Solid crystalline forms of helicase primase inhibitors and methods for their preparation

Abstract

The present invention provides solid crystalline forms of compounds useful as helicase primase inhibitors, compositions thereof, methods for their preparation, and methods of their use in the treatment of herpes simplex infections and herpes-mediated diseases.

Description

[Technical field]

[0001] The present invention provides solid crystalline forms of antiviral compounds useful as helicase primase inhibitors, compositions thereof, methods for their preparation, and methods of their use in the treatment of herpes simplex infections and herpes-mediated diseases. [Background technology]

[0002] Pandemics of viral infections have plagued humanity since ancient times, causing mucocutaneous infections such as herpes labialis and genital herpes. Disease symptoms often interfere with daily activities, and sometimes HSV infections are the cause of life-threatening (encephalitis) or vision-impairing (keratitis) diseases, especially in neonates, elderly, and immunocompromised patient populations such as transplant or cancer patients, or patients with inherited immunodeficiency syndromes or diseases. After infection, alphaherpesviruses survive in a latent state in the host's neurons and periodically reactivate, often resulting in significant psychosocial distress for the patient. Currently, no cure is available. So far, vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators and small molecule drugs with specific or non-specific mechanisms of action have lacked either the efficacy or the required safety profile to replace the nucleoside drugs acyclovir, valacyclovir and famciclovir as first line treatment.

[0003] The known aminothiazoles (e.g., pritelivir, HN0037) are the most potent drugs developed to date. These antiviral agents act by inhibiting herpesvirus helicase primase and show low resistance rates in vitro and superior efficacy in animal models compared to nucleoside drugs, but their development is hindered by off-target carbonic anhydrase activity, reduced penetration into neuronal tissues and the brain, and aberrant pharmacokinetic profiles.

[0004] Herpes viruses are neurotropic viruses, and after infection, they enter and colonize neuronal tissues, providing a means for the persistent presence of herpes viruses for survival in latent form and permanent neuronal exposure in the host's neurons. Such persistent neuronal exposure by latent herpes viruses is the reason for the lifelong risk of relapsing and periodically reactivating herpes infections, which often results in significant psychosocial distress for the patient. Such neuronal herpes virus exposure is furthermore the cause of herpes virus encephalitis (or herpes simplex encephalitis; HSE), which is thought to be caused by the spread of herpes viruses from peripheral sites in the face after HSV-1 reactivation or from neuronal tissue along nerve axons to the brain. The virus lies dormant in the ganglion of the trigeminal nerve or in nerve tissue, and gains access to the brain causing HSE. It is therefore important to provide highly active antiviral drugs that allow also to treat and eliminate (dormant) herpes viruses in nerve tissues and nerves, and at the same time avoid the recurrence and reactivation of herpes infections, or even severe effects such as HSE. For example, known aminothiazole antiviral drugs are not potent enough to enter neural tissue or cross the blood-brain barrier to enter the brain, and are unable to provide an effective and definitive cure for treating latent or dormant forms of herpes virus, as well as HSE.

[0005] This patent application discloses novel solid crystalline forms of antiviral aminothiazole compounds with more favorable pharmacokinetic and stability profiles (e.g., improved solubility and bioavailability allowing higher passage of the antiviral drug compounds into neural tissues and the brain). 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 medicines.

[0006] [Prior art] From the prior art, aminothiazoles of general formula (A) are known for use as antiviral compounds. [ka]

[0007] In particular, WO 2005 / 023663 and WO 2005 / 023999 disclose aminothiazoles (A) in which X is a sulfonamide moiety. Both documents describe a compound having the following structure, which can be prepared in the form of a yellow solid having a melting point of 184° C. using the methods described in Example 8 of WO 2005 / 023999 and Example 87 of WO 2005 / 023999: [ka]

[0008] US Pat. No. 5,399,633 describes thiazolyl amides of formula (A) where X is a sulfanimine, sulfinimidamide, sulfoximine or sulfoximidamide.

[0009] US Pat. No. 5,399,633 describes the enantiomers of the compound according to US Pat. No. 5,399,633.

[0010] WO 02 / 06331 describes the novel use of aminothiazole compounds according to WO 02 / 06331 and WO 02 / 06331 in combination therapy with oncolytic viruses for treating cancer.

[0011] US Pat. No. 5,399,633 describes deuterated analogues of compounds according to US Pat. No. 5,499,623 and US Pat. No. 5,499,633.

[0012] Non-Patent Document 1 describes the results of experimental tests using various antiviral helicase primase inhibitor compounds described in the above-mentioned prior art.

[0013] In all these patent applications, no solid crystalline forms according to formula (A) as defined herein are described or mentioned. In particular, the documents do not identify any particular salt or solid form. [ka]

[0014] Several properties such as solubility, dissolution rate, bioavailability, hygroscopicity, flavor, developability and physical / chemical stability can be modified by crystallization or salt formation.

[0015] Given the availability of a large number of pharma- ceutically acceptable counterions, and the lack of correlation between the properties of the pharma- ceutically acceptable counterions and the final properties of the corresponding salts, the salt selection process is difficult and the outcome is unpredictable a priori.

[0016] With the ultimate objective of obtaining improved manufacturing, handling, storage and pharmaceutical properties of compounds of formula (A), there is a need to provide crystalline (salt) forms of antiviral compounds of formula (A) having improved physicochemical and pharmaceutical properties without adversely affecting other important parameters such as hygroscopicity or bioavailability of the active compound. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] WO2003 / 007946 [Patent Document 2] WO2001 / 047904 [Patent Document 3] WO2017 / 174640 [Patent Document 4] WO2019 / 068817 [Patent Document 5] WO2020 / 109389 [Patent Document 6] WO2022 / 090409 [Non-patent literature]

[0018] [Non-Patent Document 1] publication of Gege et al., “A helicase-primase drug candidate with sufficient target tissue exposure affects latent neural herpes simplex virus infections”; Sci. Transl. Med. 2021;13:eabf8668 [Non-Patent Document 2] Foster in Trends Pharmacol. Sci. 1984:5;524 [Non-Patent Document 3] Comp. Biochem. Physiol. 1998;119A:725 Summary of the Invention [Problem to be solved by the invention]

[0019] [summary] The present invention relates to novel solid forms of antiviral helicase primase inhibitor compounds of formula (I) below, or pharma- ceutically acceptable salts, co-crystals, hydrates or solvates thereof. [ka] [In the formula, X is [ka] and Y is selected from CH3 and CD3.

[0020] These novel forms are useful, for example, for treating human patients suffering from herpes simplex-mediated disorders. The novel solid forms according to the present disclosure may be useful for preparing medicaments for treating herpes simplex virus infections and diseases. The novel solid forms according to the present disclosure can be used as helicase primase inhibitors.

[0021] In some embodiments, the present disclosure is directed to a novel solid form of the free base compound having the following chemical structure: [ka]

[0022] In some embodiments, the present disclosure is directed to a novel solid form of the hydrochloride salt having the following chemical structure: [ka]

[0023] In some embodiments, the present disclosure is directed to novel deuterated solid forms of the free base compound having the following chemical structure: [ka]

[0024] In some embodiments, the present disclosure is directed to a novel solid form of the hydrochloride salt having the following chemical structure: [ka]

[0025] In some embodiments, the present disclosure is directed to a novel solid form of a napadisylate salt having the following chemical structure: [ka]

[0026] In some embodiments, the present disclosure is directed to a novel solid form having the following chemical structure: [ka]

[0027] In some embodiments, the present disclosure is directed to a novel solid form having the following chemical structure: [ka]

[0028] In some embodiments, the present disclosure is directed to methods for preparing these novel solid forms. [Brief description of the drawings]

[0029] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of IM-250 free base Form I. [Diagram 2] 1 shows a combination of thermogravimetric analysis (TGA) and differential scanning calorimeter (DSC) thermograms of IM-250 free base Form I. [Diagram 3] 1 shows the XRPD pattern of IM-250 free base Form III. [Figure 4] 1 shows a combination of TGA and DSC thermograms of IM-250 free base Form III. [Diagram 5] 1 shows the XRPD pattern of IM-250 hydrochloride. [Figure 6] 1 shows a combination of TGA and DSC thermograms of IM-250 hydrochloride. [Figure 7] 1 shows the XRPD pattern of IM-250 hydrochloride when crystallized from ethanol. [Figure 8] 1 shows the XRPD pattern of IM-250 napadisylate. [Figure 9] 1 shows a combined TGA and DSC thermogram of IM-250 napadisylate. [Figure 10] The XRPD pattern of IM-315 is shown. [Figure 11] The DSC thermogram of IM-315 is shown. [Figure 12] FIG. 1 shows blood concentrations over time of various solid forms of IM-250 in mouse PK. [Figure 13] Shown are overlaid XRPD profiles (normalized scale) from IM-250 free base Form I of an unstressed sample (bottom) and samples stored at 40° C. / 75% RH and 60° C. for 2 and 4 weeks. [Figure 14]1 shows the XRPD pattern of deuterated IM-250 free base (d3-IM-250). [Figure 15] 1 shows a TGA thermogram of deuterated IM-250 free base (d3-IM-250). [Figure 16] 1 shows a DSC thermogram of deuterated IM-250 free base (d3-IM-250). [Figure 17] 1 shows the XRPD pattern of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride). [Figure 18] 1 shows a combination of TGA and DSC thermograms of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] [Detailed Description] In the following description, certain specific details are described to provide a thorough understanding of various embodiments of the present disclosure. However, those skilled in the art will understand that the present disclosure may be practiced without these detailed descriptions. The following description of some embodiments is made with the understanding that the present disclosure should be considered as an illustration of the claimed subject matter, and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the scope of the claims in any manner. An embodiment shown under any heading can be combined with an embodiment shown under any other heading.

[0031] [Definition] Unless the context otherwise requires, throughout this specification and claims, the words "comprise" and variations thereof, such as "comprising," are to be interpreted in their open and inclusive sense, i.e., "including, but not limited to."

[0032] Throughout this specification, the reference to "one embodiment" or "an embodiment" means that the particular feature, configuration or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, all occurrences of the phrase "in one embodiment" or "in an embodiment" in this specification are not necessarily describing the same embodiment.

[0033] Furthermore, the particular features, structures or characteristics may be combined in any suitable manner in one or more embodiments.

[0034] Embodiments referred to throughout this specification as "crystalline forms" include crystals, salts, co-crystals, hydrates and / or solvates of Formula (I) disclosed herein.

[0035] "Deuterated", "deuterium-labeled", "deuterium-substituted" or "deuterated" in the sense of the present invention refers to a compound of formula (I) in which one or more hydrogen atoms have been replaced with deuterium (represented by "D"). 2 H).

[0036] In some compounds of formula (I), residue Y represents CD3. Surprisingly, it has been found that such deuterated aminothiazole compounds, when administered to a mammal, e.g., a human, exhibit increased resistance to metabolism compared to the respective non-deuterated compounds, and are therefore useful for increasing the half-life of compounds of formula (I). See, e.g., J. Am. Chem. Soc. 1999, 143: 1311-1323. Such deuterated aminothiazole compounds are synthesized by means well known in the art, e.g., by using starting materials in which one or more hydrogens have been replaced by deuterium (see the Experimental Section for details).

[0037] Deuterium labeled or substituted therapeutic compounds of the present disclosure have surprisingly been found to have improved DMPK (drug metabolism and pharmacokinetic) properties related to absorption, distribution, metabolism and excretion (ADME). Substitution with deuterium has been found to provide certain therapeutic advantages due to higher metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index.

