment of cancer, based on WO2017 / 174640 and WO2019 / 068817.

[0013] International application WO2022 / 090409 describes deuterated analogues of compounds according to WO2017 / 174640 and WO2019 / 068817.

[0014] The non-patent publication “A helicase-primase drug candidate with sufficient target tissue exposure affects latent neural herpes simplex virus infections” by Gege et al. (Sci. Transl. Med. 2021;13:eabf8668) describes the experimental test results of various antiviral helicase primase inhibitor compounds described in the prior art.

[0015] None of these patent applications describe or mention the legal basis as defined in this case. [A]) in solid crystalline form. In particular, these documents do not specify any particular salt or solid form.

[0016] Several properties can be altered by crystallization or salt formation, such as solubility, dissolution rate, bioavailability, hygroscopicity, flavor, developability, and physical / chemical stability.

[0017] Given the availability of a large number of pharmaceutically acceptable relative ions and the lack of correlation between the nature of pharmaceutically acceptable relative ions and the final properties of the corresponding salts, the salt selection process is difficult and the results are unpredictable in advance.

[0018] There is a need to provide formulas with modified physicochemical and pharmaceutical properties. [A]) in the crystalline (salt) form of the antiviral compound, without negatively affecting other important parameters of the active compound, such as hygroscopicity or bioavailability, with the ultimate goal of obtaining the crystalline (salt) form of the antiviral compound according to formula (A). The manufacture, processing, storage and improvement of the pharmaceutical properties of compounds of [A]). Summary of the Invention

[0019] [summary]

[0020] This invention relates to the formula ( [I]) Novel solid form of antiviral helicase initiator inhibitor compounds: Where X is selected from and ; Y is selected from CH3 and CD3; Or a pharmaceutically acceptable salt, eutectic, hydrate or solvate thereof.

[0021] For example, these novel forms can be used to treat human patients suffering from herpes simplex-mediated diseases. The novel solid forms disclosed herein can be used to prepare pharmaceuticals for treating herpes simplex virus infection and disease. The novel solid forms disclosed herein can be used as helicase initiator enzyme inhibitors.

[0022] In some embodiments, this disclosure refers to novel solid forms of free base compounds having the following chemical structures. .

[0023] In some embodiments, this disclosure refers to novel solid forms of HCl salts having the following chemical structure. .

[0024] In some embodiments, this disclosure refers to novel deuterated solid forms of free alkali compounds having the following chemical structures. .

[0025] In some embodiments, this disclosure refers to novel solid forms of HCl salts having the following chemical structure. .

[0026] In some embodiments, this disclosure refers to novel solid forms of naphthalene disulfonates having the following chemical structure. .

[0027] In some embodiments, this disclosure refers to novel solid forms having the following chemical structures. .

[0028] In some embodiments, this disclosure refers to novel solid forms having the following chemical structures. .

[0029] In some embodiments, this disclosure refers to methods for preparing these novel solid forms. Simple Explanation of the Diagram

[0030] Figure 1 illustrates [IM-250] [Free base form] [I] X-ray powder diffraction (XRPD) pattern.

[0031] Figure 2 illustrates [IM-250] [Free base form] [I] Combined thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermal analysis chart.

[0032] Figure 3 shows the XRPD pattern of IM-250 in its free alkaline form III.

[0033] Figure 4 illustrates [IM-250] Combined TGA and DSC thermal analysis charts of [free base form III].

[0034] Figure 5 illustrates [IM-250 HCl] XRPD graph of [salt].

[0035] Figure 6 illustrates [IM-250 HCl] Combined TGA and DSC thermal analysis charts for [salt].

[0036] Figure 7 illustrates the crystallization process from EtOH. [IM-250 HCl] XRPD graph of [salt].

[0037] Figure 8 illustrates [IM-250] XRPD graph of [naphthalene disulfonate].

[0038] Figure 9 illustrates [IM-250] Combined TGA and DSC thermal analysis chromatograms of [naphthalene disulfonate].

[0039] Figure 10 illustrates XRPD graphics for [IM-315].

[0040] Figure 11 illustrates DSC thermal analysis chart of [IM-315].

[0041] Figure 12 illustrates various [IM-250] Graph showing the change in blood concentration over time in solid form in a mouse PK study.

[0042] Figure 13 illustrates the source. [IM-250] Superimposed XRPD graphs (normalized scale) of stress-free sample (below) of [free base form I] and samples stored at 40°C / 75%RH and 60°C for 2 weeks and 4 weeks.

[0043] Figure 14 illustrates [Deuteration] [IM-250] XRPD pattern of [free base (d3-IM-250)].

[0044] Figure 15 illustrates [Deuteration] [IM-250] TGA thermal analysis chromatogram of [free base (d3-IM-250)].

[0045] Figure 16 illustrates [Deuteration] [IM-250] DSC thermal analysis chromatogram of [free base (d3-IM-250)].

[0046] Figure 17 illustrates [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] XRPD graph of [salt].

[0047] Figure 18 illustrates [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] Combined TGA and DSC thermal analysis charts for [salt]. Implementation

[0048] [Detailed Description]

[0049] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments of this disclosure. However, those skilled in the art will understand that this disclosure may be practiced without these details. The following descriptions of several embodiments are provided as examples for understanding this disclosure as the claimed subject matter and are not intended to limit the scope of the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. [definition]

[0050] Unless the context otherwise requires, throughout this specification and the scope of the claims, the term "comprise" and its variations, such as "comprises" and "comprising," shall be interpreted in an open-ended, inclusive sense, meaning "including, but not limited to."

[0051] Throughout this specification, the terms "one embodiment" or "an embodiment" refer to a particular feature, structure, or characteristic described in connection with that embodiment that is included in at least one embodiment disclosed herein. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily refer to the same embodiment.

[0052] Furthermore, specific features, structures, or properties can be combined in any suitable manner in one or more embodiments.

[0053] Throughout this specification, the embodiments in which "crystalline form" is mentioned include those disclosed in this application. [I]) crystals, salts, eutectics, hydrates and / or solvates.

[0054] In the sense of this disclosure, "deuteration," "deuterated labeling," "deuterated substitution," or "deuteration" are all implied meanings. [I]) One or more hydrogen atoms in the compound are replaced with deuterium (2H, denoted by "D").

[0055] In some formulas ( In compounds [I], residue Y represents CD3. Surprisingly, these deuterated aminothiazole compounds exhibit increased metabolic resistance, and therefore, compared to individual undeuterated compounds, can be used to increase the resistance of (I] compounds when administered to mammals such as humans. [I]) The half-life of the compound. See, for example, Foster in Trends Pharmacol. Sci. 1984:5;524. Such deuterated aminothiazole compounds are synthesized by means well known in the art, for example, by using starting materials with one or more hydrogens replaced by deuterium (see Experimental Section for details).

[0056] The deuterium-labeled or substituted therapeutic compounds disclosed herein have surprisingly demonstrated modified DMPK (drug metabolism and pharmacokinetics) properties related to absorption, distribution, metabolism, and excretion (ADME). Deuterium substitution has proven to provide certain therapeutic advantages, stemming from increased metabolic stability, for example, increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index.

[0057] The concentration of deuterium can be defined by the isotopic enrichment factor. In the compounds disclosed herein, any atom not explicitly designated as a specific isotope signifies any stable or radioactive isotope of that atom. Unless otherwise stated, when a position is explicitly designated as "H" or "hydrogen," that position is understood to have hydrogen (approximately 99.98% hydrogen) in its naturally enriched isotopic composition. Therefore, in the compounds disclosed herein, any atom explicitly designated as deuterium (D) signifies deuterium with an isotopic purity of at least 50%, preferably at least 95%, and even more preferably at least 99%.

[0058] The percentage of deuterium incorporation can be obtained by quantitative analysis using many conventional methods, such as mass spectrometry (peak area) or by quantifying the residual 1H-NMR signal at a specific deuterated site in the compound compared to signals from internal standards or other non-deuterated 1H sources.

[0059] It will be recognized that, depending on the source of the chemical materials used in the synthesis, there will be some differences in the enrichment of natural isotopes in the synthesized compounds. Therefore, the preparation of non-deuterated analogs of the compounds of the present invention will inherently contain small amounts of deuterated isotope molecules. Despite this difference, the concentrations of naturally enriched stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotope substitution in the compounds of the present invention. See, for example, Comp. Biochem. Physiol. 1998;119A:725.

[0060] The term "isotope enrichment factor," typically used to describe the location occupied by hydrogen, refers to the ratio between the deuterium enrichment at that location and the natural deuterium enrichment at that location. For example, an isotope enrichment factor of 3500 means that the amount of deuterium at that location is 3500 times the natural deuterium enrichment, or that 52.5% of a compound has deuterium at that location (i.e., given a location, there is 52.5% deuterium). The enrichment of deuterium in Earth's oceans is approximately one atom out of 6500 hydrogen atoms (approximately 154 parts per million (ppm)). Therefore, deuterium accounts for approximately 0.015 percent (0.030 percent by weight) of all naturally occurring hydrogen atoms in Earth's oceans; the enrichment varies slightly from one type of natural water to another.

[0061] The deuterated compounds disclosed herein are preferably characterized by an isotope enrichment factor of at least 6300 or a deuteration degree of at least 95%. More preferably, they have an isotope enrichment factor of at least 6500 or a deuteration degree of at least 98%.

[0062] Any formula or structure given in this application is also intended to represent compounds that additionally contain isotopically labeled atoms. Examples of additional isotopes that may be incorporated into the compounds disclosed herein include additional isotopes of hydrogen, and isotopes of carbon, nitrogen, oxygen, and fluorine, such as, but not limited to, 3H (tritium), 11C, 13C, 14C, 15N, 18F, and 35S. This disclosure further includes various isotopically labeled compounds in which radioactive isotopes such as 3H, 13C, and 14C are incorporated. Such isotopically labeled compounds can be used for metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays or radiotherapy of patients. The isotopically labeled compounds and their precursors disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents using the processes disclosed in the embodiments or examples and the preparations described below.

[0063] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, gliding agents, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents and / or emulsifiers, or combinations thereof, that have been approved for use in humans or livestock by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the corresponding agencies in other countries.

[0064] "Pharmaceutical composition" refers to the compounds disclosed herein (e.g., those with formula (...) [I]) compounds and formulations generally accepted in the art for delivering bioactive compounds to mammals, such as humans (drug delivery forms). Such media include all pharmaceutically acceptable excipients.

[0065] The term "effective amount" means an amount of a compound that, when administered, is sufficient to prevent the development of one or more symptoms of an infection or condition, disease or illness, or to alleviate, to some extent, one or more symptoms of an infection or condition, disease or illness. The term "effective amount" also refers to an amount of a compound that is sought by researchers, veterinarians, physicians, or clinicians to elicit a biological or medical response in cells, tissues, systems, animals, or humans.

[0066] "Prevention," "preventing," or "prophylaxis" refers to any treatment of an infection, disease, or condition that prevents the development of clinical symptoms of that disease or condition.

[0067] In some implementations, the compound may be administered to individuals (including humans) who are at risk or have a family history of infection, disease, or condition.

[0068] The "treating" and "treatment" of a disease include the following: (1) To prevent or reduce the risk of disease development, that is, to prevent individuals who may be exposed to or susceptible to the disease but have not yet experienced or shown symptoms of the disease from developing clinical symptoms of the disease. (2) Suppressing the disease, that is, preventing or reducing the development of the disease or its clinical symptoms. (3) Alleviate (cure) the disease, that is, cause the disease or its clinical symptoms to subside, and (4) Improve or alleviate symptoms or damage caused by the disease.

[0069] The terms "individual" or "patient" refer to an animal, such as a mammal (including humans), that has been or will be a subject of treatment, observation, or experimentation. The methods described in this application can be used for human therapeutics and / or veterinary applications. In some embodiments, the individual is a mammal (or patient). In some embodiments, the individual (or patient) is a human, a livestock animal (e.g., dogs and cats), a farm animal (e.g., cattle, horses, sheep, goats, and pigs), and / or a laboratory animal (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys). In some embodiments, the individual (or patient) is a human. "A human (or patient) in need of treatment" means a human who may have or is suspected of having an infection, disease, or condition that could benefit from some form of treatment; for example, treatment with the compounds disclosed in this application.

[0070] In this case, the reference to "about" a value or parameter includes (and describes) the implementation of that value or parameter. For example, a description of "about x" includes a description of "x". Furthermore, the singular forms "a" and "the" include plural references unless the context clearly specifies otherwise. Thus, for example, a reference to "compound" includes plural such compounds, and a reference to "test" includes reference to one or more tests and equivalents known to those skilled in the art.

[0071] "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0072] When referring to, for example, XRPD graphs, DSC thermal analysis plots, or TGA thermal analysis plots, the term "substantially as shown" includes graphs, thermal analysis plots, or spectra that are not necessarily identical to those shown in this case, but which, in the opinion of someone of ordinary skill in the art, fall within the range of experimental error or deviation.

[0073] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including inorganic bases or acids and organic bases or acids. Where the compounds disclosed herein contain one or more acidic or basic groups, this disclosure also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly those that are pharmaceutically usable. Therefore, compounds of this disclosure containing acidic groups may be present on such groups and may be used according to this disclosure, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with amines or organic amines such as ethylamine, ethanolamine, triethanolamine, or amino acids. Compounds of this disclosure containing one or more basic groups, i.e., protonable groups, may be present and used according to this disclosure as 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, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds disclosed herein contain both acidic and basic groups in their molecule, then this disclosure includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions).

[0074] The corresponding salts 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 or cation exchange with other salts. This disclosure also includes all salts of the compounds disclosed herein that are unsuitable for direct use in pharmaceuticals due to low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or as intermediates in the preparation of pharmaceutically acceptable salts.

[0075] Generally speaking, according to formula ( The formation of salts of compounds of formula (I) can be carried out by conventional crystallization methods. Preferably, it is achieved by crystallizing the salts of the compounds of formula (I) [I]) The compound is mixed with a water-miscible solvent or solvent mixture, and a selected acid or base is added to form the corresponding salt. The resulting crystalline salt is isolated by conventional methods including, for example, filtration, washing and drying.

[0076] Furthermore, the compounds disclosed herein may exist in the form of solvates, including, for example, water as a solvate or pharmaceutically acceptable solvates, such as alcohols, particularly ethanol. A "solvate" is formed by the interaction of a solvent and a compound. When the solvent is water, a "solvate" is a "hydrate." It should be understood that salts disclosed herein may also include solvates.

[0077] Used to form the formula as defined in this case ( Suitable solvents for the salts and solvents of the compounds [I] include: acetonitrile, dichloromethane (DCM), alcohols, especially methanol, ethanol, 2-propanol (isopropanol), aldehydes, ketones, especially acetone, ethers, such as tetrahydrofuran (THF) or dioxane, esters, such as ethyl acetate, or alkanes, such as especially pentane, hexane, heptane or cyclohexane and water, and mixtures thereof.

[0078] In some embodiments, optical isomers, racemates, or other mixtures of the compound described herein or its pharmaceutically acceptable salts or mixtures thereof are provided. If desired, the isomers can be separated by methods well known in the art, such as liquid chromatography. In those cases, a single mirror-image isomer or diastereomeric isomer, i.e., the optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be performed, for example, by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, for example, using a microscopic high-performance liquid chromatography (HPLC) column or a microscopic supercritical fluid chromatography (SFC) column.

[0079] "Stereoisomers" refer to compounds made of identical atoms bonded by the same bonds but with different three-dimensional structures and not interchangeable. The term "mirror image isomers" means each individual optically active form of the compounds of the present invention having an optical purity of at least 80% (i.e., at least 90% of one mirror image isomer and at most 10% of other mirror image isomers), preferably at least 90%, and more preferably at least 98% (as determined by standard methods in the art).

[0080] The compounds disclosed in this invention and their pharmaceutically acceptable salts may include asymmetric centers, thus resulting in mirror-image isomers, diastereomers, and other stereoisomers, which may be defined as I- or (S)- according to absolute stereochemistry. This invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-) or (R)- and (S)- isomers can be prepared using palmitic synthon or palmitic reagent, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual mirror-image isomers include palmitic synthesis from suitable optically pure precursors or, for example, resolution by HPLC or SFC from racemic mixtures (or racemic mixtures of salts or derivatives). [Formula (I)] [The solid form of the compound]

[0081] Mode( [I]) The solid form of the compound, including crystalline and substantially pure forms, offers advantages in bioavailability and stability, making it suitable for use as an active ingredient in pharmaceutical compositions. Surprisingly, [IM-250 HCl] [Salt], for example, exhibits favorable physical properties, such as good physical and chemical stability, good water solubility, and good bioavailability, while being non-hygroscopic. Changes in the crystal structure of pharmaceutical active pharmaceutical ingredients (APIs) or active ingredients can affect dissolution rates (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, the ability to consistently prepare amounts of known strength), and the stability of pharmaceutical products or active ingredients (e.g., thermal stability, shelf life, etc.). Such changes can affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solutions or solid oral dosage forms, including tablets and capsules. Compared to other forms, such as amorphous or non-crystalline forms, specific crystalline forms can provide desired or suitable hygroscopicity, particle size control, improved dissolution rates, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Therefore, formula ( [I]) The solid (crystalline) form of a compound can provide advantages, such as improvements in: the manufacturing process of the compound, the stability or storability of the compound as a pharmaceutical product, the stability or storability of the active pharmaceutical ingredient of the compound, and / or the bioavailability and / or stability of the compound as an active agent.

[0082] It has been found that the use of certain solvents and / or processes can produce the product described in this case ( [I]) Different solid forms of the compound may exhibit one or more of the aforementioned desirable properties. The methods for preparing the solid forms described in this case and the qualitative analysis of such solid forms are detailed below.

[0083] In a particular implementation, formula () is disclosed [I]) Novel solid forms of compounds, such as crystalline forms. This invention relates in particular to the following embodiments:

[0084] In a preferred embodiment, in combination with any of the above or below embodiments, X is selected from... and .

[0085] In a preferred embodiment, in combination with any of the above or below embodiments, the X series .

[0086] In a preferred embodiment, in combination with any of the above or below embodiments, Y is selected from CH3 and CD3.

[0087] In a preferred embodiment, in combination with any of the above or below embodiments, Y-series CH3.

[0088] In a further preferred embodiment, in combination with any of the above or below embodiments, X is selected from... At the same time, Y-series CH3 or CD3.

[0089] In a further embodiment combined with any of the above or below embodiments, X is selected from... Meanwhile, Y is CH3, and compounds with the following general formula are excluded. .

[0090] Preferred embodiments in combination with any of the above or below embodiments regarding formula ( [I]) The solid (crystalline) form of the compound has the following structure , Or a pharmaceutically acceptable salt, eutectic, hydrate or solvate thereof.

[0091] Another preferred embodiment, in combination with any of the above or below embodiments, relates to formula ( [I]) The solid (crystalline) form of the compound has the following structure , Or a pharmaceutically acceptable salt, eutectic, hydrate or solvate thereof.

[0092] Another preferred embodiment, in combination with any of the above or below embodiments, relates to formula ( [I]) The solid (crystalline) form of the compound has the following structure , Or a pharmaceutically acceptable eutectic, hydrate or solvate thereof.

[0093] Another preferred embodiment, in combination with any of the above or below embodiments, relates to formula ( [I]) The solid (crystalline) form of the compound has the following structure , Or a pharmaceutically acceptable eutectic, hydrate or solvate thereof, preferably further characterized by having a melting point of 197°C (±5°C) and / or being a white solid. [IM-250] [Free base]

[0094] One embodiment of the present invention relates to formula ( [I]) solid (crystalline) compounds having the following structure , It exists in the form of a free alkali. [IM-250] [Free base form I]

[0095] In some embodiments, this type of IM-250 free alkali is in solid crystalline form. [IM-250] [Free base form I] exists, and it has the following structure , This solid [IM-250] The characteristic of [Free Alkali Form I] is the X-ray powder diffraction pattern (XRPD) containing 2θ-reflection (±0.2 degrees 2θ) (characteristic peaks) at angles of 9.2 degrees, 13.7 degrees and 18.7 degrees.

[0096] In some implementations, [IM-250] [Free base form] [I] is characterized by XRPD graphics containing one, two, or three of the following: angular 2θ-reflection (±0.2 degrees 2θ) at 9.2 degrees, 13.7 degrees, and 18.7 degrees, and angular 2θ-reflection (±0.2 degrees 2θ) at 14.4 degrees, 24.0 degrees, and 27.3 degrees.

[0097] In some implementations, [IM-250] [Free base form] [I] is characterized by XRPD graphics containing 2θ-reflection (±0.2 degrees 2θ) at angles of 9.2 degrees, 13.7 degrees, 14.4 degrees, 18.7 degrees, 24.0 degrees and 27.3 degrees.

[0098] In some implementations, [IM-250] [Free base form I] is characterized by an XRPD pattern containing at least four of the following (characteristic) peaks: 9.2°, 13.7°, 14.4°, 18.7°, 24.0° and 27.3° 2θ (±0.2° 2θ).

[0099] All values ​​were determined using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0100] In some implementations, crystallization [IM-250] [Free base form I] has an XRPD pattern with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD patterns that are substantially as shown in Figure 1, with the maximum intensity of angular reflection at 20°.

[0101] More preferably, this type of solid free base, [IM-250] [Free base form I] [,] This displays what is essentially an X-ray powder diffraction (XRPD) pattern as shown in Figure 1.

[0102] In addition, this type [IM-250] [Free base form I] can be represented by a differential scanning calorimetry (DSC) thermal analysis graph, which is essentially as shown in Figure 2.

[0103] In addition, this type [IM-250] [Free base form I] can be represented by a thermogravimetric analysis (TGA) thermal analysis diagram as shown in Figure 2.

[0104] During crystallization [IM-250] In some embodiments of [free base form I], at least one, at least two, or all of the following (a)-(c) apply: (a) crystallization [IM-250] [Free base form I] has a substantially XRPD pattern as shown in Figure 1; (b) Crystallization [IM-250] [Free base form I] has a substantially DSC thermal analysis diagram as shown in Figure 2; (c) Crystallization [IM-250] [Free base form I] has a TGA thermal analysis diagram as shown in Figure 2.

[0105] In some implementations, crystallization [IM-250] [Free base form I] has at least one, at least two, or at least three of the following characteristics: (a) Essentially, the XRPD graphic is shown in Figure 1. (b) Essentially, the DSC thermal analysis diagram shown in Figure 2 (c) Essentially, the TGA thermal analysis diagram is shown in Figure 2.

[0106] In some implementations, [IM-250] [Free base form I] has a differential scanning calorimetry chromatogram containing endothermic heat starting at about 163°C.

[0107] Therefore, solid [IM-250] Another characteristic of [free alkali form I] is that it has a melting point of 164 to 165°C (±5°C). [IM-250] [Free base form III]

[0108] In some embodiments, this type of IM-250 free alkali is in solid crystalline form. [IM-250] [Free base form III] exists, and it has the following structure , This solid [IM-250] [Free base form] [III] is characterized by XRPD graphics containing 2θ-reflection (±0.2 degrees 2θ) at angles of 9.7 degrees, 12.3 degrees and 15.6 degrees (characteristic peaks).

[0109] In some implementations, [IM-250] [Free base form] [III] is characterized by XRPD graphics containing one, two, or three of the following: angular 2θ-reflection (±0.2 degrees 2θ) at 9.7 degrees, 12.3 degrees, and 15.6 degrees, and angular 2θ-reflection (±0.2 degrees 2θ) at 12.9 degrees, 22.7 degrees, and 23.8 degrees.

[0110] In some implementations, [IM-250] [Free base form] [III] is characterized by XRPD graphics containing 2θ-reflection (±0.2 degrees 2θ) at angles of 9.7 degrees, 12.3 degrees, 12.9 degrees, 15.6 degrees, 22.7 degrees and 23.8 degrees.

[0111] In some implementations, [IM-250] [Free base form] [III] is characterized by an XRPD graph containing at least four of the following (characteristic) peaks: 9.7 degrees, 12.3 degrees, 12.9 degrees, 15.6 degrees, 22.7 degrees and 23.8 degrees 2θ (±0.2 degrees 2θ).

[0112] All values ​​were determined using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0113] In some implementations, crystallization [IM-250] [Free base form] [III] An XRPD graphic having at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD graphics with a maximum intensity of angular reflection at 20° as shown in Figure 3.

[0114] More preferably, this type of solid free base, [IM-250] [Free base form III] [,] This displays what is essentially an X-ray powder diffraction (XRPD) pattern as shown in Figure 3.

[0115] In addition, this type [IM-250] [Free base form III] can be displayed as a differential scanning calorimetry (DSC) thermal analysis graph, which is essentially as shown in Figure 4.

[0116] In addition, this type [IM-250] [Free base form III] can be represented by a thermogravimetric analysis (TGA) thermal analysis diagram, which is essentially as shown in Figure 4.

[0117] During crystallization [IM-250] In some embodiments of [free base form III], at least one, at least two, or all of the following (a)-(c) apply: (a) crystallization [IM-250] [Free base form III] has a substantially XRPD pattern as shown in Figure 3; (b) Crystallization [IM-250] [Free base form III] has a substantially DSC thermal analysis diagram as shown in Figure 4; (c) Crystallization [IM-250] [Free base form III] has a substantially TGA thermal analysis curve as shown in Figure 4.