[0038] The concentration of deuterium can be defined by the isotopic enrichment factor. Any atom not specifically designated as a particular isotope in the compounds of the present disclosure is meant to represent any stable or radioactive isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen at its natural abundance isotopic composition (about 99.98% hydrogen). Thus, any atom specifically designated as deuterium (D) in the compounds of the present disclosure is meant to represent deuterium with at least 50% isotopic purity, preferably at least 95% isotopic purity, more preferably at least 99% isotopic purity.

[0039] The percentage of deuterium incorporation can be determined by quantitative analysis using a number of conventional methods, such as mass spectroscopy (peak area) or by the incorporation of an internal standard or other non-deuterated ions in the compound. 1 The remaining residues of specific deuteration sites compared to the signal from H signal 1 It can be obtained by quantifying the H-NMR signal.

[0040] It will be recognized that some variation in natural isotope abundance will occur in the synthesized compounds depending on the origin of the chemicals used in synthesis.Thus, preparations of non-deuterated analogues of the compounds of the present invention will inherently contain small amounts of deuterated isotopologues.The concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotope substitution of the compounds of the present invention, despite this variation.See, for example, Non-Patent Document 3.

[0041] The term "isotopic enrichment factor" at a particular position normally occupied by hydrogen refers to the ratio between the abundance of deuterium at that position and the natural abundance of deuterium at that position. For example, an isotopic enrichment factor of 3500 means that the amount of deuterium at a particular position is 3500 times the natural abundance of deuterium, or 52.5% of compounds have deuterium at a particular position (i.e., 52.5% deuterium incorporation at a given position). The abundance of deuterium in the Earth's oceans is approximately 1 atom in 6500 hydrogen atoms (about 154 ppm). Thus, deuterium accounts for about 0.015% (0.030% by weight) of all natural hydrogen atoms in the Earth's oceans, and its abundance varies slightly from one type of natural water to another.

[0042] Deuterated compounds of the present disclosure are preferably characterized by an isotopic enrichment factor of at least 6300, or by a degree of deuteration of at least 95%, more preferably by an isotopic enrichment factor of at least 6500, or by a degree of deuteration of at least 98%.

[0043] Any formula or structure given herein is also intended to represent compounds that further contain additional isotopically enriched atoms. Additional isotopes that can be incorporated into the compounds of the present disclosure include, for example, isotopes of hydrogen, as well as 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F and 35 The present disclosure further includes isotopes of carbon, nitrogen, oxygen, and fluorine, such as, but not limited to, S. 3 H, 13 C and 14The present disclosure includes various isotopically labeled compounds incorporating radioisotopes such as C. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or drug or substrate tissue distribution assays or single photon emission computed tomography (SPECT) involving radioactive treatment of patients. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, by substituting readily available isotopically labeled reagents with non-isotopically labeled reagents.

[0044] "Pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, and / or emulsifier, or a combination of one or more of the above that have been approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other national counterpart as acceptable for use in humans or veterinary medicines.

[0045] "Pharmaceutical composition" refers to a formulation of a compound of the present disclosure (e.g., a compound of Formula (I)) and a vehicle (dosage form) generally accepted in the art for the delivery of a biologically active compound to a mammal, e.g., a human. Such a vehicle includes all pharma- ceutically acceptable excipients therefor.

[0046] The term "effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent or alleviate to some extent the onset of infection or one or more symptoms of the disorder, disease, or condition being treated. The term "effective amount" also refers to an amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician.

[0047] "Prevention" or "preventing" or "prophylaxis" means any treatment of an infection, disease or condition that does not result in the development of clinical symptoms of the disease or condition.

[0048] The compounds, in some embodiments, may be administered to subjects (including humans) at risk for or who have a family history of an infection, disease, or condition.

[0049] "Treatment" and "treatment" of a disease include: (1) preventing or reducing the risk of developing a disease, i.e., keeping clinical symptoms of the disease from developing in a subject who may be exposed to or has a predisposition to the disease but has not yet experienced or manifested symptoms of the disease; (2) inhibiting the disease, i.e., preventing or reducing the onset of the disease or its clinical symptoms; (3) alleviating (curing) the disease, i.e. causing regression of the disease or its clinical symptoms; and (4) Improving or alleviating symptoms or disorders caused by the disease.

[0050] The term "subject" or "patient" refers to an animal, such as a mammal (including a human), that is the object or subject of treatment, observation, or experiment. The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, a domestic animal (e.g., dogs and cats), a livestock animal (e.g., cows, 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 subject (or patient) is a human. "Human (or patient) in need thereof" refers to a human who may have or is suspected of having an infection or disease or condition that would benefit from a particular treatment, e.g., treated with a compound disclosed herein in accordance with the present application. Reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter per se. For example, a description that refers to "about x" includes a description of "x." Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those of skill in the art.

[0051] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0052] The term "substantially as depicted," when referring to, for example, an XRPD pattern, DSC thermogram, or TGA thermogram, includes patterns, thermograms, or spectra that are not necessarily identical to those shown herein, but that fall within the limits of experimental error or deviation as would be considered by one of ordinary skill in the art.

[0053] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. When the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes their corresponding pharmaceutically or toxicologically acceptable salts, particularly their pharmaceutically available salts. Thus, compounds of the present disclosure that contain acidic groups can exist on these groups and can be used according to the present disclosure, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the present disclosure that contain one or more basic groups, i.e., groups that can be protonated, can exist and can be used according to the present disclosure in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, methanesulfonic, p-toluenesulfonic, naphthalenedisulfonic, oxalic, acetic, tartaric, lactic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulfamic, phenylpropionic, gluconic, ascorbic, isonicotinic, citric, adipic, and other acids known to those skilled in the art. When the compounds of the present disclosure simultaneously contain acidic and basic groups in the molecule, the present disclosure also includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned.

[0054] The respective salts can be obtained by conventional methods known to those skilled in the art, for example by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present disclosure also includes all salts of the compounds of the present disclosure which are not directly suitable for use in medicines due to their low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0055] Generally, the salt formation of the compound of formula (I) can be carried out by conventional crystallization methods.Preferably, the crystallization is carried out by contacting the compound of formula (I) with a water-miscible solvent or solvent mixture and adding an acid or base selected to form the respective salt.The resulting crystallized salt is isolated by conventional methods, including, for example, filtration, washing and drying.

[0056] In addition, the compounds of the present disclosure may exist in the form of solvates, such as water solvates, or pharma- ceutically acceptable solvates, such as alcohol, especially ethanol. A "solvate" is formed by the interaction of a solvent with a compound. When the solvent is water, the "solvate" is a "hydrate". It is understood that the salts of the present disclosure may also include solvates.

[0057] Suitable solvents for the formation of salts and solvents of compounds according to formula (I) as defined herein include acetonitrile, dichloromethane (DCM), alcohols such as, in particular, methanol, ethanol, 2-propanol (isopropanol), and the like, aldehydes, ketones, in particular, acetone, and the like, ethers, for example, tetrahydrofuran (THF) or dioxane, esters, for example, ethyl acetate, or alkanes, for example, in particular, pentane, hexane, heptane or cyclohexane, and the like, and water, and mixtures thereof.

[0058] In certain embodiments, optical isomers, racemates or other mixtures of the compounds described herein or pharma- ceutically acceptable salts or mixtures thereof are provided. If necessary, isomers can be separated by methods known in the art, for example, liquid chromatography. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or resolution. Resolution can be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high pressure liquid chromatography (HPLC) column or a chiral supercritical fluid chromatography (SFC) column.

[0059] "Stereoisomers" refer to compounds composed of the same atoms linked by the same bonds, but with different three-dimensional structures that are not interchangeable. The term "enantiomers" refers to individual optically active forms of the compounds of the present invention having an optical purity or enantiomeric excess (as determined by routine methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, more preferably at least 98%.

[0060] The compounds disclosed herein and their pharma- ceutically acceptable salts may contain asymmetric centers and thus give rise to enantiomers, diastereomers and other stereoisomeric forms that may be defined, with respect to absolute stereochemistry, as I- or (S)-. The present invention is meant 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 chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, for example, HPLC or SFC.

[0061] [Solid forms of the compound of formula (I)] Solid forms of the compound of formula (I), including crystalline forms and substantially pure forms, may provide bioavailability and stability advantages suitable for use as an active ingredient in pharmaceutical compositions. Surprisingly, for example, IM-250 hydrochloride exhibits advantageous physical properties such as good physical and chemical stability, good water solubility and good bioavailability, yet is non-hygroscopic. Variations in the crystalline structure of a pharmaceutical substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (ease of handling, ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.) of the pharmaceutical substance or active ingredient. Such variations may 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 non-crystalline or amorphous forms, certain crystalline forms may provide desired or suitable hygroscopicity, particle size control, improved dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Thus, solid (crystalline) forms of the compound of formula (I) may provide advantages such as improving the manufacturing process of the compound, the stability or storage of a formulation of the compound, the stability or storage of an active pharmaceutical ingredient of the compound, and / or the bioavailability and / or stability of the compound as an active pharmaceutical agent.

[0062] The use of certain solvents and / or processes has been found to produce different solid forms of the compounds of formula (I) described herein, which may exhibit one or more of the preferred characteristics described above. Methods for preparing the solid forms described herein and characterization of these solid forms are described in detail below.

[0063] In certain embodiments, novel solid forms, such as crystalline forms, of the compound of formula (I) are disclosed.

[0064] The present invention relates in particular to the following embodiments: In a preferred embodiment in combination with any of the above or below embodiments, X is [ka] is selected from.

[0065] In a more preferred embodiment in combination with any of the above or below embodiments, X is [ka] It is.

[0066] In a preferred embodiment in combination with any of the above or below embodiments, Y is selected from CH3 and CD3.

[0067] In a more preferred embodiment in combination with any of the above or below embodiments, Y is CH3.

[0068] In a further preferred embodiment in combination with any of the above or below embodiments, X is [ka] wherein Y is CH3 or CD3.

[0069] In a further embodiment in combination with any of the above or below embodiments, X is [ka] and Y is CD3, thereby excluding compounds having the general formula: [ka]

[0070] A preferred embodiment in combination with any of the above or below embodiments is a compound having the following structure: [ka] or a pharma- ceutically acceptable salt, co-crystal, hydrate or solvate thereof.

[0071] Another preferred embodiment in combination with any of the above or below embodiments is a compound having the following structure: [ka] or a pharma- ceutically acceptable salt, co-crystal, hydrate or solvate thereof.

[0072] Another preferred embodiment in combination with any of the above or below embodiments is a compound having the following structure: [ka] or a pharma- ceutically acceptable co-crystal, hydrate or solvate thereof.

[0073] Another preferred embodiment in combination with any of the above or below embodiments is a compound having the following structure: [ka] or a pharma-ceutically acceptable co-crystal, hydrate or solvate thereof, preferably further characterized by having a melting point of 197° C. (± 5° C.) and / or being a white solid.

[0074] [IM-250 free base] One embodiment of the present invention relates to a solid (crystalline) compound of formula (I) having the following structure in free base form: [ka]

[0075] [IM-250 free base form I] In some embodiments, such IM-250 free base form is in the solid crystalline form IM-250 free base Form I, having the following structure: [ka] The solid IM-250 free base Form I is characterized by an X-ray powder diffraction pattern (XRPD) that includes reflections at 9.2, 13.7, and 18.7 degrees 2θ (signature peaks) (±0.2 degrees 2θ).