[0118] In some implementations, crystallization [IM-250] [Free base form III] has at least one, at least two, or at least three of the following characteristics: (a) Essentially, the XRPD graphic is shown in Figure 3. (b) Essentially, the DSC thermal analysis diagram shown in Figure 4 (c) Essentially, the TGA thermal analysis diagram is shown in Figure 4.

[0119] In some implementations, [IM-250] [Free base form III] has a differential scanning calorimetric chromatogram that includes endothermic activity starting at approximately 141 °C.

[0120] Therefore, solid [IM-250] [Free base form III] is also characterized by having a melting point of 143°C (±5°C). [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base]

[0121] Another embodiment of the present invention relates to formula ( [I]) solid (crystalline) compounds, which are [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base], which has the following structure , This solid [Deuteration] [IM-250] [Free base (d3-IM-250)] The characteristic of [free base] is the X-ray powder diffraction pattern (XRPD) containing 2θ-reflection (±0.2 degrees 2θ) (characteristic peaks) at angles of 9.3 degrees, 13.7 degrees and 18.6 degrees.

[0122] In some implementations, [Deuteration] [IM-250] [Free base (d3-IM-250)] The [free base] is characterized by XRPD graphics containing one, two, three, or four of the following: angular 2θ-reflection (±0.2 degrees 2θ) at 9.3 degrees, 13.7 degrees, and 18.6 degrees, and angular 2θ-reflection (±0.2 degrees 2θ) at 14.4 degrees, 15.3 degrees, 15.5 degrees, and 24.1 degrees.

[0123] In some implementations, [Deuteration] [IM-250] [Free base (d3-IM-250)] The [free base] is characterized by XRPD graphics containing 2θ-reflection (±0.2 degrees 2θ) at angles of 9.3 degrees, 13.7 degrees, 14.4 degrees, 15.3 degrees, 15.5 degrees, 18.6 degrees and 24.1 degrees.

[0124] In some implementations, [Deuteration] [IM-250] [Free base (d3-IM-250)] The [free base] is characterized by an XRPD pattern containing at least four of the following (characteristic) peaks: 9.3°, 13.7°, 14.4°, 15.3°, 15.5°, 18.6° and 24.1° 2θ (±0.2° 2θ).

[0125] All values ​​were determined using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0126] In some implementations, crystallization [Deuteration] [IM-250] [Free base] [(d3-IM-250)] [Free base] has an XRPD pattern with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD patterns that are substantially as shown in Figure 14, with the maximum intensity of the angle 20-reflection.

[0127] More preferably, this type of solid free base, [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base], which essentially displays the X-ray powder diffraction (XRPD) pattern shown in Figure 14.

[0128] In addition, this type [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base] can be displayed as a differential scanning calorimetry (DSC) thermal analysis graph, as shown in Figure 16.

[0129] In addition, this type [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base] can be displayed as a thermogravimetric analysis (TGA) thermal analysis diagram, as shown in Figure 15.

[0130] During crystallization [Deuteration] [IM-250] [Free base (d3-IM-250)] In some embodiments of [free base], at least one, at least two, or all of the following (a)-(c) apply: (a) crystallization [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base] has a substantially XRPD pattern as shown in Figure 14; (b) Crystallization [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base] has a DSC thermal analysis chart as shown in Figure 16; (c) Crystallization [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base] has a TGA thermal analysis diagram as shown in Figure 15.

[0131] In some implementations, crystallization [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base] has at least one, at least two, or at least three of the following characteristics: (a) Essentially, the XRPD graphic is shown in Figure 14. (b) Essentially, the DSC thermal analysis diagram shown in Figure 16 (c) Essentially, the TGA thermal analysis diagram is shown in Figure 15.

[0132] In some implementations, [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base] has a differential scanning calorimetry chromatogram that includes endothermic activity starting at about 163°C.

[0133] Therefore, solid [Deuteration] [IM-250] [Free base (d3-IM-250)] Another characteristic of [free alkali] is that it has a melting point of 163 to 165°C (±5°C). [Selected salt forms of the compounds of this invention]

[0134] Another embodiment of the present invention relates to formula ( The preferred salt form is (I) [I]), among which X Series .

[0135] Particularly preferred are the HCl salts and naphthalene disulfonates of the compounds of the present invention, for example, especially those of formula ( [I]) HCl salt and naphthalene disulfonate of the compound, wherein the HCl salt is preferred, and wherein X Series ,as well as Y is selected from CH3 and CD3; and its hydrates or solvates. [IM-250 HCl] [Salt]

[0136] Another embodiment of the present invention relates to the HCl salt of compound IM-250, which is [IM-250 HCl] [Salt] has the following structure .

[0137] In one embodiment of the present invention, such [IM-250 HCl] The characteristic of [salt] is the XRPD pattern containing 2θ-reflection (±0.3 degrees 2θ) at angles of 13.7 degrees, 17.7 degrees, and 22.8 degrees (characteristic peaks).

[0138] In some implementations, [IM-250 HCl] The characteristic of [salt] is that it contains one, two or three of the following XRPD graphics: angular 2θ-reflection (±0.3 degrees 2θ) at 13.7 degrees, 17.7 degrees and 22.8 degrees, and angular 2θ-reflection (±0.3 degrees 2θ) at 17.0 degrees, 19.8 degrees and 21.8 degrees.

[0139] In some implementations, [IM-250 HCl] The [salt] is characterized by XRPD graphics containing 2θ-reflection (±0.3 degrees 2θ) at angles of 13.7 degrees, 17.0 degrees, 17.7 degrees, 19.8 degrees, 21.8 degrees and 22.8 degrees.

[0140] In some implementations, [IM-250 HCl] The characteristic of [salt] is that it contains at least four of the following XRPD peaks: 13.7°, 17.0°, 17.7°, 19.8°, 21.8° and 22.8° 2θ (±0.3° 2θ).

[0141] All values ​​were determined using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0142] In some implementations, crystallization [IM-250 HCl] [Salt] has an XRPD graphic that displays an XRPD graphic of substantially the same intensity as shown in Figure 5, with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD graphics with a maximum intensity of 20° reflection.

[0143] In some implementations, crystallization [IM-250 HCl] [Salt] has an XRPD graphic that displays an XRPD graphic of substantially the same intensity as shown in Figure 7, with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD graphics with an angle of 20° of maximum intensity.

[0144] In some embodiments, such solid HCl salts are used. [IM-250 HCl] [Salt] displays an X-ray powder diffraction (XRPD) pattern, which is essentially as shown in Figure 5.

[0145] In some embodiments, such solid HCl salts are used. [IM-250 HCl] [Salt] displays an X-ray powder diffraction (XRPD) pattern, which is essentially as shown in Figure 7.

[0146] In addition, this type [IM-250 HCl] [Salt] can be displayed as a differential scanning calorimetry (DSC) thermal analysis graph, as shown in Figure 6.

[0147] In addition, this type [IM-250 HCl] [Salt] can be displayed as a thermogravimetric analysis (TGA) thermal analysis diagram, as shown in Figure 6.

[0148] During crystallization [IM-250] [HCl] In some embodiments of the [salt], at least one, at least two, or all of the following (a)-(c) apply: (a) crystallization [IM-250 HCl] [Salt] has a substantially XRPD pattern as shown in Figure 5; (b) Crystallization [IM-250 HCl] [Salt] has a substantially DSC thermal analysis diagram as shown in Figure 6; (c) Crystallization [IM-250 HCl] [Salt] has a TGA thermal analysis diagram as shown in Figure 6.

[0149] In some implementations, crystallization [IM-250] [HCl] [Salt] has at least one, at least two, or at least three of the following properties: (a) Essentially, the XRPD graphic is shown in Figure 5. (b) Essentially, the DSC thermal analysis diagram shown in Figure 6 (c) Essentially, the TGA thermal analysis diagram is shown in Figure 6.

[0150] During crystallization [IM-250] [HCl] In some embodiments of the [salt], at least one, at least two, or all of the following (a)-(c) apply: (a) crystallization [IM-250] [HCl] [Salt] has a substantially XRPD pattern as shown in Figure 7; (b) Crystallization [IM-250] [HCl] [Salt] has a substantially DSC thermal analysis diagram as shown in Figure 6; (b) Crystallization [IM-250] [HCl] [Salt] has a TGA thermal analysis diagram as shown in Figure 6.

[0151] In some implementations, crystallization [IM-250] [HCl] [Salt] has at least one, at least two, or at least three of the following properties: (a) Essentially, the XRPD graphic is shown in Figure 7. (b) Essentially, the DSC thermal analysis diagram shown in Figure 6 (c) Essentially, the TGA thermal analysis diagram is shown in Figure 6.

[0152] In some implementations, [IM-250 HCl] Thermogravimetric analysis (TGA) of the [salt] showed a mass loss of approximately 9.8% when heated at a start / end temperature of approximately 151 / 170°C.

[0153] In some implementations, [IM-250 HCl] Thermogravimetric analysis (TGA) of the salt showed that the decomposition began at approximately 221°C.

[0154] In some embodiments, this application provides a structure with the following features [IM-250 HCl] [Salt] , The hydrochloride and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonylimino)thiazo-2-yl)acetamide are in a molar ratio of 1:1±0.2.

[0155] The HCl salt, [IM-250 HCl] [Salt] surprisingly exhibits several advantages regarding chemical and physical stability, (lack) hygroscopicity, and improved bioavailability, while other tested salts, as shown in the following examples, are less advantageous. Therefore, compounds [IM-250 HCl] [Salt] is a particularly preferred embodiment of the present invention. [Deuteration] [IM-250 HCl] [Salt - d3-IM-250 HCl] [Salt]

[0156] Other embodiments of the present invention [IM-250 HCl] [Salt] The HCl salt of the corresponding deuterated compound of the compound ( [d3-IM-250 HCl] [salt]), has the following structure .

[0157] In one embodiment of the present invention, such [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] The characteristic of [salt] is the XRPD pattern containing 2θ-reflection (±0.3 degrees 2θ) at angles of 13.8 degrees, 17.8 degrees and 21.8 degrees (characteristic peaks).

[0158] In some implementations, [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] The [salt] is characterized by XRPD graphics containing one, two, three, four, or five of the following: angular 2θ-reflection (±0.3 degrees 2θ) at 13.8 degrees, 17.8 degrees, and 21.8 degrees, and angular 2θ-reflection (±0.3 degrees 2θ) at 11.3 degrees, 11.9 degrees, 19.8 degrees, 21.0 degrees, and 21.3 degrees.

[0159] In some implementations, [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] The [salt] is characterized by XRPD graphics containing 2θ-reflection (±0.3 degrees 2θ) at angles of 11.3 degrees, 11.9 degrees, 13.8 degrees, 17.8 degrees, 19.8 degrees, 21.0 degrees, 21.3 degrees and 21.8 degrees.

[0160] In some implementations, [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] is characterized by an XRPD pattern containing at least four of the following peaks: 11.3°, 11.9°, 13.8°, 17.8°, 19.8°, 21.0°, 21.3° and 21.8° 2θ (±0.3° 2θ).

[0161] All values ​​were determined using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0162] In some implementations, crystallization [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] has an XRPD graphic that displays an XRPD graphic of substantially the same intensity as shown in Figure 17, with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine reflections at an angle of 20° with maximum intensity.

[0163] In some embodiments, such solid HCl salts are used. [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] displays an X-ray powder diffraction (XRPD) pattern, which is essentially as shown in Figure 17.

[0164] In addition, this type [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] can be displayed as a differential scanning calorimetry (DSC) thermal analysis graph, as shown in Figure 18.

[0165] In addition, this type [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] can be displayed as a differential scanning calorimetry (TGA) thermal analysis graph, as shown in Figure 18.

[0166] During crystallization [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] In some embodiments of [salt], at least one, at least two, or all of the following (a)-(c) apply: (a) crystallization [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] has a substantially XRPD pattern as shown in Figure 17; (b) Crystallization [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] has a DSC thermal analysis diagram substantially as shown in Figure 18; (c) Crystallization [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] has a TGA thermal analysis diagram that is essentially as shown in Figure 18.

[0167] In some implementations, crystallization [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] has at least one, at least two, or at least three of the following properties: (a) Essentially, the XRPD graphic is shown in Figure 17. (b) Essentially, the DSC thermal analysis diagram shown in Figure 18 (c) Essentially, the TGA thermal analysis diagram is shown in Figure 18.

[0168] In some implementations, [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] Thermogravimetric analysis (TGA) of the [salt] showed a mass loss of approximately 7.8% when heated at a start / end temperature of approximately 149 / 167°C.