[0076] In some embodiments, IM-250 free base Form I is characterized by an XRPD pattern comprising one, two or three of the following reflections: 9.2, 13.7 and 18.7 degrees 2θ (±0.2 degrees 2θ) and 14.4, 24.0 and 27.3 degrees 2θ (±0.2 degrees 2θ).

[0077] In some embodiments, IM-250 free base Form I is characterized by an XRPD pattern comprising angle 2θ reflections at 9.2, 13.7, 14.4, 18.7, 24.0, and 27.3 degrees 2θ (±0.2 degrees 2θ).

[0078] In some embodiments, IM-250 free base Form I is characterized by an XRPD pattern that includes at least four of the following (signature) peaks: 9.2, 13.7, 14.4, 18.7, 24.0, and 27.3 degrees 2θ (±0.2 degrees 2θ).

[0079] All values ​​are measured on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

[0080] In some embodiments, crystalline IM-250 free base Form I has an XRPD pattern exhibiting 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 angle 2θ reflections having a maximum intensity substantially as the XRPD pattern shown in FIG.

[0081] More preferably, such a solid free base form, IM-250 Free Base Form I, exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0082] Moreover, such IM-250 free base Form I can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0083] Moreover, such IM-250 free base Form I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0084] In some embodiments of crystalline IM-250 free base Form I, at least one, at least two, or all of the following (a)-(c) apply: (a) Crystalline IM-250 free base Form I has an XRPD pattern substantially as shown in FIG. 1; (b) crystalline IM-250 free base Form I has a DSC thermogram substantially as shown in FIG. 2; (c) Crystalline IM-250 free base Form I has a TGA thermogram substantially as shown in FIG.

[0085] In some embodiments, the crystalline IM-250 free base Form I has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0086] In some embodiments, IM-250 free base Form I has a differential scanning calorimetry thermogram that includes an endotherm with an onset at about 163°C.

[0087] Thus, solid IM-250 free base Form I may be further characterized as having a melting point of 164-165° C. (± 5° C.).

[0088] [IM-250 free base form III] In some embodiments, such IM-250 free base forms are present in the solid crystalline form IM-250 free base form III having the following structure: [ka] In the above structure, this solid IM-250 free base Form III is characterized by an XRPD pattern that includes (signature peak) angle 2θ reflections at 9.7, 12.3, and 15.6 degrees (±0.2 degrees 2θ).

[0089] In some embodiments, IM-250 free base Form III is characterized by an XRPD pattern that includes one, two, or three of the following reflections: 9.7, 12.3, and 15.6 degrees 2θ (±0.2 degrees 2θ) and 12.9, 22.7, and 23.8 degrees 2θ (±0.2 degrees 2θ).

[0090] In some embodiments, IM-250 free base Form III is characterized by an XRPD pattern comprising angle 2θ reflections at 9.7, 12.3, 12.9, 15.6, 22.7, and 23.8 degrees 2θ (±0.2 degrees 2θ).

[0091] In some embodiments, IM-250 free base Form III is characterized by an XRPD pattern that includes at least four of the following (signature) peaks: 9.7, 12.3, 12.9, 15.6, 22.7, and 23.8 degrees 2θ (±0.2 degrees 2θ).

[0092] All values ​​are measured on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

[0093] In some embodiments, crystalline IM-250 free base Form III has an XRPD pattern exhibiting 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 of the angle 2θ reflections having maximum intensities substantially as the XRPD pattern shown in FIG.

[0094] More preferably, such solid free base form, IM-250 Free Base Form III, exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0095] Moreover, such IM-250 free base Form III can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0096] Moreover, such IM-250 free base Form III may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0097] In some embodiments of crystalline IM-250 free base Form III, at least one, at least two, or all of the following (a)-(c) are true: (a) Crystalline IM-250 free base Form III has an XRPD pattern substantially as shown in FIG. 3; (b) crystalline IM-250 free base Form III has a DSC thermogram substantially as shown in FIG. 4; (c) Crystalline IM-250 free base Form III has a TGA thermogram substantially as shown in FIG.

[0098] In some embodiments, the crystalline IM-250 free base Form III has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0099] In some embodiments, IM-250 free base Form III has a differential scanning calorimetry thermogram that includes an endotherm with an onset at about 141°C.

[0100] Thus, solid IM-250 free base Form III may be further characterized as having a melting point of 143° C. (± 5° C.).

[0101] [Deuterated IM-250 free base (d3-IM-250 free base)] A further embodiment of the present invention relates to a solid (crystalline) compound of formula (I) having the following structure, which is deuterated IM-250 free base (d3-IM-250 free base). [ka] In the above structure, this solid deuterated IM-250 free base (d3-IM-250 free base) is characterized by an X-ray powder diffraction pattern (XRPD) that includes (signature peaks) angle 2θ reflections at 9.3, 13.7, and 18.6 degrees (±0.2 degrees 2θ).

[0102] In some embodiments, deuterated IM-250 free base (d3-IM-250 free base) is characterized by an XRPD pattern that includes one, two, three, or four of the following reflections: 9.3, 13.7, and 18.6 degrees 2θ (±0.2 degrees 2θ) and 14.4, 15.3, 15.5, and 24.1 degrees 2θ (±0.2 degrees 2θ).

[0103] In some embodiments, deuterated IM-250 free base (d3-IM-250 free base) is characterized by an XRPD pattern comprising angle 2θ reflections at 9.3, 13.7, 14.4, 15.3, 15.5, 18.6, and 24.1 degrees 2θ (±0.2 degrees 2θ).

[0104] In some embodiments, deuterated IM-250 free base (d3-IM-250 free base) is characterized by an XRPD pattern that includes at least four of the following (signature) peaks: 9.3, 13.7, 14.4, 15.3, 15.5, 18.6, and 24.1 degrees 2θ (±0.2 degrees 2θ).

[0105] All values ​​are measured on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

[0106] In some embodiments, crystalline deuterated IM-250 free base (d3-IM-250 free base) has an XRPD pattern exhibiting 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 angle 2θ reflections having maximum intensities as an XRPD pattern substantially as shown in FIG.

[0107] More preferably, such solid free base form, deuterated IM-250 free base (d3-IM-250 free base), exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0108] Moreover, such deuterated IM-250 free base (d3-IM-250 free base) can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0109] Moreover, such deuterated IM-250 free base (d3-IM-250 free base) can exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0110] In some embodiments of crystalline deuterated IM-250 free base (d3-IM-250 free base), at least one, at least two, or all of the following (a)-(c) are true: (a) Crystalline deuterated IM-250 free base (d3-IM-250 free base) has an XRPD pattern substantially as shown in FIG. 14; (b) crystalline deuterated IM-250 free base (d3-IM-250 free base) has a DSC thermogram substantially as shown in FIG. 16; (c) Crystalline deuterated IM-250 free base (d3-IM-250 free base) has a TGA thermogram substantially as shown in FIG.

[0111] In some embodiments, the crystalline deuterated IM-250 free base (d3-IM-250 free base) has at least one, at least two, or at least three of the following properties: (a) An XRPD pattern substantially as shown in FIG. 14; (b) A DSC thermogram substantially as shown in FIG. 16; (c) TGA thermogram substantially as shown in FIG.

[0112] In some embodiments, deuterated IM-250 free base (d3-IM-250 free base) has a differential scanning calorimetry thermogram that includes an endotherm with an onset at about 163°C.

[0113] Thus, solid deuterated IM-250 free base (d3-IM-250 free base) may be further characterized as having a melting point of 163-165° C. (± 5° C.).

[0114] Selected Salt Forms of Compounds of the Invention A further aspect of the invention relates to selected salt forms of compounds of formula (I), preferably compounds of formula (I) where X is [ka]

[0115] Particularly preferred are the hydrochloride and napadisylate salts of the compounds of the invention and hydrates or solvates thereof, such as, in particular, the hydrochloride and napadisylate salts of compounds of formula (I), wherein X is [ka] and Y is selected from CH3 and CD3. The hydrochloride salt is most preferred.

[0116] [IM-250 hydrochloride] A further embodiment of the present invention relates to the hydrochloride salt of the compound IM-250, which is IM-250 hydrochloride having the following structure: [ka]

[0117] In one embodiment of the present invention, such IM-250 hydrochloride salt is characterized by an XRPD pattern that includes (signature peak) angle 2θ reflections at 13.7 degrees, 17.7 degrees, and 22.8 degrees (±0.3 degrees 2θ).

[0118] In some embodiments, IM-250 hydrochloride is characterized by an XRPD pattern that includes one, two, or three of the following reflections: 13.7, 17.7, and 22.8 degrees 2θ (±0.3 degrees 2θ) and 17.0, 19.8, and 21.8 degrees 2θ (±0.3 degrees 2θ).

[0119] In some embodiments, IM-250 hydrochloride is characterized by an XRPD pattern comprising angle 2θ reflections at 13.7, 17.0, 17.7, 19.8, 21.8, and 22.8 degrees 2θ (±0.3 degrees 2θ).

[0120] In some embodiments, IM-250 hydrochloride is characterized by an XRPD pattern that includes at least four of the following peaks: 13.7, 17.0, 17.7, 19.8, 21.8, and 22.8 degrees 2θ (±0.3 degrees 2θ).

[0121] All values ​​are measured on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

[0122] In some embodiments, the crystalline IM-250 hydrochloride salt has an XRPD pattern exhibiting 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 angle 2θ reflections having a maximum intensity as an XRPD pattern substantially as shown in FIG.

[0123] In some embodiments, crystalline IM-250 hydrochloride has an XRPD pattern exhibiting 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 degree 2θ reflections having maximal intensities as an XRPD pattern substantially as shown in FIG.

[0124] In some embodiments, such a solid hydrochloride salt form of IM-250 hydrochloride exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0125] In some embodiments, such a solid hydrochloride salt form of IM-250 hydrochloride exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0126] Moreover, such IM-250 hydrochloride salt may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0127] Moreover, such IM-250 hydrochloride salt may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0128] In some embodiments of crystalline IM-250 hydrochloride, at least one, at least two, or all of the following (a)-(c) are true: (a) Crystalline IM-250 hydrochloride has an XRPD pattern substantially as shown in FIG. 5; (b) crystalline IM-250 hydrochloride has a DSC thermogram substantially as shown in Figure 6; (c) Crystalline IM-250 hydrochloride has a TGA thermogram substantially as shown in FIG.

[0129] In some embodiments, the crystalline IM-250 hydrochloride salt has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 5; (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0130] In some embodiments of the crystalline IM-250 hydrochloride salt, at least one, at least two, or all of the following (a)-(c) are true: (a) Crystalline IM-250 hydrochloride has an XRPD pattern substantially as shown in FIG. 7; (b) crystalline IM-250 hydrochloride has a DSC thermogram substantially as shown in Figure 6; (c) Crystalline IM-250 hydrochloride has a TGA thermogram substantially as shown in FIG.

[0131] In some embodiments, the crystalline IM-250 hydrochloride salt has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 7; (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0132] In some embodiments, IM-250 hydrochloride has a thermogravimetric analysis thermogram that exhibits a mass loss of about 9.8% upon heating with a start / end temperature of about 151 / 170°C.

[0133] In some embodiments, IM-250 hydrochloride salt has a thermogravimetric analysis thermogram that exhibits an onset decomposition temperature of about 221°C.

[0134] In some embodiments, provided herein is IM-250 hydrochloride having the following structure: [ka] In the above formula, the hydrochloride salt and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)acetamide are in a molar ratio of 1 to 1±0.2.

[0135] Said hydrochloride salt, IM-250 hydrochloride, was surprisingly found to exhibit some advantages in terms of chemical and physical stability, (lack of) hygroscopicity and improved bioavailability, whereas the other tested salts were less advantageous, as shown in the following examples. Thus, the compound, IM-250 hydrochloride, is a particularly preferred embodiment of the present invention.

[0136] [Deuterated IM-250 hydrochloride - d3-IM-250 hydrochloride] A further embodiment of the present invention relates to the hydrochloride salt of the corresponding deuterated compound of IM-250 hydrochloride (d3-IM-250 hydrochloride), a compound having the following structure: [ka]

[0137] In one embodiment of the present invention, such deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) is characterized by an XRPD pattern that includes (signature peak) angle 2θ reflections at 13.8, 17.8, and 21.8 degrees (±0.3 degrees 2θ).

[0138] In some embodiments, deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) is characterized by an XRPD pattern that includes one, two, three, four or five of the following reflections at 13.8, 17.8, and 21.8 degrees 2θ (±0.3 degrees 2θ) and 11.3, 11.9, 19.8, 21.0, and 21.3 degrees 2θ (±0.3 degrees 2θ).

[0139] In some embodiments, deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) is characterized by an XRPD pattern comprising angle 2θ reflections at 11.3, 11.9, 13.8, 17.8, 19.8, 21.0, 21.3, and 21.8 degrees 2θ (±0.3 degrees 2θ).

[0140] In some embodiments, deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) is characterized by an XRPD pattern including at least four of the following peaks: 11.3, 11.9, 13.8, 17.8, 19.8, 21.0, 21.3, and 21.8 degrees 2θ (±0.3 degrees 2θ).

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

[0142] In some embodiments, crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) has an XRPD pattern exhibiting 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 angle 2θ reflections having maximum intensities as an XRPD pattern substantially as shown in FIG.

[0143] In some embodiments, such a solid hydrochloride salt form of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0144] Moreover, such deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0145] Moreover, such deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0146] In some embodiments of crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride), at least one, at least two, or all of the following (a)-(c) apply: (a) Crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) has an XRPD pattern substantially as shown in FIG. 17; (b) crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) has a DSC thermogram substantially as shown in FIG. 18; (c) Crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) has a TGA thermogram substantially as shown in FIG. 18.

[0147] In some embodiments, crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 17; (b) A DSC thermogram substantially as shown in FIG. 18; (c) TGA thermogram substantially as shown in FIG.

[0148] In some embodiments, deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) has a thermogravimetric analysis thermogram that exhibits a mass loss of about 7.8% upon heating with start / end temperatures of about 149 / 167°C.

[0149] In some embodiments, deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) has a thermogravimetric analysis thermogram that exhibits an onset decomposition temperature of about 225°C.

[0150] In some embodiments, deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) has a differential scanning calorimetry thermogram that includes an endotherm with an onset at about 188°C.

[0151] Thus, solid deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) may be further characterized as having a melting point of 188-194°C (± 5°C).

[0152] In some embodiments, provided herein is deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride), having the following structure: [ka] In the above formula, the hydrochloride salt and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonimidoyl)thiazol-2-yl)acetamide are in a molar ratio of 1 to 1±0.2.

[0153] Said deuterated hydrochloride salt, deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride), was surprisingly found to exhibit several advantages in terms of chemical and physical stability, (lack of) hygroscopicity and improved bioavailability, whereas the other tested salts were less advantageous. Thus, crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) is a particularly preferred embodiment of the present invention.

[0154] [IM-250 napadisilate salt] A further embodiment of the present invention relates to a naphthalene disulfonate salt of the compound IM-250, which is IM-250 napadisilate, having the following structure: [ka]

[0155] In one embodiment of the present invention, such IM-250 napadisylate is characterized as having an XRPD pattern that includes (signature peak) angle 2θ reflections at 9.1, 14.5, and 18.1 degrees (±0.2 degrees 2θ).

[0156] In some embodiments, IM-250 napadisylate is characterized by an XRPD pattern including one, two, or three of the following reflections: 9.1, 14.5, and 18.1 degrees 2θ (±0.2 degrees 2θ) and 15.6, 19.1, and 20.9 degrees 2θ (±0.2 degrees 2θ).

[0157] In some embodiments, IM-250 napadisylate is characterized by an XRPD pattern comprising angle 2θ reflections at 9.1, 14.5, 15.6, 18.1, 19.1, and 20.9 degrees 2θ (±0.2 degrees 2θ).

[0158] In some embodiments, IM-250 napadisylate is characterized by an XRPD pattern including at least four of the following peaks: 9.1, 14.5, 15.6, 18.1, 19.1, and 20.9 degrees 2θ (±0.2 degrees 2θ).

[0159] All values ​​are measured on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

[0160] In some embodiments, crystalline IM-250 napadisylate has an XRPD pattern exhibiting 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 angle 2θ reflections having maximum intensities as an XRPD pattern substantially as shown in FIG.

[0161] More preferably, such solid form IM-250 napadisylate exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0162] Moreover, such IM-250 napadisylate may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0163] Moreover, such IM-250 napadisylate may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG.

[0164] In some embodiments of crystalline IM-250 napadisylate, at least one, at least two, or all of the following (a)-(c) apply: (a) Crystalline IM-250 napadisylate has an XRPD pattern substantially as shown in FIG. 8; (b) crystalline IM-250 napadisylate has a DSC thermogram substantially as shown in Figure 9; (c) Crystalline IM-250 napadisylate has a TGA thermogram substantially as shown in FIG.

[0165] In some embodiments, the crystalline IM-250 napadisylate has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 8; (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0166] In some embodiments, IM-250 napadisylate has a differential scanning calorimetry thermogram that includes an exotherm with an onset at about 223°C.

[0167] Thus, solid IM-250 napadisylate may be further characterized as having a melting point of 230° C. (±5° C.).

[0168] In some embodiments, provided herein is IM-250 napadisylate having the following structure: [ka] In the above structure, naphthalene-1,5-disulfonic acid and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)acetamide are in a molar ratio of 1 to 2±0.2.

[0169] Surprisingly, it was found that the napadisylate salt, IM-250 napadisylate salt, exhibits several advantages in terms of chemical and physical stability, (lack of) hygroscopicity and improved bioavailability, whereas the other tested salts were less advantageous, as shown in the following examples. Thus, the compound, IM-250 napadisylate salt, is a particularly preferred embodiment of the present invention.

[0170] [Deuterated IM-250 napadisylate salt - d3-IM-250 napadisylate] In another embodiment of the present invention, the IM-250 napadisilate salt can also exist in the deuterated form of the naphthalene disulfonate salt of the deuterated compound IM-250, represented by the following structure: [ka]

[0171] [Solid form IM-315] A further embodiment of the present invention relates to a solid (crystalline) compound of formula (I), which is IM-315, having the following structure: [ka] In the above structure, this solid IM-315 form is characterized as having an XRPD pattern that includes (signature peak) angle 2θ reflections at 6.4, 12.5, and 18.3 degrees (±0.2 degrees 2θ).

[0172] In some embodiments, IM-315 is characterized by an XRPD pattern that includes one or two of the following reflections: 6.4, 12.5, and 18.3 degrees 2θ (±0.2 degrees 2θ) and 22.3 and 23.1 degrees 2θ (±0.2 degrees 2θ).

[0173] In some embodiments, IM-315 has an XRPD pattern including angle 2θ reflections at 6.4, 12.5, 18.3, 22.3, and 23.1 degrees 2θ (±0.2 degrees 2θ).

[0174] In some embodiments, IM-315 has an XRPD pattern including at least three of the following peaks: 6.4, 12.5, 18.3, 22.3, and 23.1 degrees 2θ (±0.2 degrees 2θ).

[0175] All values ​​are measured on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

[0176] In some embodiments, crystalline IM-315 has an XRPD pattern displaying 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 of the angle 2θ reflections having maximum intensity as an XRPD pattern substantially as shown in FIG. 10.

[0177] More preferably, such solid form IM-315 exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0178] Moreover, such IM-315 may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG.

[0179] In some embodiments of crystalline IM-315, at least one or all of the following (a)-(b) are true: (a) crystalline IM-315 has an XRPD pattern substantially as shown in FIG. 10; (b) Crystalline IM-315 has a DSC thermogram substantially as shown in FIG.

[0180] In some embodiments, the crystalline IM-315 has at least one or at least two of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 10; (b) DSC thermogram substantially as shown in FIG.

[0181] Moreover, such IM-315 forms have a differential scanning calorimetry thermogram that includes an exotherm with an onset at about 196°C.

[0182] Thus, the solid IM-315 form may be further characterized as having a melting point of 197° C. (± 5° C.).

[0183] As described in Example 5, IM-315 forms according to the present invention exists as a white solid.

[0184] In contrast, Example Compound No. 87 disclosed in WO 02 / 06363 and WO 02 / 06363 is characterized in that it has a melting point of 184° C. and is obtained in the form of a pale yellow solid. It can therefore be concluded that IM-315 according to the present invention is different from Example Compound No. 87 in WO 02 / 06363 and WO 02 / 06363, and that this form IM-315 constitutes a new polymorphic form different from Example Compound No. 87 in WO 02 / 06363 and WO 02 / 06363.

[0185] Dosage forms and medical uses of solid forms of the compound of formula (I) A further aspect of the invention relates to pharmaceutical formulations comprising one or more of the compounds of any of the above embodiments.

[0186] A further aspect of the invention relates to a compound of any of the above embodiments for use as a medicament.

[0187] In particular, the invention relates to the compounds described for use in the treatment or prevention of a disease or disorder associated with a viral infection.

[0188] More particularly, the present invention relates to the compounds described for use in the treatment or prevention of a disease or disorder associated with a viral infection caused by a herpes virus, in particular a herpes simplex virus, i.e. for use in the treatment or prevention of a herpes infection, such as a herpes simplex virus infection.

[0189] In a further aspect, the invention relates to the described compounds for use in treating and eliminating latent (dormant) forms of herpes viruses in nervous tissue and neurons, preferably to avoid or prevent recurrence and reactivation of herpes infection or the serious effects associated therewith, such as herpes simplex encephalitis (HSE).

[0190] In a further aspect, the invention relates to the described compounds for use in the treatment or prevention of neurodegenerative diseases caused by viruses, such as, for example, neurodegenerative diseases such as Alzheimer's disease, especially caused by a virus, especially herpes simplex virus.

[0191] In a further aspect, the present invention relates to a compound as described above for use in a patient comprising: Patients with herpes infections, especially herpes simplex infections, patients with herpes labialis, genital herpes and herpes associated keratitis, Alzheimer's disease, encephalitis, pneumonia, hepatitis; patients with suppressed immune systems, such as AIDS patients, cancer patients, patients with genetic immunodeficiencies, transplant patients; newborns and infants; herpes positive patients, especially herpes simplex positive patients, patients for suppression of recurrences (suppressive therapy); or patients resistant to nucleoside antiviral therapy such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and / or foscarnet or cidofovir, especially herpes positive patients, especially herpes simplex positive patients.