[0169] In some implementations, [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] Thermogravimetric analysis (TGA) of the [salt] showed that the decomposition began at approximately 225°C.

[0170] In some implementations, [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] has a differential scanning calorimetry thermal analysis plot that includes endothermic activity starting at approximately 188°C.

[0171] Therefore, solid [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] Another characteristic of [salt] is that it has a melting point of 188 to 194°C (±5°C).

[0172] In some embodiments, this application provides a structure with the following features [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt)] , The hydrochloride and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-d3)-5-(S-methylsulfonylimino)thiazolyl)acetamide are in a molar ratio of 1:1±0.2.

[0173] This deuterated HCl salt, [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] surprisingly exhibits several advantages regarding chemical and physical stability, (lack) hygroscopicity, and improved bioavailability, while other tested salts are less favorable. Therefore, crystallization... [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] is a particularly preferred embodiment of the present invention. [IM-250] [Naphthalene disulfonate]

[0174] Another embodiment of the present invention relates to the naphthalene disulfonate of compound IM-250, which is [IM-250] [Naphthalene disulfonate] has the following structure .

[0175] In one embodiment of the present invention, such [IM-250] [Naphthalene disulfonate] is characterized by having XRPD patterns containing 2θ-reflection (±0.2 degrees 2θ) (characteristic peaks) at angles of 9.1 degrees, 14.5 degrees and 18.1 degrees.

[0176] In some implementations, [IM-250] [Naphthalene disulfonate] is characterized by XRPD graphics containing one, two, or three of the following: angular 2θ-reflection (±0.2 degrees 2θ) at 9.1 degrees, 14.5 degrees, and 18.1 degrees, and angular 2θ-reflection (±0.2 degrees 2θ) at 15.6 degrees, 19.1 degrees, and 20.9 degrees.

[0177] In some implementations, [IM-250] [Naphthalene disulfonate] is characterized by XRPD graphics containing 2θ-reflection (±0.2 degrees 2θ) at angles of 9.1 degrees, 14.5 degrees, 15.6 degrees, 18.1 degrees, 19.1 degrees and 20.9 degrees.

[0178] In some implementations, [IM-250] [Naphthalene disulfonate] is characterized by an XRPD pattern containing at least four peaks at 2θ: 9.1°, 14.5°, 15.6°, 18.1°, 19.1° and 20.9° (±0.2° 2θ).

[0179] All values ​​were determined using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0180] In some implementations, crystallization [IM-250] [Naphthalene disulfonate] has an XRPD pattern that displays substantially the XRPD pattern shown in Figure 8, with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine XRPD patterns with maximum intensity of angular reflection at 20°.

[0181] More preferably, such solid forms [IM-250] [Naphthalene disulfonate] exhibits an X-ray powder diffraction (XRPD) pattern, essentially as shown in Figure 8.

[0182] In addition, this type [IM-250] [Naphthalene disulfonate] can be displayed using differential scanning calorimetry (DSC) thermal analysis, as shown in Figure 9.

[0183] In addition, this type [IM-250] [Naphthalene disulfonate] can be displayed in a thermogravimetric analysis (TGA) thermal analysis diagram as shown in Figure 9.

[0184] During crystallization [IM-250] In some embodiments of [naphthalene disulfonate], at least one, at least two, or all of the following (a)-(c) are applicable: (a) crystallization [IM-250] [Naphthalene disulfonate] has a substantially XRPD pattern as shown in Figure 8; (b) Crystallization [IM-250] [Naphthalene disulfonate] has a substantially similar DSC thermal analysis pattern as shown in Figure 9; (c) Crystallization [IM-250] [Naphthalene disulfonate] has a substantially similar TGA thermal analysis curve as shown in Figure 9.

[0185] In some implementations, crystallization [IM-250] [Naphthalene disulfonate] has at least one, at least two, or at least three of the following properties: (a) Essentially, the XRPD graphic is shown in Figure 8. (b) Essentially, the DSC thermal analysis diagram shown in Figure 9 (c) Essentially, the TGA thermal analysis diagram is shown in Figure 9.

[0186] In some implementations, [IM-250] [Naphthalene disulfonate] has a differential scanning calorimetry chromatogram containing an exothermic reaction starting at about 223 °C.

[0187] Therefore, solid [IM-250] Another characteristic of [naphthalene disulfonate] is that it has a melting point of 230°C (±5°C).

[0188] In some embodiments, this application provides a structure with the following features [IM-250] [Naphthalene disulfonate] , Naphthalene-1,5-disulfonate and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonylimino)thiazo-2-yl)acetamide are in a molar ratio of 1:2±0.2.

[0189] The naphthalene disulfonate, [IM-250] [Naphthalene disulfonate] surprisingly exhibits several advantages regarding chemical and physical stability, (lack) hygroscopicity, and improved bioavailability, while other tested salts, as shown in the examples below, are less advantageous. Therefore, the compound... [IM-250] [Naphthalene disulfonate] is a particularly preferred embodiment of the present invention. [Deuteration] [IM-250] [Naphthalene disulfonate] [– d3-IM-250] [Naphthalene disulfonate]

[0190] In another embodiment of the invention, [IM-250] [Naphthalene disulfonate] salts can also deuterate compounds. [IM-250] exists in its deuterated form as shown in the following structure. . [Solid form IM-315]

[0191] Another embodiment of the present invention relates to formula ( [I]) solid (crystalline) compounds, which are [IM-315] has the following structure , This solid The [IM-315] form is characterized by having XRPD graphics containing 2θ-reflections (±0.2 degrees 2θ) at angles of 6.4 degrees, 12.5 degrees, and 18.3 degrees (characteristic peaks).

[0192] In some implementations, [IM-315] is characterized by an XRPD graphic containing one or both of the following: angular 2θ-reflection (±0.2 degrees 2θ) at 6.4 degrees, 12.5 degrees and 18.3 degrees, and angular 2θ-reflection (±0.2 degrees 2θ) at 22.3 degrees and 23.1 degrees.

[0193] In some implementations, [IM-315] has XRPD graphics containing 2θ-reflection (±0.2 degrees 2θ) at angles of 6.4 degrees, 12.5 degrees, 18.3 degrees, 22.3 degrees and 23.1 degrees.

[0194] In some implementations, [IM-315] has at least 3 XRPD graphs of the peaks below: 6.4°, 12.5°, 18.3°, 22.3° and 23.1° 2θ (±0.2° 2θ).

[0195] All values ​​were determined using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0196] In some implementations, crystallization [IM-315] has an XRPD graphic that displays an XRPD graphic of substantially the same intensity as shown in Figure 10, with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine reflections at a maximum intensity angle of 20.

[0197] More preferably, such solid forms [IM-315] displays an X-ray powder diffraction (XRPD) pattern, which is essentially as shown in Figure 10.

[0198] In addition, this type [IM-315] can display a differential scanning calorimetry (DSC) thermal analysis plot, which is essentially as shown in Figure 11.

[0199] During crystallization In some embodiments of [IM-315], at least one or all of the following (a)-(b) apply: (a) crystallization [IM-315] has a substantially XRPD pattern as shown in Figure 10; (b) crystallization [IM-315] has a DSC thermal analysis chart that is essentially as shown in Figure 11.

[0200] In some implementations, crystallization [IM-315] has at least one or at least two of the following characteristics: (a) Essentially, the XRPD graphic is shown in Figure 10. (b) Essentially, the DSC thermal analysis diagram is shown in Figure 11.

[0201] In addition, this type The [IM-315] form has a differential scanning calorimetry thermal analysis plot containing exothermic data starting at approximately 196°C.

[0202] Therefore, solid The [IM-315] form is also characterized by having a melting point of 197°C (±5°C).

[0203] As described in Example 5, according to the present invention [IM-315] exists as a white solid.

[0204] Conversely, the compound of example number 87 disclosed in WO2003 / 007946 and WO2001 / 047904 is characterized by having a melting point of 184°C and being obtained as a pale yellow solid. Accordingly, according to the present invention... [IM-315] is different from example compound number 87 of WO2003 / 007946 and WO2001 / 047904, and can be summarized in this form. [IM-315] constitutes a novel polymorph of 87th instance compounds, which are different from those of WO2003 / 007946 and WO2001 / 047904. [Formula (I)] [Solid form of the compound and its pharmaceutical uses]

[0205] Another aspect of the present invention relates to pharmaceutical formulations comprising one or more compounds of any of the above embodiments.

[0206] Other embodiments of the present invention relating to any of the compounds described above are intended for use as pharmaceuticals.

[0207] In particular, the present invention relates to the use of the said compound for the treatment or prevention of diseases or conditions related to viral infections.

[0208] More specifically, the present invention relates to the use of the said compound for the treatment or prevention of diseases or conditions associated with viral infections caused by herpesviruses, particularly those caused by herpes simplex virus, i.e., for the treatment or prevention of herpes infections, such as herpes simplex infection.

[0209] In a further embodiment, the present invention relates to the use of the said compound for treating and eliminating latent (dormant) forms of herpesvirus in neuronal tissue and nerves, preferably for avoiding or preventing recurrence and reactivation of herpes infection or even its associated serious consequences, such as herpes simplex encephalitis (HSE).

[0210] In a further embodiment, the present invention relates to the use of the said compound for the treatment or prevention of neurodegenerative diseases caused by viruses, particularly by herpes simplex virus, such as Alzheimer's disease, especially caused by a virus.

[0211] In a further embodiment, the present invention relates to the use of the said compound for patients presenting with cold sores, genital herpes and herpes-associated keratitis, Alzheimer's disease, encephalitis, pneumonia, hepatitis; for patients with suppressed immune systems, such as patients with AIDS, cancer, genetic immunodeficiency, transplant recipients; for newborns and infants; for herpes-positive patients, particularly herpes simplex-positive patients, for patients undergoing relapse suppression (suppressive therapy); or for the treatment and prevention of herpes infection, particularly herpes simplex infection, in patients resistant to nucleoside antiviral therapy, such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and / or foscarnet or cidofovir, particularly herpes-positive patients, particularly herpes simplex-positive patients.

[0212] The compounds according to the invention are intended for use in the prevention and treatment of corresponding symptoms and diseases in humans and animals.

[0213] Therefore, this invention relates to the use of the compounds described in this case in the preparation of pharmaceutical products.

[0214] Furthermore, the present invention relates to a method for preventing or treating diseases or conditions associated with viral infections, such as those caused by herpesviruses, particularly herpes simplex virus; and a method for treating and eliminating latent (dormant) forms of herpesviruses in neuronal tissue and nerves, preferably for avoiding or preventing recurrence and reactivation of herpes infection or even its associated serious consequences, such as herpes simplex encephalitis (HSE); or a method for treating or preventing neurodegenerative diseases caused by viruses, particularly herpes simplex virus, such as Alzheimer's disease, particularly caused by viruses, comprising administering an effective amount of the compound or a composition containing the compound described herein to a human or animal in need of it.

[0215] In practical applications, the compounds used in this invention can be used as active ingredients, tightly mixed with pharmaceutical carriers according to conventional pharmaceutical formulation techniques. The carrier can take various forms, depending on the desired dosage form, such as oral or parenteral (including intravenous) administration. When preparing the composition for oral dosage forms, any commonly used pharmaceutical medium can be used. In the case of oral liquid dosage forms, for example, water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., such as suspensions, elixirs, and solutions; or in the case of oral solid dosage forms, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., such as powders, hard capsules, soft capsules, and tablets, with solid oral dosage forms preferred over liquid dosage forms.

[0216] Due to ease of administration, tablets and capsules represent the most advantageous form of oral dosage unit, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets can be coated using standard aqueous or non-aqueous techniques. Such compositions and formulations should contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can, of course, vary and can conveniently be between about 2.0 percent and about 60.0 percent by weight. The amount of active compound in compositions useful for such treatment is such that an effective dose will be obtained. The active compound can also be administered intranasally, for example, as drops or sprays or as eye drops.

[0217] Tablets, pills, and capsules may also contain binders such as gum arabic, gum arabic, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginate; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit is in capsule form, in addition to the above-mentioned materials, it may also contain a liquid carrier, such as fatty oil.

[0218] Various other materials may exist as coatings or as a physical form to change the dosage unit. For example, tablets may 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, dyes, and flavorings, such as cherry or orange flavorings.

[0219] The compounds used in this invention can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared by appropriately mixing them with a surfactant such as hydroxypropyl cellulose in water. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0220] Suitable pharmaceutical forms for injection include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be a fluid present to a degree that facilitates injection. It must be stable under manufacturing and storage conditions and must be protected against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0221] The compounds of this invention can be administered to mammals, especially humans, using any suitable route of administration. For example, they can be administered orally, rectally, topically, parenterally (including intravenously), ocularly, pulmonaryly, or nasally. Dosage forms include lozenges, sublingual tablets, dispersions, suspensions, solutions, capsules, creams, gels, ointments, aerosols, etc. Preferably, the compounds of this invention are administered orally or topically in the form of eye drops, creams, or gels; more preferably, the compounds of this invention are administered orally.