[0192] The compounds according to the invention are contemplated for use in the prevention and treatment of the respective disorders and diseases in humans as well as animals.

[0193] Thus, the present invention relates to the use of the compounds described herein for the preparation of a medicament.

[0194] Furthermore, the present invention relates to a method for preventing or treating a disease or disorder associated with a viral infection, such as a disease or disorder associated with a viral infection caused in particular by a herpes virus, such as herpes simplex virus, as well as a method for treating and eliminating latent (dormant) forms of herpes virus in nervous tissue and neurons, preferably to avoid or prevent recurrence and reactivation of herpes infection, or even severe effects associated with infection, such as herpes simplex encephalitis (HSE), or a method for preventing or treating a neurodegenerative disease caused in particular by a virus, such as Alzheimer's disease, which method comprises administering to a human or animal in need thereof an effective amount of a compound as described herein or a composition comprising said compound.

[0195] In practical use, the compound used in the present invention can be combined as active ingredient in intimate mixture with pharmaceutical carrier according to conventional pharmaceutical compounding technology.The carrier can take a wide variety of forms, depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous).When preparing the composition for oral dosage form, any of the usual pharmaceutical media can be used, such as, for example, water, glycol, oil, alcohol, flavoring agent, preservative, coloring agent, etc., for oral liquid preparations such as suspension, elixir and solution; or, for example, for oral solid preparations such as powder, hard and soft capsules and tablets, carriers such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, disintegrant, etc., and solid oral preparations are preferred over liquid preparations.

[0196] Due to their ease of administration, tablets and capsules provide the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used. If necessary, tablets can be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can of course vary and can conveniently be from about 2.0 percent to about 60.0 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage is obtained. The active compound can also be administered intranasally, for example, as liquid drops or spray, or as eye drops.

[0197] Tablets, pills, capsules and the like may also contain binders such as tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, alginic acid, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose or saccharin. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0198] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

[0199] The compounds used in the present invention can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerin, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0200] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that it can be easily injected. It must be stable under the conditions of manufacture and preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0201] Any suitable route of administration may be used to provide a mammal, particularly a human, with an effective dose of a compound of the invention. For example, oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal, etc. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, gels, ointments, aerosols, etc. Preferably, the compounds of the invention are administered orally or topically as eye drops, creams or gels, and more preferably, the compounds of the invention are administered orally.

[0202] The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosage may be readily ascertained by one skilled in the art.

[0203] The compounds of the present invention may also be present in combination with further active ingredients, in particular one or more active ingredients that show advantageous effects in the treatment of any of the disorders or diseases described herein.Very particularly, the compounds of the present invention are present in the composition in combination with at least one further active substance that is effective for treating diseases or disorders related to viral infections (antiviral active compounds), preferably diseases or disorders related to viral infections caused by herpes viruses, in particular herpes simplex viruses, thus so-called combined therapy.At least one further active substance (immunomodulator, for example glucocorticoid) is effective for treating diseases or disorders related to viral infections, and more preferably, antiviral active compounds selected from the group consisting of nucleoside drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir and trifluridine, as well as compounds such as foscarnet and cidofovir are effective.

[0204] Accordingly, the present invention further relates to pharmaceutical compositions comprising one or more of the compounds as described herein effective for the treatment of a disease or disorder associated with a viral infection (antiviral active compounds) and at least one pharma- ceutically acceptable carrier and / or excipient and / or at least one further active substance.

[0205] A further aspect of the present invention relates to the use of the compounds described herein that act as helicase primase inhibitors in combination therapy with an oncolytic virus for the treatment of a tumor, cancer or neoplasm.

[0206] A further embodiment of this additional aspect of the invention relates to a pharmaceutical composition for use as an antidote in combination therapy with an oncolytic virus for treating cancer, comprising at least one helicase primase inhibitor as defined in any embodiment described herein, which acts to control, modulate, inhibit or block the activity of an oncolytic virus sensitive to said inhibitor used in the treatment of cancer, and which may further comprise at least one pharma- ceutical acceptable carrier and / or excipient and / or at least one further active substance such as an antiviral active or immunomodulatory compound, and which comprises a checkpoint inhibitor that is effective in treating a disease or disorder associated with an oncolytic virus infection used in the treatment of cancer.

[0207] A further embodiment of this additional aspect of the invention relates to a helicase primase inhibitor compound or pharmaceutical composition of the invention for use in combination therapy with an oncolytic virus as described in detail in WO 2014 / 023994, wherein the cancer to be treated is a solid cancer, preferably the cancer disease is selected from liver cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, brain cancer, melanoma, glioblastoma, etc.

[0208] A further embodiment of this additional aspect of the invention relates to a helicase primase inhibitor compound or a pharmaceutical composition of the invention for use in combination therapy with an oncolytic virus as described in WO 2007 / 023991, wherein the oncolytic virus is an oncolytic herpes virus.

[0209] A further embodiment of this additional aspect of the invention relates to a helicase primase inhibitor compound or pharmaceutical composition of the invention for use in combination therapy with an oncolytic virus as described in WO 2014 / 023994, wherein the cancer therapy comprises infusion, injection, intratumoral injection or topical or transdermal application of an oncolytic virus or oncolytic virus-infected cells and / or a helicase primase inhibitor or a pharmaceutical composition comprising same.

[0210] A further embodiment of this additional aspect of the invention relates to a helicase primase inhibitor compound or pharmaceutical composition of the invention for use in combination therapy with an oncolytic virus as described in WO 2007 / 023994, wherein the oncolytic virus or oncolytic virus-infected cells are selected from an oncolytic wild-type, clinical isolate or experimental herpesvirus strain, or a genetically engineered or polymutated, optionally attenuated or boosted oncolytic herpesvirus.

[0211] A further embodiment of this additional aspect of the invention relates to a kit comprising at least one helicase primase inhibitor compound or pharmaceutical composition of the invention and at least one oncolytic virus selected from wild-type, laboratory strains, clinical isolates, and engineered or multi-mutated oncolytic viruses for use in combination therapy with an oncolytic virus as described in WO 2014 / 023366.

[0212] A further embodiment of this additional aspect of the invention relates to said kit for use in the treatment of cancer as defined herein.

[0213] The helicase primase inhibitor compounds, pharmaceutical compositions or kits for use in combination therapy with oncolytic viruses as described herein may be applied to one or more of the following patient groups: Infants; herpes positive patients, particularly oncolytic herpes simplex positive patients, to suppress recurrence or oncolytic viral shedding; patients resistant to nucleoside antiviral therapy such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and / or foscarnet or cidofovir, particularly herpes positive patients, particularly oncolytic herpes simplex positive patients.

[0214] A further aspect of the present invention is a compound having the following structure: [ka] or a pharma- ceutically acceptable salt, co-crystal, hydrate or solvate thereof, (a) Compound P2b: [ka] The following compounds: [ka] contacting with (b) Compound P2c: [ka] with Rh2(OAc)4, tert-butyl carbamate, magnesium oxide and (diacetoxy)iodobenzene to form compound P2d: [ka] contacting under conditions sufficient to form (c) the structure: [ka] deprotecting compound P2d under conditions sufficient to form a compound having the formula: (d) optionally converting compound IM-250 into a pharma- ceutically acceptable salt, co-crystal, hydrate or solvate thereof; Includes.

[0215] A further embodiment relates to the process described above, comprising the compound P2d: [ka] is deprotected with hydrochloric acid in step (c) to give compound IM-250 hydrochloride: [ka] The hydrochloride salt of compound IM-250 is formed, which corresponds to

[0216] In a preferred embodiment, IM-250 hydrochloride is recrystallized from isopropanol or ethanol, preferably from ethanol.

[0217] In another embodiment of the above method, compound P2d: [ka] is deprotected in step (c) with 1,5-naphthalenedisulfonic acid tetrahydrate to form the napadisilate salt of compound IM-250.

[0218] In a similar manner, the corresponding deuterated compound can be obtained, including a step of deuterium addition at the position corresponding to Y in formula (I). EXAMPLES

[0219] [Experimental part] [Abbreviation] HPMC Hydroxypropyl methylcellulose DMF Dimethylformamide DMSO Dimethyl sulfoxide DSC Differential Scanning Calorimeter EA Ethyl acetate EDCI·HCl 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride FCC Silica Gel Flash 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

[0220] [Experimental Section] [X-ray powder diffraction (XRPD)] XRPD analysis was performed on a Bruker D2 Phase diffractometer using a copper anticathode, a single crystal silicone sample holder, and a position sensitive detector (LynxExe). Powder samples were loaded onto a flat single crystal silicone sample holder in such a way as to avoid preferred orientation and to sense the planarity of the sample surface. The instrument operating conditions were as follows: Ambient temperature and atmosphere, X-ray generator voltage 30 kV and intensity 10 mA, X-ray source: target copper; emission radiation Kα1 = 0.15406 nm, Kα2 = 0.15444 nm, ratio Kα2 / Kα1 = 0.5, Kβ filter radiation nickel, slit: divergence prevention 1 nM, Soller slit 2.5°, goniometer: angular sector analyzed from 4° to 45° or 4° to 50° for 2θ, step size 0.07° for 2θ, sample holder rotation speed: 30 rpm, detection: exposure time per step size of goniometer 1 s.

[0221] [Differential scanning calorimeter (DSC)] DSC analysis was performed on a Q1000 TA Instruments analyzer. The samples to be analyzed were weighed into aluminum capsules, which were then crimped and placed in the calorimeter oven. The instrument operating conditions were as follows: heater lamp 10° C. / min, final temperature 230° C. or 240° C., carrier gas: nitrogen (Messer “qualite Azote 5.0”), flow rate 50 mL / min.

[0222] [Thermogravimetric analysis (TGA)] TGA analysis was performed on a TA Instruments TGA Hi-Res 2950. Samples were placed in open aluminum baskets and analyzed as follows: Mass assay 5 mg; heat ramp 10 °C / min; final temperature 500 °C; carrier gas: nitrogen (Messer “qualite Azote 5.0”) at a flow rate of 95-105 mL / min.

[0223] Example 1: Synthesis of IM-250 free base form I The title compound was prepared by separating the racemic mixture by chiral SFC chromatography (as described in Example 7 of US Pat. No. 5,993,336) using Chiralcel OJ as the stationary phase and 60 / 40 vol.% CO2 / IPA as the mobile phase with the following additional data: Equipment: SFC-200 (Thar, Waters) Column: OJ 20 x 250 mm, 10 μm (Daicel) Column temperature: 35℃ Flow rate: 100g / min Back pressure: 100bar Detection wavelength: 214 nm Cycle time: 6 minutes Sample solution: 70 g dissolved in 2000 mL of dichloromethane Injection volume: 3mL

[0224] The title compound IM-250 free base form I can be obtained by removing the mobile phase (solvent) of the first eluting enantiomer after evaporating the CO2 (retention time: 3.25 min) and removing the IPA by rotary evaporator at 40°C.

[0225] XRPD analysis was performed. Figure 1 shows the XRPD pattern of IM-250 free base Form I. The XRPD peaks were identified and are included in Table 1 below.

[0226] [Table 1]

[0227] TGA and DSC analyses were performed. Figure 2 shows an overlay of DSC and TGA thermograms of IM-250 free base Form I. The TGA analysis (right curve) showed that the solid lost about 0.1 wt% below about 160°C, and the solid lost about 76 wt% (decomposition) between about 240-300°C. The DSC analysis revealed an endotherm with an onset at about 163°C and a peak at 164°C (transition enthalpy 83 J / g).

[0228] Example 2: Synthesis of IM-250 Free Base Form III [Step 1: N,4-Dimethyl-5-(methylsulfinyl)thiazol-2-amine (P2a)] [ka] To a solution of N,4-dimethyl-5-(methylthio)thiazol-2-amine (as described in Example P4a of Patent Document 4) (80 g, 0.46 mol) in CHCl (1.0 L) was added metachloroperoxybenzoic acid (83 g, 85%, 0.46 mol) at room temperature, and the mixture was stirred for 30 min. Saturated NaHCO was then added. The mixture was extracted with CHCl (1.5 L) and washed with brine (500 mL). The organic layer was dried over NaSO, filtered, concentrated, and purified by FCC (CHCl:MeOH=10:1) to give the title compound P2a (58 g, 66%) as a yellow solid.

[0229] [Step 2: (-)-(S)-N,4-dimethyl-5-(methylsulfinyl)thiazol-2-amine (P2b)] [ka] The title compound P2b was prepared by separation of the racemic mixture P2a by chiral SFC chromatography using the following equipment and conditions: Equipment: SFC-80 (Thar, Waters) Column: IC 20 x 250 mm, 10 μm (Daicel) Column temperature: 35℃ Mobile phase: CO2 / MeOH=65 / 35 with 0.2% NH3 Flow rate: 80g / min Back pressure: 100bar Detection wavelength: 214 nm Cycle time: 5.6 minutes Sample solution: 58g dissolved in 1L Volume of injection: 1.5mL

[0230] Compound P2b was obtained as a pale yellow solid (22.5 g) as the first eluting enantiomer (retention time: 2.38 min).

[0231] This is [α] 20 589nm It has a negative optical rotation of -33.5° (c=1.00 g / 100 mL MeOH).

[0232] 1 H-NMR (DMSO-d6, 400MHz): 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 actual value: 191.2[M+H] + .

[0233] [Step 3: (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(methylsulfinyl)thiazol-2-yl)acetamide (P2c)] [ka] 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 compound P2b (74.0 g, 389 mmol) and EDCI·HCl (112 g, 583 mmol) were added. The mixture was stirred overnight, concentrated in vacuum, redissolved in EA (1.0 L) and washed with water (2×0.5 L). The organic layer was dried over Na2SO4, concentrated in vacuum and purified by FCC (PE:EA=1:2) to give compound P2c (145 g, 89%) as a white solid.

[0234] 1 H-NMR (DMSO-d6,400MHz):7.57(dd,J=8.0,1.6Hz,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 actual value: 421.1[M+H]+ .

[0235] [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)sulfonimidoyl)thiazol-2-yl)acetamide (P2d)] [ka] Magnesium oxide (55.2 g, 1.38 mol), tert-butyl carbamate (80.7 g, 690 mmol), Rh2(OAc)4 (14.5 g, 32.8 mmol) and (diacetoxy)iodobenzene (167 g, 517 mmol) were added to an aqueous solution of compound P2c (145 g, 345 mmol) in CHCl2 (1.0 L). The mixture was stirred at 40 °C for 1 h. Additional Rh2(OAc)4 (4.8 g, 11 mmol), MgO (18.4 g, 460 mmol), tert-butyl carbamate (26.9 g, 230 mmol) and (diacetoxy)iodobenzene (55.5 g, 172 mmol) were added and stirred overnight. The mixture was then filtered through a pad of Celite, the solvent was removed under reduced pressure, and the crude product was purified by FCC (PE:EA=1:1) to give compound P2d (160 g, 87%) as a white solid.

[0236] 1 H-NMR(DMSO-d6,400MHz):7.57(dd,J=8.0,1.2Hz,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 actual value: 536.1[M+H] + .

[0237] [Step 5: (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)acetamide (IM-250 free base)] [ka] Compound P2d (160 g, 299 mmol) was added to a stirred solution of TFA (80 mL) acid in CHCl (0.5 L) at ambient temperature and stirring was continued for 90 min. The mixture was concentrated, then dissolved in CHCl, washed with saturated NaHCO (3×0.5 L), dried over NaSO, concentrated, and purified by FCC (PE:EA=1:2) to give IM-250 free base Form III (120 g, 92%) as a white solid after removal of organic solvents on a rotary evaporator at 30° C.

[0238] XRPD analysis was performed. Figure 3 shows the XRPD pattern of IM-250 free base Form III. The XRPD peaks were identified and are included in Table 2 below.

[0239] [Table 2]

[0240] TGA and DSC analyses were performed. Figure 4 shows an overlay of DSC and TGA thermograms of IM-250 free base Form III. The TGA analysis (right curve) showed that the solid lost about 0.2% weight below about 130°C and the solid lost about 75% weight (decomposition) between about 240-300°C. The DSC analysis revealed an endotherm with an onset at about 141°C and a peak at 143°C (transition enthalpy 83 J / g), an exotherm with a peak at 148°C (transition enthalpy 43 J / g) for recrystallization, and an endotherm with an onset at about 163°C and a peak at 164°C (transition enthalpy 52 J / g).

[0241] (Example 3: Synthesis of IM-250 hydrochloride) [ka] IM-250 Form I (205 mg, 470 μmol) was solubilized in acetone (5 mL) by stirring on a rotary evaporator at 50° C. and atmospheric pressure. A volume of 1 N hydrochloric acid corresponding to a 1:1 stoichiometry was added. The solvent was then evaporated to dryness at 50° C., giving a film. The film was resuspended and solubilized in ethanol (4 mL) at room temperature. The solvent was then evaporated to dryness at 50° C., giving a meringue. The film was resuspended and solubilized in isopropanol (1 mL) at 50° C., kept at room temperature, partially demixed (after about 30 min), and then warmed again to 50° C. for resolubilization. Very quickly, strong crystallization occurred. One additional heating (50° C.) and cooling (rt) cycle was performed (20 min each) and the sample was kept at room temperature for 2 days. The supernatant solvent was removed and the powder was finally dried under dynamic vacuum (70° C. for 40 min) to give IM-250 hydrochloride as colorless crystals.

[0242] XRPD analysis was performed. Figure 5 shows the XRPD pattern of IM-250 hydrochloride salt. The XRPD peaks were identified and are included in Table 3 below.

[0243] [Table 3]

[0244] TGA and DSC analysis was performed. Figure 6 shows an overlay of DSC and TGA thermograms of IM-250 hydrochloride salt. TGA analysis (right curve) showed a mass loss of 9.8% upon heating with onset / end temperatures of 151 / 170°C before the main thermal decomposition was detected at an onset temperature of 221°C. The 9.8% mass loss can be attributed to the exodus of the hydrochloric acid moiety. DSC analysis showed no true melting point. The unresolved double endothermic event observed from 160°C is associated with the loss of the hydrochloric acid moiety observed on the TGA profile.

[0245] [Alternative synthesis of IM-250 hydrochloride using ethanol] IM-250 Form III (4.75 g) was solubilized in acetone (150 mL) by stirring on a rotary evaporator at room temperature and atmospheric pressure. A volume of 1N hydrochloric acid corresponding to a 1:1 stoichiometry was then added. The solvent was partially evaporated at 50° C. (approximately 100 mL). To better capture the water brought by the hydrochloric acid solution, ethanol (50 mL) was added to the solution, followed by a new evaporation to a remaining volume of a few milliliters (a syrupy liquid). The sample was then returned to room temperature, resulting in the onset of crystallization. More ethanol (50 mL) was then added to the sample (always to help better remove the water brought with the hydrochloric acid solution), resulting in an unexpected increase in crystallization. XRPD analysis was performed. Figure 7 shows the XRPD pattern of IM-250 hydrochloride salt. The identified XRPD peaks were similar to those shown in Figure 5, indicating that the same hydrochloric acid polymorph was produced.

[0246] [Alternative synthesis of IM-250 hydrochloride via direct Boc-deprotection] Compound P2d was dissolved in acetone (10 eq.) and heated to 50° C., then hydrochloric acid (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., slurried in 3.5% aqueous hydrochloric acid (10 eq.) at room temperature for 1 h, then filtered and washed with 3.5% aqueous hydrochloric acid. The hydrochloric acid solution (10 eq.) was dried under vacuum at 50° C. to give the crude hydrochloride, which was recrystallized in ethanol to give pure IM-250 hydrochloride.

[0247] Example 4: Synthesis of IM-250 napadisylate [ka] IM-250 form I (150 mg, 344 μmol) and 1,5-naphthalenedisulfonic acid tetrahydrate (124 mg, 344 μmol) are weighed in a glass vial. A mixture of methanol (5 mL) and THF (5 mL) is added and the suspension is stirred at atmospheric pressure at 50° C. on a rotary evaporator until complete solubilization. The solvent is then evaporated to dryness at 50° C. to obtain a film. The film is resuspended in a mixture of water (1 mL) and ethanol (1 mL) and stirred at atmospheric pressure at 40° C. for a few minutes until partial solubilization. An additional mixture of water (1 mL) and ethanol (1 mL) is added and completely solubilized after about 20 minutes of stirring at 55° C. at atmospheric pressure. Very quickly, a strong crystallization of small particles occurs. Then, two cycles of heating (15 min at 60° C.) and cooling (15 min at room temperature) are performed. Finally, the sample is kept at room temperature overnight. The supernatant is removed from the flask. The powder was dried at room temperature for 15 min and finally dried under vacuum at 70° C. for 45 min to give IM-250 napadisylate as colorless crystals.

[0248] XRPD analysis was performed. Figure 8 shows the XRPD pattern of IM-250 napadisylate. The XRPD peaks were identified and are included in Table 4 below.

[0249] [Table 4]

[0250] TGA and DSC analyses were performed. Figure 9 shows an overlay of DSC and TGA thermograms for IM-250 napadisylate. The TGA analysis (right curve) showed that the solids were reduced by about 0.8% by weight below about 110°C, and the solids were reduced by about 67% by weight (decomposition) between about 150 and 370°C. The DSC analysis showed that an exotherm began at about 223°C, peaking at 230°C (transition enthalpy 152 J / g).

[0251] Comparative Experiment for Example 4: Synthesis of Additional IM-250 Salt Forms Several additional strong acids (e.g. hydrobromic acid, sulfuric acid, camphorsulfonic acid, 1,2-ethanesulfonic acid, toluenesulfonic acid, nitric acid, methanesulfonic acid, 2-naphthalenesulfonic acid) were tested in microcrystallization experiments in different crystallization media such as water or pure organic solvents (e.g. methanol, acetonitrile, isopropyl alcohol, ethanol, acetone, tetrahydrofuran) or mixtures of these organic solvents with water (50 / 50 v / v). The counterions were tested in a 1 / 1 (IM-250 free base form I / counterion) molar ratio. After the crystallization experiments, the samples (corresponding to all counterion / crystallization medium pairs) were analyzed to identify the "counterion / crystallization medium" pair that led to crystallization. This made it possible to define "crystallization hits", which were then further characterized.