[0222] The effective dose of the active ingredient used can vary depending on the specific compound used, the administration method, the condition being treated, and the severity of the condition. Such doses can be easily determined by those skilled in the art.

[0223] The compounds of the present invention can also be combined with other active ingredients, particularly with one or more active ingredients that have shown beneficial effects in treating any of the conditions or diseases described herein. In particular, the compounds of the present invention are contained in a composition in combination with at least one other active substance (antiviral active compound) that is effective in treating diseases or conditions associated with viral infections, preferably with diseases or conditions associated with viral infections caused by herpesviruses, such as, particularly, herpes simplex virus, thus relating to so-called combination therapy. This at least one other active substance (immunomodulator, such as a glucocorticoid) is effective in treating diseases or conditions associated with viral infections, or is preferably selected from antiviral active compounds of the group consisting of nucleoside drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir, and trifluridine, and compounds such as foscarnet and cidofovir.

[0224] Therefore, the present invention further relates to pharmaceutical compositions comprising one or more compounds described herein and at least one pharmaceutically acceptable carrier and / or excipient and / or at least one other active substance (antiviral active compound) that is effective in treating diseases or conditions associated with viral infection.

[0225] Another aspect of the invention relates to the use of the compound described herein as a helicase initiator enzyme inhibitor in combination therapy with oncolytic viruses for the treatment of tumors, cancers, or neoplasms.

[0226] Another embodiment of the invention relates to a pharmaceutical composition for use as an antidote in combination therapy with oncolytic viruses to treat cancer, comprising at least one helicase initiator enzyme inhibitor as defined in any embodiment described herein, acting to control, modulate, inhibit, or shut down the activity of oncolytic viruses sensitive to the inhibitor used in cancer therapy, and may further comprise at least one pharmaceutically acceptable carrier and / or excipient and / or at least one additional active substance, such as an antiviral or immunomodulatory compound, including a checkpoint inhibitor, which is effective in treating diseases or conditions associated with oncolytic virus infection used to treat cancer.

[0227] Another embodiment of the present invention relates to the helicase initiator enzyme inhibitor compound or pharmaceutical composition of the present invention for use in combination therapy with oncolytic viruses, as detailed in WO2020 / 109389, wherein the cancer to be treated is a solid cancer, preferably selected from liver cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, brain cancer, melanoma, and glioblastoma, etc.

[0228] Another embodiment of the invention relates to the helicase initiator enzyme inhibitor compound or pharmaceutical composition of the invention for use in combination therapy with oncolytic viruses, as described in WO2020 / 109389, wherein the oncolytic virus is an oncolytic herpesvirus.

[0229] Another embodiment of the invention relates to the helicase inducing enzyme inhibitor compounds or pharmaceutical compositions of the invention for use in combination therapies with oncolytic viruses as described in WO2020 / 109389, wherein the cancer therapy includes infusion, injection, intratumoral injection or local or transdermal administration of oncolytic viruses or oncolytic virus-infected cells and / or helicase inducing enzyme inhibitors or pharmaceutical compositions containing them.

[0230] Another embodiment of the invention relates to the helicase initiator enzyme inhibitor compound or pharmaceutical composition of the invention for use in combination therapy with oncolytic viruses as described in WO2020 / 109389, wherein the oncolytic virus or the oncolytic virus-infected cells are selected from oncolytic wild-type, clinical isolates or laboratory herpesvirus strains or genetically engineered or multimutated selectively attenuated or enhanced oncolytic herpesviruses.

[0231] Another embodiment of the invention relates to a kit comprising one of the helicase initiator enzyme inhibitor compounds or pharmaceutical compositions of the invention for use in combination therapy with oncolytic viruses as described in WO2020 / 109389, and at least one oncolytic virus selected from wild-type, laboratory strains, clinical isolates, and genetically engineered or multimutant oncolytic viruses.

[0232] Another embodiment of the invention relates to the kit for treating cancer as defined in this case.

[0233] Helicase initiator enzyme inhibitor compounds, pharmaceutical compositions, or kits used in combination therapy with the oncolytic viruses described in this case may be administered to one or more of the following patient groups: infants; herpes-positive patients, especially oncolytic herpes simplex-positive patients, to inhibit recurrence or oncolytic virus shedding; and patients resistant to nucleoside antiviral therapy, such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir, and / or foscarnet or cidofovir, especially herpes-positive patients, particularly oncolytic herpes simplex-positive patients.

[0234] A further aspect of the present invention relates to the preparation of compounds having the following structures: , Or its pharmaceutically acceptable salts, eutectics, hydrates, or solvates, (a) Contains compounds [P2b]: Steps for contacting the following compounds: , (b) to make the compound [P2c]: Rh2(OAc)4, tributyl carbamate, magnesium oxide, and (diethoxy)iodobenzene are sufficient to form a compound. Contact steps under [P2d] conditions: , (c) to make the compound [P2d] Deprotection steps under conditions sufficient to form compounds having the following structure ,as well as (d) arbitrarily using compounds [IM-250] can be converted into its pharmaceutically acceptable salt, eutectic, hydrate, or solvate.

[0235] Another embodiment relates to the above method, wherein the compound is made [P2d]: , In step (c), hydrochloric acid is used for deprotection to form an HCl salt of compound IM-250, which corresponds to compound [IM-250 HCl] [Salt]: .

[0236] In a preferred embodiment, [IM-250 HCl] The salt is derived from isopropanol or ethanol, preferably by recrystallization from ethanol.

[0237] In another embodiment of the above method, the compound is made [P2d]: , In step (c), the compound is deprotected with 1,5-naphthalenedisulfonic acid tetrahydrate to form the compound. [IM-250] naphthalene disulfonate.

[0238] The corresponding deuterated compounds can be obtained by a similar method, including those in formula ( [I]) is the step of deuteration at the position corresponding to Y. [Experimental Section] [abbreviation] HPMC Hydroxypropyl methylcellulose DMF dimethylformamide DMSO Dimethicone DSC Differential scanning calorimeter EA Ethyl acetate EDCI·HCl 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride FCC Silicone rapid column chromatography HOBt 1-Hydroxybenzotriazole PE petroleum ether rt room temperature SFC Supercritical fluid chromatography TFA Trifluoroacetic acid TGA Thermogravimetric analysis THF Tetrahydrofuran XRPD X-ray powder diffraction [Experimental Section] [X] [Optical powder diffraction (XRPD)]

[0239] XRPD analysis was performed using a copper countercathode, a single-crystal silicide sample holder, and a position-sensitive detector (LynxExe) on a Bruker D2 phase diffractometer. Powder samples were loaded onto the flat single-crystal silicide sample holder in a manner that avoided optimal orientation and ensured the flatness of the sampling surface. Instrument operating conditions were as follows: ambient temperature and atmosphere; X-ray generator voltage 30 kV and intensity 10 mA; X-ray source: copper target; emitted radiation Kα1 = 0.15406 nm, Kα2 = 0.15444 nm, ratio Kα2 / Kα1 = 0.5, Kβ filtered radiation nickel; slit: anti-divergence 1 nM, Soles slit 2.5°; goniometer: angular sector analysis from 4° to 45° or 4° to 50° 2θ, step size 0.07° 2θ; sample holder rotation speed: 30 rpm; detection: exposure time per goniometer step was 1 s. Differential Scan [Calories] [(DSC)]

[0240] DSC analysis was performed on a Q1000 TA Instruments analyzer. The sample to be analyzed was weighed in an aluminum box, then bulged and placed in a calorimeter oven. The instrument operating conditions were as follows: heater gradient 10°C / min; final temperature 230°C or 240°C; carrier gas: nitrogen (Messer "qualité Azote 5.0"), flow rate 50 mL / min. [Thermogravimetric Analysis] [(TGA)]

[0241] TGA analysis was performed on a TA Instruments TGA Hi-Res 2950. The sample was placed in an open aluminum basket and analyzed as follows: mass test 5 mg; heating gradient 10°C / min; final temperature 500°C; carrier gas: nitrogen (Messer "qualité Azote 5.0"), flow rate 95-105 mL / min. [Example 1] [:IM-2​​50] [Free base form I] [The synthesis of]

[0242] The title compound was prepared by palmar SFC chromatography using Chiralcel OJ as the static phase and 60 / 40 vol.% CO2 / IPA as the dynamic phase to separate racemic mixtures (as described in Example 7 of WO2019 / 068817) and the following data: Instrument: SFC-200 (Thar, Waters) String: OJ 20×250 mm, 10 µm (Daicel) Column temperature: 35°C Flow rate: 100 g / min Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 6 min Sample solution: 70 g dissolved in 2000 mL dichloromethane Injection volume: 3 mL

[0243] Title Compound [IM-250] [Free base form I] can be obtained by removing the dynamic phase (solvent) of the first extract mirror isomer (retention time: 3.25 min) after removing CO2 by rotary evaporation at 40°C.

[0244] XRPD analysis was performed. Figure 1 illustrates this. [IM-250] XRPD graph of [free base form I]. Identify the XRPD peaks and include them in Table 1 below. [, , ] [Table 1] [:XRPD] [Peak position] [(] [°2] [Θ)] [and intensity] [°2-] [θ (] [°2] [Θ)] [Relative Intensity (%)] 7.7 11 9.1 46 [9.2]

[64] 13.3 25 [13.7]

[0100] 13.8 76 [14.4]

[54] 15.3 15 15.5 19 16.8 10 18.1 10 [18.7]

[72] 19.3 twenty two 23.4 15 [24.0]

[39] 24.6 18 26.0 twenty two 26.4 29 26.7 28 [27.3]

[37] 30.6 10

[0245] TGA and DSC analyses were performed. Figure 2 shows... [IM-250] [Free base form] [I] is a superimposed plot of DSC and TGA thermal analysis curves. TGA analysis (right curve) shows that the solid loses about 0.1% of its weight below about 160°C and about 76% of its weight from about 240-300°C (decomposition). DSC analysis shows that endothermic reaction begins at about 163°C and peaks at 164°C (transition enthalpy –83 J / g). [Example 2] [:IM-2​​50] [Free base form III] [The synthesis of] Step 1: N,4-Dimethyl-5-(methylsulfinyl)thiazol-2-amine ( [P2a])

[0246] At room temperature, 80 g, 0.46 mol of N,4-dimethyl-5-(methylthio)thiazol-2-amine (as described in Example P4a of WO2019 / 068817) in a solution of CH₂Cl₂ (1.0 L) was mixed with m-chloroperoxybenzoic acid (83 g, 85%, 0.46 mol) and stirred for 30 min. A saturated NaHCO₃ solution was then added. The mixture was extracted with CH₂Cl₂ (1.5 L) and washed with brine (500 ml). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by FCC (CH₂Cl₂:MeOH = 10:1), yielding the title compound as a yellow solid. [P2a](58 g, 66%). Step 2: (–)-(S)-N,4-dimethyl-5-(methylsulfinyl)thiazol-2-amine [P2b])

[0247] Using the following equipment and conditions, racemic mixtures were separated by spherical SFC chromatography. [P2a] to prepare the title compound [P2b]: Instrument: SFC-80 (Thar, Waters) Column: IC 20×250 mm, 10 µm (Daicel) Column temperature: 35°C Molecular phase: CO2 / MeOH and 0.2% NH3 = 65 / 35 Flow rate: 80 g / min Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 5.6 min Sample solution: 58 g dissolved in 1 L Injection volume: 1.5 mL

[0248] The first extraction of the mirror isomer (retention time: 2.38 min) yielded a compound resembling a pale yellow solid. [P2b](22.5 g).

[0249] It has a negative optical rotation [α] 20 589 nm–33.5° (c = 1.00 g / 100 mL MeOH).

[0250] ¹H-NMR (DMSO-d 6, 400 MHz): 8.22 (d, J = 4.4 Hz, ¹H), 2.84 (d, J = 4.8 Hz, ³H), 2.79 (s, ³H), 2.24 (s, ³H). MS detection: 191.2 [M+H]+. Step 3: (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(methylsulfinyl)thiazolyl-2-yl)acetamide [P2c])

[0251] 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)acetic acid (96.4 g, 389 mmol) and HOBt (78.7 g, 583 mmol) were dissolved in DMF (800 mL). The mixture was stirred at room temperature for 30 min, and then added... [P2b] (74.0 g, 389 mmol) and EDCI·HCl (112 g, 583 mmol). The mixture was stirred overnight, concentrated under vacuum, redissolved in EA (1.0 L), and washed with water (2 × 0.5 L). The organic layer was dried over Na₂SO₄, concentrated under vacuum, and purified by FCC (PE:EA = 1:2), giving a compound as a white solid. [P2c](145 g, 89%).