[0252] Visual observation of the screen plate demonstrated that the tested acids, when combined with IM-250 free base form I, resulted in little solid residue. Moreover, no clearly visible crystalline forms were observed in any of these samples. In contrast, solid residues with significant amounts of material were observed for IM-250 free base form I samples recrystallized alone in different media (solvents or solvent / water mixtures). For example, for hydrobromic and nitric acids, combination with IM-250 free base form I results in solid residues with significant amounts of material only in a few samples. For sulfuric, ethanedisulfonic, toluenesulfonic and methanesulfonic acids, combination with IM-250 free base form I results in liquid / glassy residues with solid residues only in a few samples. For camphorsulfonic and naphthalenesulfonic acids, combination with IM-250 free base form I results in liquid / glassy residues with little or no solid residues. For each of these tested counterions, taking into account the number of crystallization occurrences and the quality of the obtained material, for each counterion, relevant samples were selected to be further characterized (also taking into account appropriate reference samples) and finally upscaled. A certain number of "IM-250 free base form I / counterion / crystallization medium" pairs were selected and observed by optical microscopy under cross-polarized light. The morphology of the crystals (if a well-defined crystal shape was observed) was compared between the different samples and analyzed by XRPD. From many possibilities, only a few promising XRPDs were obtained and upscaled for further investigation of development potential. In the following paragraphs, some representative attempts are outlined.

[0253] [IM-250 Hydrobromide] Approximately 150 mg of IM-250 free base form I was first solubilized in 5 mL of acetone (stirred by rotary evaporator at 30° C. and atmospheric pressure). A volume of 48% hydrobromic acid corresponding to a 1:1 stoichiometry was then added. The solvent was then evaporated to dryness at 40° C. to obtain a crust / meringue. This film was resuspended and solubilized in 6 mL of THF at room temperature and atmospheric pressure, resulting in a very rapid and intense crystallization. Several cycles (2) of heating (15 min at 40° C.) and cooling (15 min at room temperature) were then performed to provisionally increase the size and quality of the crystals.

[0254] The sample was then kept at room temperature for several hours. Only a small amount of supernatant could be easily removed (the crystals occupying the entire initial solution mixture), so the sample was filtered under vacuum. The isolated powder was finally dried under dynamic vacuum at room temperature for 10 minutes, then at 60° C. for about 30 minutes. Micrographs of the isolated sample showed high birefringence of the particles when viewed between crossed polarizers and an analyzer, indicating that the sample was well crystallized.

[0255] Overlaid XRPD profiles demonstrated that the above sample of IM-250 free base crystallized with one equivalent of hydrobromic acid exhibited a different XPRD pattern than that of the parent form of IM-250 free base Form I.

[0256] Upon heating, distinct mass losses were detected in the TGA profile before the main thermal decomposition was detected at an onset temperature of 223°C: 1) The first mass loss of 0.5% detected at start / end temperatures of 17 / 25°C would simply correspond to the loss of water and / or solvent that would be adsorbed in the powder; 2) A second mass loss of 3.5% detected at start / end temperatures of 78 / 85°C; 3) A third mass loss of 5.7% was detected at start / end temperatures of 103 / 115°C; and 4) A fourth mass loss of 5.7% was detected at start / end temperatures of 124 / 130°C.

[0257] FTIR analysis of the evolved gases from the TGA analysis showed that the THF FTIR spectrum best matched the FTIR spectrum of the volatile species leaving the sample between 3.5% and 5.7% mass loss, thus making the hypothesis of crystallization of a solvated form more likely.

[0258] The percentage of IM-250 free base in the salt sample, as determined by comparison with the free base, was found to be 78.1% by HPLC (compared to a theoretical IM-250 free base percentage of 84.3% in the target IM-250 hydrobromide salt with a 1:1 stoichiometry).

[0259] This result is lower than expected and confirms that this sample is likely to crystallize in a solvated form.

[0260] The HPLC profile showed very little decomposition of the active ingredient in the isolated solid, with the appearance of several new impurities (% purity at 285 nm = 99.5%, compared to % purity of the parent free base = 99.8%).

[0261] In conclusion, a crystalline sample of IM-250 hydrobromide salt was obtained in THF. Unfortunately, the results of HPLC and TGA-FTIR analysis prove that the hydrobromide salt produced is in fact a THF solvate, which is not suitable for development. The experiment was repeated with a second batch, with the same results.

[0262] This comparative experiment with IM-250 hydrobromide highlights that from the many possibilities of generating crystals in the "IM-250 free base / counterion / crystallization medium" matrix, surprisingly only a few setups ultimately provided IM-250 salt forms suitable for further development as pharmaceuticals, such as, for example, IM-250 napadisylate and IM-250 hydrochloride.

[0263] Example 5: Synthesis of crystalline 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)acetamide IM-315 [ka] 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-(methylamino)thiazole-5-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 (2×250 mL) and brine. The organic layer was dried over Na2SO4, concentrated and purified by FCC (PE:EA=1:2) to give IM-315 (25.2 g, 65%) as a white solid.

[0264] 1 H NMR (400MHz, 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 actual value: 438.0[M+H] + .

[0265] XRPD analysis was performed. Figure 10 shows the XRPD pattern of IM-315. The XRPD peaks were identified and are included in Table 5 below.

[0266] [Table 5]

[0267] DSC analysis was performed. Figure 11 shows the DSC thermogram of IM-315. The DSC analysis showed an exotherm at about 196°C with a peak at 197°C (transition enthalpy 117 J / g). Notably, this melting point is higher than the specified melting point of 184°C described in Example 8 of US Patent No. 5,999,233 and Example 87 of US Patent No. 5,999,233, which was obtained by slurrying the evaporated reaction mixture in water and isopropanol.

[0268] Example 6: Relative bioavailability in male mice The relative bioavailability of the crystals and different salt forms versus suspended IM-250 (from DMSO stock solution) was investigated after a single oral dose in male C57bl / 6 mice. Animals (3 per group) were weaned from food approximately 2 hours prior to dosing. The suspensions were prepared from the DMSO stock solution, which was diluted 1:20 with 0.5% HPMC in PBS, sonicated, and administered orally at a gavage volume of 5 mL / kg. Suspensions of the crystalline and different salt forms were prepared directly by adding the powder to 0.5% HPMC in PBS, sonicated, and administered orally at a gavage volume of 5 mL / kg. Blood samples were collected at 0.5, 1, 2, 5, 12, and 24 hours by capillary microsampling, and bioanalyticals were measured by non-chiral LC-MS. Area under the curve (AUC 0-24h ) and relative bioavailability was calculated. Doses for the above salts were adjusted to 10 mg / kg free IM-250.

[0269] Figure 12 shows the blood concentrations over time. The following data (Table 6) were obtained:

[0270] [Table 6]

[0271] Example 7: Chemical and physical stability The accelerated chemical and physical stability of the crystalline material was studied in order to predict potential stability problems upon storage or aging. Crystals were stored for 1 month at 40°C / 75% relative humidity (RH) and for 1 month at 60°C (and %HR<10%RH). Chemical stability was assessed against freshly prepared (unstressed) standard solutions by HPLC with external standardization. For this purpose, 6 samples (precisely weighted) are stored for each condition: 3 for 2 week stability and 3 for 4 week stability. Physical stability was also assessed by XRPD and DSC analysis, comparing the XRPD and DSC profiles of stressed samples with those of unstressed samples, by storing at least two samples (one for each time point) at each condition (40°C / 75% RH and 60°C, respectively).

[0272] [Chemical stability results] The results of HPLC analysis (UV at 285 nm) for IM-250 free base Form I (three independent assays) are shown in Table 7.

[0273] [Table 7]

[0274] Considering these results, IM-250 free base Form I can be considered chemically stable as a bulk powder after storage at 40° C. / 75% RH, 60° C. for at least 4 weeks.

[0275] [Physical stability results] Table 8 shows the physical DSC characterization results of bulk samples of IM-250 free base Form I stored at 40° C. / 75% RH and 60° C. for 2 and 4 weeks compared to the initial characterization. The XRPD diffractograms under stressed conditions were similar to the initial diffractogram. FIG. 13 shows the staggered XRPD patterns from a non-stressed sample of IM-250 free base Form I and for samples stored at 40° C. / 75% RH and 60° C. for 2 and 4 weeks.

[0276] [Table 8]

[0277] In conclusion, IM-250 free base Form I can be considered physically stable as a bulk powder after storage at 40° C. / 75% RH, 60° C. for at least 4 weeks.

[0278] Example 8: ICH Stability Study Long-term and accelerated evaluation of chemical and physical stability was performed at a contract manufacturing facility. IM-250 hydrochloride samples were primarily packaged in double PE bags (50 μm, Semadeni, e.g., catalogue no. 2439 with each tag tied with plastic twist). Secondary packaging was HDPE drums closed with HDPE screw caps (CurTec). Storage conditions were 25 ± 2 °C / 60 ± 5% relative humidity and 40 ± 2 °C / 75 ± 5% relative humidity. The results obtained were as shown in Table 9.

[0279] [Table 9]

[0280] In conclusion, IM-250 hydrochloride can be considered physically stable as a bulk powder after storage at 25°C and 40°C for at least 6 months.

[0281] Example 9: Synthesis of deuterated IM-250 free base (d3-IM-250 free base) [Step 1: 1-Bromopropan-2-one-1,1,3,3,3-d5 (9a)] [ka] Br2 (2.5 g, 15 mmol) was added to propan-2-one-d6 (2.0 g, 31 mmol) at room temperature and stirred for 2 h, after which the mixture was used immediately in the next step.

[0282] [Step 2: N-methyl-4-(methyl-d3)thiazol-2-amine (9b)] [ka] To a solution of compound 9a in ethanol (20 mL) was added 1-methylthiourea (1.4 g, 15 mmol) at 75° C. and stirred for 2 h, followed by addition of saturated NaHCO3 solution. The mixture was extracted with EA (2×20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and then purified by FCC (EA:PE=1:1) to give compound 9b.

[0283] [Step 3: 5-bromo-N-methyl-4-(methyl-d3)thiazol-2-amine (9c)] [ka] To a solution of compound 9b (400 mg, 3.0 mmol) in CHCl3 (4 mL) was added Br2 (740 mg, 4.7 mmol) at room temperature and stirred overnight, followed by addition of water (10 mL). The pH of the solution was adjusted to 8 with saturated NaHCO3 solution. The mixture was extracted with CHCl3 (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give compound 9c as a solid.

[0284] [Step 4: N-methyl-4-(methyl-d3)-5-(methylthio)thiazol-2-amine (9d)] [ka] To a solution of compound 1c (350 mg, 1.6 mmol) in 1,4-dioxane (4 mL) was added MeSNa (230 mg, 3.2 mmol) at room temperature. After stirring overnight, the mixture was evaporated to give an oil, which was then purified by FCC (EA:PE=1:1) to give compound 9d as a yellow solid.

[0285] [Step 5: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(methylthio)thiazol-2-yl)acetamide (9e)] [ka] 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 Et3N (171 mg, 0.85 mmol) in CHCl2 (2.0 mL) was added compound 9d (100 mg, 0.56 mmol) at room temperature. 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 compound 9e as a white solid.

[0286] [Step 6: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(methylsulfinyl)thiazol-2-yl)acetamide (9f)] [ka] To a solution of compound 9e (180 mg, 0.44 mmol) in CHCl (1 mL) was added metachloroperoxybenzoic acid (76 mg, 85% purity). The mixture was stirred at room temperature for 20 min and partitioned between CHCl and 5% sodium carbonate solution. The organic phase was washed with brine, dried over NaSO, filtered, concentrated and purified by FCC (PE:EA=1:2) to give compound 9f as a white solid.