[0252] ¹H-NMR (DMSO-d 6, 400 MHz): 7.57 (dd, J = 8.0, 1.6 Hz, 2H), 7.46–7.36 (m, 4H), 7.30–7.24 (m, 1H), 4.24 (s, 2H), 3.74 (s, 3H), 2.91 (s, 3H), 2.41 (s, 3H). MS detection: 421.1 [M+H]+. Step 4: (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methyl-N-(1,1-dimethylethoxy)carbonyl)sulfonimino)thiazolyl)acetamide [P2d])

[0253] Magnesium oxide (55.2 g, 1.38 mol), tributyl carbamate (80.7 g, 690 mmol), Rh₂(OAc)₄ (14.5 g, 32.8 mmol), and (diethoxy)iodobenzene (167 g, 517 mmol) were added to the compound. [P2c] (145 g, 345 mmol) was added to a solution of CH2Cl2 (1.0 L). The mixture was stirred at 40 °C for 1 hour. Additional Rh2(OAc)4 (4.8 g, 11 mmol), MgO (18.4 g, 460 mmol), tributyl carbamate (26.9 g, 230 mmol), and (diethoxy)iodobenzene (55.5 g, 172 mmol) were added and stirred overnight. The mixture was then filtered through a diatomaceous earth mat, the solvent was removed under reduced pressure, and the crude product was purified by FCC (PE:EA = 1:1) to give the compound a white solid. [P2d](160 g, 87%).

[0254] ¹H-NMR (DMSO-d 6, 400 MHz): 7.57 (dd, J = 8.0, 1.2 Hz, 2H), 7.45–7.35 (m, 4H), 7.29–7.24 (m, 1H), 4.26 (s, 2H), 3.75 (s, 3H), 3.47 (s, 3H), 2.51 (s, 3H), 1.32 (s, 9H). MS detection: 536.1 [M+H]+. Step 5: (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonylimino)thiazolyl-2-yl)acetamide [IM-250] [Free base])

[0255] At ambient temperature, the compound [P2d] (160 g, 299 mmol) was added to TFA (80 mL) in a stirred solution of CH2Cl2 (0.5 L) and stirring was continued for 90 min. The mixture was concentrated and then dissolved in CH2Cl2, washed with saturated NaHCO3 solution (3 × 0.5 L), dried over Na2SO4, concentrated and purified with FCC (PE:EA = 1:2), and the organic solvent was evaporated to dryness on a rotary evaporator at 30°C, resulting in a white solid. [IM-250] [Free base form III] (120 g, 92%).

[0256] XRPD analysis was performed. Figure 3 illustrates this. [IM-250] XRPD graph of [free base form III]. Identify the XRPD peaks and include them in Table 2 below. [Table 2] [:XRPD] [Peak position] [(] [°2] [Θ)] [and intensity] [°2-] [θ (] [°2] [Θ)] [Relative Intensity (%)] [9.7]

[28] [12.3]

[79] [12.9]

[40] 13.6 12 [15.6]

[0100] 16.1 twenty one 17.4 28 18.3 12 19.4 18 20.3 11 20.9 16 21.4 19 21.7 12 [22.7]

[34] 23.0 10 [23.8]

[32] 24.7 10 26.0 twenty three 27.4 17 27.9 17 29.0 14 29.5 11

[0257] TGA and DSC analyses were performed. Figure 4 shows... [IM-250] A superimposed plot of DSC and TGA thermal analysis chromatograms for [Free Base Form III]. TGA analysis (right curve) shows that the solid loses approximately 0.2% of its weight below approximately 130°C, and approximately 75% of its weight from approximately 240-300°C (decomposition). DSC analysis shows that endothermic reaction begins at approximately 141°C, peaks at 143°C (transition enthalpy –83 J / g), and the exothermic peak for recrystallization occurs at 148°C (transition enthalpy 43 J / g), while endothermic reaction begins at approximately 163°C, peaks at 164°C (transition enthalpy –52 J / g). [Example 3] [:IM-250 HCl] [Salt synthesis]

[0258] At 50°C and atmospheric pressure, by stirring in a rotary evaporator, the... [IM-250] [Form I] (205 mg, 470 µmol) was dissolved in acetone (5 mL). 1N HCl was added at a 1:1 stoichiometric volume. The solvent was then evaporated at 50°C to form a thin film. This film was resuspended at room temperature and dissolved in EtOH (4 mL). The solvent was then evaporated at 50°C to form a meringue. This film was resuspended at 50°C and dissolved in isopropanol (1 mL), allowed to stand at room temperature, and partially separated (after approximately 30 min). The mixture was then reheated to 50°C for further dissolution. Vigorous crystallization occurred rapidly. An additional heating (50°C) and cooling (room temperature) cycle was performed (20 min each time), and the sample was stored at room temperature for 2 days. The supernatant solvent was removed, and the powder was finally dried under dynamic vacuum (70°C, 40 min) to obtain a colorless crystal-like powder. [IM-250 HCl] [Salt].

[0259] XRPD analysis was performed. Figure 5 shows... [IM-250 HCl] XRPD graph of [salt]. Identify the XRPD peaks and include them in Table 3 below. [Table 3] [:XRPD] [Peak position] [(] [°2] [Θ)] [and intensity] [°2-] [θ (] [°2] [Θ)] [Relative Intensity (%)] 9.1 twenty four 11.2 13 11.8 20 [13.7]

[0100] 14.1 17 16.4 23 [17.0]

[55] 17.3 21 [17.7]

[98] 18.2 34 19.4 26 [19.8]

[42] 21.1 23 21.3 33 [21.8]

[33] 22.6 15 [22.8]

[62] 23.4 11 23.7 11 24.0 15 24.2 16 25.0 30 26.3 35 26.9 12 27.1 19 27.4 11 27.7 22 32.0 11

[0260] TGA and DSC analyses were performed. Figure 6 shows... [IM-250 HCl] Overlay of DSC and TGA thermal analysis plots for the [salt]. TGA analysis (right curve) shows a 9.8% mass loss upon heating at onset / endset temperatures of 151 / 170°C, followed by major thermal decomposition detectable at an onset temperature of 221°C. The 9.8% mass loss can be attributed to the loss of the HCl fraction. DSC analysis shows no true melting point. An unresolved double endothermic event observed from 160°C is accompanied by the loss of the HCl fraction observed on the TGA curve. Using ethanol [IM-250 HCl] Alternative synthesis of [salt]:

[0261] At room temperature and atmospheric pressure, by stirring in a rotary evaporator, [IM-250] [Form III] (4.75 g) was dissolved in acetone (150 mL). Then, 1 N HCl was added at a stoichiometric volume of 1:1. The solvent was partially evaporated (approximately 100 mL) at 50°C. To better capture the water introduced by the HCl solution, EtOH (50 mL) was added to the solution before further evaporation until a few mL of syrupy liquid remained. The sample was then allowed to return to room temperature, resulting in the initiation of crystallization. Additional EtOH (50 mL) was then added to the sample (always to help better remove the water introduced by the HCl solution), resulting in an unexpected increase in crystallization. XRPD analysis was performed. Figure 7 shows... [IM-250 HCl] XRPD pattern of [salt]. The identified XRPD peaks are similar to those shown in Figure 5, indicating that the same HCl polymorph was produced. Protect it through direct BOC [IM-250 HCl] Alternative synthesis of [salt]:

[0262] compound [P2d] dissolved in acetone (10 eq.), heated to 50°C, then HCl (4N, in dioxane, 4 eq.) was added. After complete conversion, the mixture was allowed to reach room temperature, filtered, and washed with acetone. The product was dried under vacuum at 50°C and slurried in a 3.5% HCl aqueous solution (10 eq.) at room temperature for 1 hour, then filtered, washed with a 3.5% HCl aqueous solution (10 eq.), and dried under vacuum at 50°C to obtain a crude HCl salt, which was recrystallized from EtOH to obtain a pure HCl salt. [IM-250 HCl] [Salt]. [Example 4] [:IM-2​​50] Synthesis of naphthalene disulfonate

[0263] Will [IM-250] [Form I] (150 mg, 344 µmol) and 1,5-naphthalenedisulfonic acid tetrahydrate (124 mg, 344 µmol) were weighed in a glass vial. A mixture of MeOH (5 mL) and THF (5 mL) was added, and the suspension was stirred on a rotary evaporator at 50 °C and atmospheric pressure until completely dissolved. The solvent was then evaporated to dryness at 50 °C to obtain a film. The film was resuspended in a mixture of water (1 mL) and EtOH (1 mL) and stirred at 40 °C and atmospheric pressure for several minutes to cause partial dissolution. An additional mixture of water (1 mL) and EtOH (1 mL) was added, and the mixture was stirred at 55 °C and atmospheric pressure for about 20 min to cause complete dissolution. Rapid, vigorous small-particle crystallization occurred. Two heating cycles (60 °C, 15 min) and cooling (room temperature, 15 min) were then performed. Finally, the sample was allowed to stand overnight at room temperature. The supernatant was removed from the flask. The powder was dried at room temperature for 15 minutes, and then vacuum dried at 70°C for 45 minutes to obtain a colorless crystal-like product. [IM-250] [Naphthalene disulfonate].

[0264] XRPD analysis was performed. Figure 8 shows... [IM-250] XRPD graph of [naphthalene disulfonate]. Identify the XRPD peaks and include them in Table 4 below. [Table 4] [:XRPD] [Peak position] [(] [°2] [Θ)] [and intensity] [°2-] [θ (] [°2] [Θ)] [Relative Intensity (%)] [9.1]

[38] 11.0 10 13.4 33 [14.5]

[0100] 14.9 19 [15.6]

[39] 16.5 30 17.0 20 17.3 15 17.6 13 [18.1]

[58] 18.5 10 [19.1]

[37] 20.3 14 20.7 28 [20.9]

[37] 21.3 15 21.8 17 22.3 36 22.7 11 23.2 28 23.6 16 24.5 28 24.8 13 25.3 10 25.4 12 26.2 11 26.7 20 27.3 16

[0265] TGA and DSC analyses were performed. Figure 9 shows... [IM-250] Overlay of DSC and TGA thermal analysis chromatograms for [naphthalene disulfonate]. TGA analysis (right curve) shows that the solid loses approximately 0.8% of its weight below approximately 110°C, and approximately 67% of its weight from approximately 150–370°C (decomposition). DSC analysis shows that the exothermic reaction begins at approximately 223°C and peaks at 230°C (transition enthalpy 152 J / g). [Comparative Example 4] [Additional IM-250] [Synthesis in salt form]

[0266] Microcrystallization experiments were conducted on several additional strong acids (such as hydrobromic acid, sulfuric acid, camphor sulfonic acid, 1,2-ethanesulfonic acid, toluene sulfonic acid, nitric acid, methanesulfonic acid, and 2-naphthalene sulfonic acid) in different crystallization media, such as water or pure organic solvents (such as methanol, acetonitrile, isopropanol, ethanol, acetone, and tetrahydrofuran) or mixtures of these organic solvents with water (50 / 50 v / v). In 1 / 1 ( [IM-250] [Free base form I] / opposite ion) Mohr's test for opposite ions. After the crystallization experiment, the sample (corresponding to all opposite ion / crystallization media pairs) is analyzed to identify the "opposite ion / crystallization media" pair that caused the crystallization. This allows for the definition of a "crystallization hit," which can then be further qualitatively determined.

[0267] Macroscopic observation of the sieve plate confirmed that the tested acid bound to... [IM-250] [Free base form I] resulted in only a small amount of solid residue. Furthermore, no clearly visible crystal morphology was observed in any of these samples. In contrast, for individual recrystallization in different media (solvent or solvent / water mixture)... [IM-250] [Free base form I] sample, solid residue containing a large amount of material was observed. For example, with hydrobromic acid and nitric acid, and... [IM-250] The combination of [free base form I] results in solid residues containing large amounts of material only in a few samples. For sulfuric acid, ethanedisulfonic acid, toluenesulfonic acid, and methanesulfonic acid, with... [IM-250] The combination of [free alkali form I] resulted in liquid / vitreous residues and solid residues only in a few samples. For camphorsulfonic acid and naphthalenesulfonic acid, with... [IM-250] The combination of [free alkali form I] results in liquid / vitreous residues and only some solid residues or no solid residues. For each of these opposite ions tested, the number of crystallization events and the quality of the resulting material are then considered to select relevant samples for further qualitative analysis of each opposite ion (while also considering appropriate reference samples), and finally scale up. A certain number of " [IM-250] The pair "[Free base form I] / opposite ion / crystallization medium" was selected for observation under orthogonally polarized light by optical microscopy. Crystal morphologies were compared between different samples (when well-defined crystal shapes were observed) and analyzed by XRPD. From many possibilities, only a few promising XRPDs were obtained and scaled up for further investigation of potential. Some representative attempts are outlined in the following paragraphs: [IM-250] [hydrobromide]

[0268] First, approximately 150 mg [IM-250] [Free base form I] was dissolved in 5 mL of acetone (stirred on a rotary evaporator at 30°C and atmospheric pressure). Then, 48% hydrobromic acid was added at a stoichiometric volume of 1:1. The solvent was then evaporated to dryness at 40°C, forming a shell / crisp crust. The film was resuspended at room temperature and atmospheric pressure and dissolved in 6 mL of THF, which quickly led to vigorous crystallization. Several cycles of heating (40°C, 15 min) and cooling (room temperature, 15 min) were then performed (2) to temporarily increase the size and quality of the crystals.