[0287] [Step 7: tert-butyl ((2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methylacetamido)-4-(methyl-d3)thiazol-5-yl)(methyl)(oxo)-16-sulfanylidene)carbamate (9g)] [ka] MgO (57 mg, 1.40 mmol), tert-butyl carbamate (83 mg, 0.70 mmol), Rh2(OAc)4 (15 mg, 33 μmol) and (diacetoxy)iodobenzene (171 mg, 0.52 mmol) were added to an aqueous solution of compound 9f (150 mg, 0.35 mmol) in CHCl2 (2.5 mL). The mixture was stirred at 40° C. overnight, cooled to room temperature and filtered through a pad of Celite. The solvent was removed under reduced pressure and the crude product was purified by FCC (PE:EA=1:1) to give compound 9g as a white solid.

[0288] [Step 8: 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonimidoyl)thiazol-2-yl)acetamide (9h)] [ka] Compound 9g (150 mg, 0.28 mmol) was added to a stirred aqueous solution of trifluoroacetic acid (2 mL) in CH2Cl2 (8 mL) at room temperature. Stirring was continued for 1 h, then the mixture was concentrated, partitioned in CH2Cl2, washed with saturated NaHCO3 (2 x 20 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to give compound 9h as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ:7.57(d,J=7.2Hz,2H),7.46-7.35(m,4H),7.31-7.24(m,1H),4.69(s,1H),4.23(s,2H),3.72(s,3H),3.14(s,3H). MS:439.1[M+1] + .

[0289] [Step 9: (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonimidoyl)thiazol-2-yl)acetamide (deuterated IM-250 free base, d3-IM-250 free base)] [ka] The title compound was prepared by separation of racemic mixture 9h by chiral SFC chromatography using Chiralcel OJ as the stationary phase, 55 / 45% by volume CO2 / IPA as the mobile phase, and the following additional data:

[0290] Equipment: SFC-150 (Thar, Waters) Column: OJ20 x 250 mm, 10 μm (Daicel) Column temperature: 35℃ Flow rate: 100g / min Back pressure: 100bar Detection wavelength: 214 nm Cycle time: 3.7 minutes Sample solution: 300 mg dissolved in 40 mL of MeOH Volume of injection: 1.0mL

[0291] The title compound deuterated 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 eluting enantiomer after distilling off CO2 (retention time: 2.99 min) and removing IPA by rotary evaporation at 40 °C.

[0292] XRPD analysis was performed. Figure 14 shows the XRPD pattern of deuterated IM-250 free base (d3-IM-250 free base). The XRPD peaks were identified and are included in Table 10 below.

[0293] [Table 10]

[0294] TGA and DSC analyses were performed. Figure 15 shows the TGA thermogram of deuterated IM-250 free base (d3-IM-250 free base). The TGA analysis showed onset / end temperatures of 243 / 305°C due to thermal decomposition. The DSC analysis (Figure 16) revealed a strong exothermic transition with an onset at approximately 163°C and a peak at 165°C (transition enthalpy 85 J / g).

[0295] (Example 10: Synthesis of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride)) [ka] To a solution of deuterated IM-250 free base (850 mg) in acetone (50 mL) was added an amount of 1N hydrochloric acid corresponding to a 1:1 stoichiometry. The solution was homogenized at 40 °C before the solvent was removed under vacuum (50 °C) to induce spontaneous crystallization of a white solid when only a few mL remained in the flask. To completely remove the water contributed by the hydrochloric acid addition, ethanol (2 × 5 mL) was added to the flask and concentration at 50 °C was completed to dryness (only partial resolubilization was observed during ethanol addition and stirring at 50 °C). Further ethanol (5 mL) was then added to the flask and this was stirred at 50 °C and room temperature to resuspend the crystals. The supernatant was removed from the solid, which was then further dried under vacuum at 50-60 °C for about 3 h. White crystals of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) were obtained in good yield.

[0296] XRPD analysis was performed. Figure 17 shows the XRPD pattern of IM-250 hydrochloride (d3-IM-250 hydrochloride). The XRPD peaks were identified and are included in Table 11 below.

[0297] [Table 11]

[0298] TGA and DSC analyses were performed. Figure 18 shows an overlay of DSC and TGA thermograms of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride). The TGA analysis (right curve) showed a mass loss of 7.8% upon heating with onset / end temperatures of 149 / 167°C before the main thermal decomposition was detected at an onset temperature of 225°C. The 7.8% mass loss can be attributed to the escape of the hydrochloric acid moiety. This DSC analysis did not show a true melting point, but rather a broad endotherm with an onset of about 188°C and a peak at 194°C (transition enthalpy -15 J / g).

[0299] (Example 11: Synthesis of deuterated IM-250 napadisylate salt (d3-IM-250 napadisylate)) Deuterated IM-250 napadisylate salt forms of compounds of formula (I) may similarly be prepared by preparing the deuterated free base form as described above, followed by conversion to the napadisylate salt as described above.

[0300] Example 12: Relative Bioavailability and Brain Exposure of d3-IM-250 Hydrochloride vs. IM-250 Hydrochloride in Male Mice The relative bioavailability of suspended crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) versus suspended IM-250 hydrochloride after a single oral dose to male C57bl / 6 mice (approximately 8 weeks of age) was investigated. Animals (3 per group) were deprived of food approximately 2 hours prior to administration of 10 mg / kg test article. The suspension was directly prepared by adding the powder to 0.5% HPMC in PBS, sonicated, and administered orally at a gavage volume of 5 mL / kg. Blood samples (20 μL) were taken at 0.5, 1, 2, 5, 12, and 24 hours by capillary microsampling and collected into Li-heparin tubes from the tail vein. The samples were frozen on dry ice within 1-2 minutes of sampling and stored at -20 °C until LC-MS / MS analysis measured via non-chiral LC-MS. 24 hours after dosing, animals were sacrificed and perfused with PBS until the PBS was clear, and the brains were collected and stored at -20°C until processed for LC-MS analysis to determine brain / blood exposure. max), elimination half-life (t 1 / 2 ), area under the curve (AUC 0-24h ) and blood / brain ratio (as a readily obtained surrogate parameter for nervous tissue exposure) were measured. The following data (Table 12) were obtained:

[0301] [Table 12]

[0302] [Conclusion] In this embodiment, the AUC of IM-250 hydrochloride is compared to Example 6. 0-24 Although the deuteration rate is somewhat lower, selective deuteration at the 4-methyl position of the thiazole ring is max , t 1 / 2 and AUC 0-24 Further improving the PK parameters as evident in this matched pair comparison of 100 mg / kg / day ...

Claims

1. Formula (I) 【Chemistry 1】 wherein X is 【Chemistry 2】 and Y is CH ３ and CDs ３ is selected from. or a crystalline form of a pharmaceutically acceptable salt, co-crystal, hydrate or solvate thereof.

2. In the compound represented by formula (I), X is 【Transformation 3】 and Y is CH ３ and CDs ３ Selected from:

2. The crystalline form of claim 1, wherein the crystalline form exists in the form of a hydrochloride salt, a hydrate or a solvate of the compound.

3. The compound represented by formula (I) The following structure: 【Chemistry 4】 The compound IM-250 has the formula The crystalline form is a crystalline form of the compound IM-250, or a pharmaceutically acceptable salt, co-crystal, hydrate or solvate thereof; The crystalline form of claim 1.

4. The compound IM-250 is selected from the following crystalline forms: The X-ray powder diffractogram measured on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å is IM-250 free base form I: 9.2, 13.7 and 18.7 degrees; IM-250 free base form III: 9.7, 12.3 and 15.6 degrees; 4. The crystalline form of claim 3, comprising a characteristic peak (±0.2 degrees 2θ) at

5. The crystalline form of any one of claims 1 to 3, wherein the compound IM-250 exists as a salt and is selected from salt forms having the following structure: 【Transformation 5】

6. Existing as a hydrochloride salt having the structure: 【Transformation 6】 3. The crystalline form of claim 2, wherein the hydrochloric acid and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazol-2-yl)acetamide are present in a 1:1 molar ratio.

7. Existing as a salt selected from salt forms having the structure: 【Transformation 7】 and The X-ray powder diffractogram, measured on a diffractometer using Cu-Kα radiation of 1.54 Å wavelength, shows the following peaks (±0.2 degrees 2θ): IM-250 hydrochloride: 13.7, 17.0, 17.7, 19.8, 21.8 and 22.8, IM-250 napadisylate salt: 9.1, 14.5, 15.6, 18.1, 19.1 and 20.9, 2. The crystalline form of claim 1, comprising at least four of:

8. The compound has the following structure: 【Transformation 8】 and 2. The crystalline form of claim 1, wherein the X-ray powder diffractogram, measured on a diffractometer using Cu-Kα radiation of 1.54 Å wavelength, contains characteristic peaks at 9.3, 13.7, and 18.6 degrees (±0.2 degrees 2θ).

9. The compound has the following structure: 【Chemistry 9】 and 3. The crystalline form of claim 1 or 2, wherein the X-ray powder diffractogram, measured on a diffractometer using Cu-Kα radiation of 1.54 Å wavelength, contains characteristic peaks at 13.8, 17.8, and 21.8 degrees (±0.2 degrees 2θ).

10. The crystalline form of claim 1, wherein the compound has an XRPD pattern substantially as shown in Figure 1, 3, 5, 7, 8, 14 or 17.

11. 10. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of formula (I) according to claim 1 and a pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of formula (I) of claim 3 and a pharmaceutically acceptable excipient.

13. 13. A crystalline form according to claim 1 or 3 or a pharmaceutical composition according to claim 11 or 12 for use in the prevention and treatment of herpes simplex infections or vector-borne diseases.

14. A crystalline form according to claim 1 or 3 or a pharmaceutical composition according to claim 11 or 12 for use in treating or eliminating latent herpes viruses in nervous tissue and nerves.

15. A crystalline form according to claim 1 or 3 or a pharmaceutical composition according to claim 11 or 12 for use in the prevention and treatment of recurrent and reactivating herpes infections or the serious effects associated with such infections, and / or in the prevention and treatment of herpes simplex encephalitis (HSE).

16. The following structure: 【Chemistry 10】 a crystalline form of the compound of or a method for preparing a pharmaceutically acceptable salt, co-crystal, hydrate or solvate of the compound, comprising the steps of: (a) Compound P2b: 【Chemistry 11】 Compound: 【Chemistry 12】 contacting the (b) Compound P2c: 【Chemistry 13】 to compound P2d: 【Chemistry 14】 under conditions sufficient to form Rh ２ (OAc) ４ tert-butylcarbamic acid, magnesium oxide and (diacetoxy)iodobenzene; (c) a compound having the following structure: 【Chemistry 15】 deprotecting compound P2d under conditions sufficient to form compound IM-250 having the formula: (d) optionally converting said compound IM-250 into a pharmaceutically acceptable salt, co-crystal, hydrate or solvate thereof; A method comprising:

17. The compound P2d: 【Chemistry 16】 is deprotected with hydrochloric acid to give compound IM-250 hydrochloride: 【Chemistry 17】 or forming a hydrochloride salt represented by The compound P2d was deprotected with 1,5-naphthalenedisulfonic acid tetrahydrate to give the compound IM-250 napadisilate salt: [Chemistry 18] forming a napadisylate salt represented by 17. The method of claim 16.

18. The method further comprises the step of deuteration to obtain deuterated analogs of the crystalline forms of the compounds and salts, wherein the deuterated analogs have the following structure: 【Chemistry 19】 or a co-crystal, hydrate or solvate thereof.

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