[0269] The sample was then allowed to stand at room temperature for several hours. Since only a small amount of supernatant could be easily removed (crystals occupied the entire initial solution mixture), the sample was filtered under vacuum. The separated powder was finally dried at room temperature under dynamic vacuum for 10 minutes, followed by drying at 60°C for approximately 30 minutes. Micrographs of the separated sample, when observed between an orthogonal polarizer and the analyzer, showed high birefringence of the particles, indicating that the sample system was well-crystallized.

[0270] Overlapping XRPD graphs demonstrate crystallization with 1 eq of hydrobromic acid. [IM-250] [Free base] samples exhibit different characteristics [IM-250] An XPRD graphic of one of the parent forms of [Free Base Form I].

[0271] After heating, prior to the detection of major thermal decomposition at an initial temperature of 223°C, different mass losses were detected in the TGA curve: 1) a first mass loss of 0.5% was detected at the start / end temperature of 17 / 25°C, possibly corresponding to the loss of water and / or solvent, which would simply adsorb onto the powder; 2) a second mass loss of 3.5% was detected at the start / end temperature of 78 / 85°C; 3) a third mass loss of 5.7% was detected at the start / end temperature of 103 / 115°C; and 4) a fourth mass loss of 5.7% was detected at the start / end temperature of 124 / 130°C.

[0272] TGA analysis followed by FTIR analysis of the escaped gases showed that the THF FTIR spectra best matched the FTIR spectra of the volatiles leaving the sample during the 3.5% and 5.7% mass loss periods. Therefore, the hypothesis of crystallization in a solvated form is plausible.

[0273] In salt samples [IM-250] The percentage of [free base] was determined by HPLC to be 78.1% (compared to the 1:1 stoichiometric target). [IM-250] The theory of [hydrobromide] [IM-250] [Free base] percentage is 84.3%).

[0274] This result was lower than expected, confirming that the sample was likely crystallized in a solvated form.

[0275] HPLC curves showed that the degradation of the active ingredient in the separated solid was very slight, while some new impurities appeared (purity at 285 nm = 99.5%, compared to purity of 99.8% in the parent free base).

[0276] The conclusion is that it has been obtained in THF. [IM-250] A crystalline sample of [hydrobromide] was obtained. Unfortunately, HPLC and TGA-FTIR analyses confirmed that the resulting hydrobromide was actually a THF solvate, making it unsuitable for development. The experiment was repeated with a second batch, yielding the same results.

[0277] This is for [IM-250] Comparative experiments on [hydrobromide] highlight that, in " [IM-250] Of the many possibilities for crystal formation in the "[free base] / opposite ion / crystallization medium" model, surprisingly only a few settings ultimately provided suitable conditions for further development of the IM-250 salt form as a pharmaceutical product, for example... [IM-250] [Naphthalene disulfonate] and [IM-250 HCl] [Salt]. [Example 5] [:crystallization 2-(2',5'-] [difluoride-[1,1'-] [Biphenyl]-4-] [base)-, N , - ] [methyl-, N , -(4- ] [Methyl-5-] [Aminosulfonamide-2-] [base)] [Acetamide IM-315] [The synthesis of]

[0278]

[0279] 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)acetic acid (22.0 g, 88.7 mmol) and HOBt (18.0 g, 133 mmol) were dissolved in DMF (0.4 L), and the mixture was stirred at room temperature for 30 min. Then, 4-methyl-2-(methylaminothiazolium)sulfonamide (18.4 g, 88.7 mmol) and EDCI·HCl (26.0 g, 133 mmol) were added. The mixture was stirred at room temperature overnight, diluted with EtOAc (0.5 L), and washed with water (2 x 250 mL) and brine. The organic layer was dried over Na₂SO₄, concentrated, and purified by FCC (PE:EA = 1:2), giving a white solid. [IM-315](25.2 g, 65%).

[0280] ¹H NMR (400 MHz, DMSO-d₆) δ: 7.65 (s, 2H), 7.60–7.52 (m, 2H), 7.46–7.33 (m, 4H), 7.30–7.22 (m, 1H), 4.23 (s, 2H), 3.72 (s, 3H), 2.48 (s, 3H). MS detection: 438.0 [M+H]⁺.

[0281] XRPD analysis was performed. Figure 10 shows... XRPD graph of [IM-315]. Identify the XRPD peaks and include them in Table 5 below. [Table 5] [:XRPD] [Peak position] [(] [°2] [Θ)] [and intensity] [°2-] [θ (] [°2] [Θ)] [Relative Intensity (%)] [6.4]

[37] 9.8 13 [12.5]

[0100] 13.8 10 15.7 15 16.6 14 [18.3]

[63] 18.6 13 18.8 15 [22.3] [twenty four] 22.6 15 [23.1]

[19] 24.3 13 24.4 10 27.4 11

[0282] DSC analysis was performed. Figure 11 shows... DSC thermal analysis of [IM-315]. DSC analysis shows that the exothermic reaction begins at approximately 196°C and peaks at 197°C (transition enthalpy 117 J / g). Notably, this is a higher melting point than the claimed melting point of 184°C in Example 8 of WO2003 / 007946 and Exp. 87 of WO2001 / 047904, which is obtained by slurrying the evaporated reaction mixture in water and isopropanol. [Example 6] [Relative bioavailability of male mice]

[0283] Following a single oral administration in male C57bl / 6 mice, crystallization and different salt forms were examined and compared with those obtained by suspension. Relative bioavailability of [IM-250] (derived from DMSO stock solution). Animals (3 per group) were fasted approximately 2 h prior to administration. Suspensions were prepared by diluting DMSO stock solution 1:20 with 0.5% HPMC in PBS, followed by ultrasonic treatment, and administered orally via tube feeding at a volume of 5 mL / kg. Suspensions in crystalline and different salt forms were prepared directly by adding powder to 0.5% HPMC in PBS, followed by ultrasonic treatment, and administered orally via tube feeding at a volume of 5 mL / kg. Blood samples were collected via capillary microsampling at 0.5 h, 1 h, 2 h, 5 h, 12 h, and 24 h, and bioanalyses were measured by non-palm-mounted LC-MS. Calculations were performed. The area under the curve (AUC 0-24 h) and relative bioavailability of the [IM-250] suspension were measured. The dosage of the saline was adjusted to 10 mg / kg free. [IM-250]. Figure 12 shows the blood concentration over time. The following data were obtained (Table 6): [Table 6] [:IM-2​​50] [Area under the curve (AUC) in male mice] 0-24 h , ) ] [And relative biological availability] [sample] [AUC, 0-24 h , (ng / mL*h) [Relative bioavailability (%)] Suspended from DMSO [IM-250] (Reference Standard) 66406 –– [IM-250] [Free base form] [I] 7683 12 [IM-250] [Naphthalene disulfonate] 48241 73 [IM-250 HCl] [Salt] 68289 103 [Example 7] Chemical and physical stability

[0284] The chemical and physical accelerated stability of the crystalline materials were investigated to anticipate potential stability issues during storage or aging. The crystals were stored for one month at 40°C / 75% RH and another month at 60°C (%HR < 10% RH). Chemical stability was assessed by HPLC using externally standardized and freshly prepared (stress-free) standard solutions. For this purpose, six samples (accurately weighed) were stored for each condition: stability 3 after 2 weeks and stability 3 after 4 weeks. Physical stability was also assessed by XRPD and DSC analysis, which involved comparing the XRPD and DSC curves of the stressed samples with those of the stress-free samples. For this purpose, two additional samples were stored (one at each time point) under each condition (40°C / 75% RH and 60°C, respectively). [Chemical stability results]

[0285] against [IM-250] The results of HPLC analysis (UV at 285 nm) of [free base form I] (3 independent tests) are shown in Table 7. [Table 7] [Evaluation of chemical degradation under temperature and humidity stress] [Stress Conditions] [time] [point] [Remaining unchanged compounds %] [Impurity curve compared to standard curve] 40°C / 75%RH 2 wk 99.4 (%CV = 0.3%) Similar to standard curve No extra impurities 4 wk 100.2 (%CV = 1.5%) Similar to standard curve No extra impurities 60°C 2 wk 99.6 (%CV = 1.2%) Similar to standard curve No extra impurities 4 wk 101.4 (%CV = 0.6%) Similar to standard curve No extra impurities Compared with the determination of the percentage of the remaining unchanged compound in the standard solution Container: Open-faced (for storage at 40°C / 75%RH only) light-proof glass bottle

[0286] The conclusion is that [IM-250] [Free base form I] can be considered chemically stable as a bulk powder after being stored at 40°C / 75%RH and 60°C for at least 4 weeks. [Physical stability results]

[0287] Table 8 shows the results compared to the initial qualitative analysis. [IM-250] [Free Alkali Form I] Physical DSC qualitative results of batch samples stored at 40°C / 75%RH and 60°C for 2 and 4 weeks. XRPD diffraction patterns under stress conditions are similar to the initial diffraction patterns. Figure 13 shows... [IM-250] Interleaved XRPD patterns of stress-free samples of [free alkali form I] and samples stored at 40°C / 75%RH and 60°C for 2 weeks and 4 weeks. [Table 8] [DSC following temperature and humidity stress] [Evaluate IM-250] [Free base form I] [Physical stability] [Stress Conditions] [time] [point] [Conversion] [temperature] (°C) Initial peak [Enthalpy] [change] (J / g) none Preliminary analysis Strongly endothermic (melting) 163 164 –83 40°C / 75%RH 2 wk Strongly endothermic (melting) 163 165 -77 4 wk Strongly endothermic (melting) 163 165 -80 60°C 2 wk Strongly endothermic (melting) 163 164 -85 4 wk Strongly endothermic (melting) 163 165 -80

[0288] The conclusion is that [IM-250] [Free base form I] can be considered physically stable as a bulk powder after being stored at 40°C / 75%RH and 60°C for at least 4 weeks. [Example 8] [:ICH] [Stability Test]

[0289] The Contract Manufacturing Organization assessed the long-term and accelerated chemical and physical stability. [IM-250 HCl] [Salt] Samples were initially packaged in double-layered PE bags (50 µm, Semadeni, e.g., CAT. #2439, each label secured with plastic twine). Secondary packaging consisted of HDPE drums sealed with HDPE screw caps (CurTec). Storage conditions were 25±2°C / 60±5% RH and 40±2°C / 75±5% RH. The results are shown in Table 9. [Table 9] [:] [test] [initial] [6] [Month 25] [°C] [6] [40 months] [°C] Color and appearance White to off-white solid White to off-white solid White to off-white solid Purity (HPLC area %) 99.2% 99.2% 99.1% Experiment (HPLC, % w / w, original sample) 98.5% 97.9% 98.6% Palm purity (HPLC area %) 99.8% 99.9% 99.9% Moisture content (% w / w) 0.08% 0.08% 0.10% Identification via XRPD Conforms to reference values Untested Conforms to reference values The conclusion is that [IM-250 HCl] [Salt] can be considered physically stable as a bulk powder after being stored at 25°C and 40°C for at least 6 months. [Example 9] [:Deuterated IM-250] [Free base (d3-IM-250)] [Free base] [The synthesis of] Step 1: 1-Bromoprop-2-one-1,1,3,3,3-d5 ( [9a])

[0290] Br 2 (2.5 g, 15 mmol) was added to acetone-d6 (2.0 g, 31 mmol) at room temperature, and the mixture was stirred for 2 h. The mixture was then immediately used for the next step. Step 2: N-methyl-4-(methyl-d3)thiazolyl-2-amine ( [9b])

[0291] Compound at 75°C [9a] 1-Methylthiourea (1.4 g, 15 mmol) was added to a solution of EtOH (20 mL), and after stirring for 2 h, a saturated NaHCO3 solution was added. The mixture was extracted with EA (2 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and then purified by FCC (EA:PE = 1:1) to give the compound. [9b] Step 3: 5-Bromo-N-methyl-4-(methyl-d3)thiazolyl-2-amine ( [9c])

[0292] Compounds at room temperature [9b] Br2 (740 mg, 4.7 mmol) was added to a solution of 4 mL CHCl3 (4 mmol), stirred overnight, and then water (10 mL) was added. The pH was adjusted to 8 with a saturated NaHCO3 solution. The mixture was extracted with 2 x 10 mL CHCl3. The combined organic layers were washed with 10 mL brine, dried over Na2SO4, filtered, and concentrated to give a solid-like compound. [9c] Step 4: N-methyl-4-(methyl-d3)-5-(methylthio)thiazole-2-amine [9d])

[0293] Compounds at room temperature [1c] (350 mg, 1.6 mmol) was added to a solution of 1,4-dioxane (4 mL) with MeSNa (230 mg, 3.2 mmol). After stirring overnight, the mixture was evaporated to obtain an oil, which was then purified by FCC (EA:PE = 1:1) to give a compound that appeared as a yellow solid. [9d]. Step 5: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(methylthio)thiazolyl-2-yl)acetamide ( [9e])

[0294] Compounds were added to a solution of 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)acetic acid (140 mg, 0.56 mmol), HATU (322 mg, 0.85 mmol), and Et 3N (171 mg, 0.85 mmol) in CH 2Cl 2 (2.0 mL) at room temperature. [9d] (100 mg, 0.56 mmol). After stirring overnight, the mixture was washed with water (2 x 2.5 mL). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by FCC (PE:EA = 2:1) to give a white solid. [9e] Step 6: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(methylsulfinyl)thiazolyl-2-yl)acetamide [9f])

[0295] For compounds [9e](180 mg, 0.44 mmol) of m-chloroperoxybenzoic acid (76 mg, 85% purity) was added to a solution of CH₂Cl₂ (1 mL). The mixture was stirred at room temperature for 20 min and partitioned between CH₂Cl₂ and 5% sodium carbonate solution. The organic layer was washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by FCC (PE:EA = 1:2) to give a white solid. [9f]. Step 7: Tertiary butyl ((2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methylacetamino)-4-(methyl-d3)thiazolyl-5-yl)(methyl)(oxo)-l6-thionyl)aminocarbamate ( [9g])

[0296] MgO (57 mg, 1.40 mmol), tributyl carbamate (83 mg, 0.70 mmol), Rh₂(OAc)₄ (15 mg, 33 µmol), and (diethoxy)iodobenzene (171 mg, 0.52 mmol) were added to the compound. [9f] (150 mg, 0.35 mmol) in a solution of CH₂Cl₂ (2.5 mL). The mixture was stirred overnight at 40 °C, cooled to room temperature, and filtered through a diatomaceous earth mat. The solvent was removed under reduced pressure, and the crude product was purified by FCC (PE:EA = 1:1) to give a compound as a white solid. [9g]. Step 8: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonylimino)thiazolyl)acetamide ( [9h]) ( [9h])

[0297] At ambient temperature, the compound [9 g] (150 mg, 0.28 mmol) was added to a stirred solution of trifluoroacetic acid (2 mL) in CH₂Cl₂ (8 mL). Stirring was continued for 1 h. The mixture was then concentrated, dissolved in CH₂Cl₂, washed with saturated NaHCO₃ (2 x 20 mL), dried over Na₂SO₄, filtered, concentrated, and purified by preparative HPLC to give a compound as a white solid. [9h]. 1H-NMR (400 MHz, DMSO- d 6) δ: 7.57 (d, J = 7.2 Hz, 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] +. Step 9: (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonylimino)thiazolyl-2-yl)acetamide [Deuteration] [IM-250] [Free base] [,] [d3-IM-250] [Free base])

[0298] By using palmar SFC chromatography, Chiralcel OJ was used as the static phase, and 55 / 45 vol.% CO2 / IPA was used as the dynamic phase to separate the racemic mixture. [9h] to prepare the title compound and other data: Instrument: SFC-150 (Thar, Waters) String: OJ 20×250 mm, 10 µm (Daicel) Column temperature: 35°C Flow rate: 100 g / min Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 3.7 min Sample solution: 300 mg dissolved in 40 mL MeOH Injection volume: 1.0 mL

[0299] Title Compound [Deuteration] [IM-250] [Free base (d3-IM-250)] [Free base] can be obtained with a purity of 99.7% by removing the mobile phase (solvent) of the first extract mirror isomer (retention time: 2.99 min) after removing CO2 by rotary evaporation at 40°C.

[0300] XRPD analysis was performed. Figure 14 shows... [Deuteration] [IM-250] [Free base (d3-IM-250)] XRPD graph of [free base]. Identify the XRPD peaks and include them in Table 10 below. [Table 10] [:XRPD] [Peak position] [(] [°2] [Θ)] [and intensity] [°2-] [θ (] [°2] [Θ)] [Relative Intensity (%)] 9.1 35 [9.3]

[56] 13.3 17 [13.7]

[0100] [14.4]

[76] [15.3]

[17] [15.5]

[15] 18.2 10 [18.6]

[75] 19.4 20 23.0 11 23.4 14 [24.1]

[67] 24.6 19 26.2 17 26.4 36 26.7 twenty three 27.4 34 28.1 10

[0301] TGA and DSC analyses were performed. Figure 15 shows... [Deuteration] [IM-250] [Free base (d3-IM-250)] The TGA thermal analysis plot of [free base] shows an onset / end temperature of 243 / 305°C, which can be attributed to thermal decomposition. DSC analysis (Figure 16) shows a strong exothermic transition starting at approximately 163°C and peaking at 165°C (transition enthalpy 85 J / g). [Example 10] [:Deuterated IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt)] [The synthesis of]

[0302] right [Deuteration] [IM-250] A solution of [free base] (850 mg) in acetone (50 mL) was mixed with a stoichiometric amount of 1N HCl (1:1). The solution was homogenized at 40°C, and then the solvent was removed under vacuum (50°C). Spontaneous crystallization of a white solid was initiated when only a few mL remained in the flask. To completely remove the water introduced by the HCl addition, EtOH (2 x 5 mL) was added to the flask, and the mixture was concentrated to dryness at 50°C (only partial redissolution was observed during the addition of EtOH and stirring at 50°C). More EtOH (5 mL) was then added to the flask, and the mixture was stirred at 50°C and room temperature to resuspend the crystals. The supernatant was removed from the solid, and the mixture was further dried under vacuum at 50–60°C for approximately 3 hours. The solution was obtained in good yield. [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [Salt] is a white crystal.

[0303] XRPD analysis was performed. Figure 17 shows... [IM-250 HCl] [Salt (d3-IM-250 HCl)] XRPD graph of [salt]. Identify the XRPD peaks and include them in Table 11 below. [Table 11] [:XRPD] [Peak position] [(] [°2] [Θ)] [and intensity] [°2-] [θ (] [°2] [Θ)] [Relative Intensity (%)] 9.2 27 [11.3]

[13] [11.9]

[15] [13.8]

[0100] 14.2 twenty three 16.5 32 16.9 29 17.4 13 [17.8]

[90] 18.3 30 19.5 17 [19.8]

[28] [21.0]

[25] [21.3] [twenty four] [21.8]

[29] 22.9 54 24.0 18 24.3 14 25.1 33 26.3 37 26.9 10 27.2 18 27.5 11 27.8 36 32.0 10 33.2 12

[0304] TGA and DSC analyses were performed. Figure 18 shows... [Deuteration] [IM-250 HCl] [Salt]( [d3-IM-250 HCl] A superimposed plot of DSC and TGA thermal analysis curves for the [salt]. TGA analysis (right curve) shows a 7.8% mass loss upon heating at onset / end temperature of 149 / 167°C, followed by major thermal decomposition detectable at an onset temperature of 225°C. The 7.8% mass loss can be attributed to the loss of the HCl moiety. DSC analysis shows no true melting point, but rather a broad endothermic start at approximately 188°C, peaking at 194°C (transition enthalpy –15 J / g). [Example 11] [:Deuterated IM-250] [Naphthalene disulfonate (d3-IM-250)] [Naphthalene disulfonate] [The synthesis of]

[0305] By preparing the deuterated free base form as described above, and then converting it to naphthalene disulfonate as described above, formula ( ) can be prepared in a similar manner. [I]) [Deuteration] [IM-250] [Naphthalene disulfonate]. [Example 12] [:d3-IM-250 HCl] [Salt and IM-250 HCl] [Relative bioavailability and brain exposure of salt in male mice]

[0306] Suspension crystals were examined in male C57bl / 6 mice (approximately 8 weeks old) after a single oral administration. [Deuteration] [IM-250 HCl] [Salt (d3-IM-250 HCl)] [salt] and suspension [IM-250 HCl] Relative bioavailability of [salt]. Animals (n=3 per group) were fasted approximately 2 h before administration of 10 mg / kg test substance. The suspension was prepared directly by adding the powder to 0.5% HPMC in PBS, followed by ultrasonic treatment, and administered orally via tube feeding at a volume of 5 mL / kg. Blood samples (20 µL) were collected from the tail vein into Li-heparin tubes via capillary microsampling at 0.5 h, 1 h, 2 h, 5 h, 12 h, and 24 h. Samples were frozen on dry ice for 1–2 min during sampling and stored at –20°C until LC-MS / MS analysis was performed by non-palm-type LC-MS. 24 hours after administration, animals were sacrificed and perfused with PBS until the PBS became clear. The brain was removed and stored at –20°C until LC-MS analysis was performed to determine brain / blood exposure. Peak plasma concentration (Cmax), elimination half-life (t1 / 2), area under the curve (AUC 0–24 h), and blood / brain ratio (as an easily obtainable surrogate parameter for neural tissue exposure) were determined. The following data were obtained (Table 12): [Table 12] [:IM-2​​50 HCl] [The effect of salt deuteration on PK in male mice] [The effect of parameters] [sample] [IM-250 HCl] [Salt] [d3-IM-250 HCl] [Salt] [C, max [ng / mL] 1210 2570 [t, 1 / 2 , [h] ] 5.7 6.9 [AUC, 0-24 , [ng / mL*h] 14400 28600 [Brain positioning @ 24 h [ng / g]] 175 568 [Blood / ] [Brain Comparison] 0.60±0.20 0.49±0.10 [in conclusion]:

[0307] Although in this experiment, [IM-250 HCl] [Salt] compared to [Reality] [example] [6] had a lower AUC 0-24 for some reason, but selective deuteration at the 4-methyl position of the thiazole ring further improved the PK parameters, which was also very evident in paired comparisons of C max., t 1 / 2 and AUC 0-24. Both compounds yielded beneficial and durable blood / brain ratios.

[0308] (none)

Claims

1. A crystalline form of a compound, the crystalline form of which is based on the following structure: , characterized by containing an X-ray powder diffraction pattern of at least four peaks (±0.2 degrees 2θ): IM-250 HCl salt: 13.7 degrees, 17.0 degrees, 17.7 degrees, 19.8 degrees, 21.8 degrees and 22.8 degrees, which are determined on a diffractometer using Cu-Kα radiation at a wavelength of 0.154 nm (1.54 Å).

2. The crystalline form of the compound of claim 1, wherein hydrochloric acid and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methyl-sulfonylimino)thiazolyl-2-yl)acetamide are in a 1:1 molar ratio.

3. The crystalline form of the compound of claim 1, having substantially the XRPD pattern shown in Figure 5 or 7.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound such as claimed in claims 1, 2 or 3 in crystalline form, and a pharmaceutically acceptable excipient.

5. Use of a crystalline form of a compound as claimed in claim 1, 2 or 3, or a pharmaceutical composition as claimed in claim 4, in the preparation of a pharmaceutical product for the prevention and treatment of herpes simplex infection or mediated conditions.

6. Use of a crystalline form of a compound as claimed in claim 1, 2 or 3, or a pharmaceutical composition as claimed in claim 4, in the preparation of a pharmaceutical product for the treatment or elimination of latent forms of herpesvirus in neuronal tissue and nerves, or for the prevention and treatment of recurrence and reactivation of herpes infection or serious consequences thereof.

7. Use of a crystalline form of a compound as claimed in claim 1, 2 or 3, or a pharmaceutical composition as claimed in claim 4, in the preparation of a pharmaceutical product for the prevention and treatment of herpes simplex encephalitis (HSE).

8. A method for preparing a crystalline form of a compound as claimed in claim 1, the crystalline form of which has the following structure: , the method comprising (a) contacting compound P2b with the following compound: , (b) contacting compound P2c with Rh2(OAc)4, tributyl carbamate, magnesium oxide and (diethoxy)iodobenzene under conditions sufficient to form compound P2d: , (c) deprotecting compound P2d with hydrochloric acid to form an HCl salt according to the following compound IM-250 HCl salt: .

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