EP4 Antagonist Crystal Form

Abstract

The present invention relates to a crystalline form of a compound of formula (1). The present invention also relates to compositions and pharmaceutical compositions comprising the crystalline form, medical uses of the crystalline form, and methods for producing the crystalline form. TIFF2026513320000019.tif67170

Description

[Technical Field]

[0001] The present invention relates to the crystalline form of (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid and a method for producing the same. The present invention also relates to compositions, such as pharmaceutical compositions, that contain the crystalline form of (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid, and therapeutic uses of the crystalline form. [Background technology]

[0002] International Publication No. 2021 / 069927 discloses the compound of formula (1) below, (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid, as an antagonist of prostaglandin E2 receptor 4 (EP4).

[0003] [ka]

[0004] Prostaglandins (PGs) are small molecule (approximately 400 Da) products produced by cyclooxygenase (COX; constitutively active COX1 and inducible COX2) and PG synthase acting on arachidonic acid (AA) with minimal contribution from the isoprostane pathway. Prostaglandin E2 (PGE2) is the major COX product in myeloid and stromal cells, and its levels are determined by the balance between synthesis and degradation mediated by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). PGE2 has four receptors (EP1-EP4), which are present on multiple cell types including macrophages, monocytes, platelets, sensory neurons, and cells in the gastrointestinal tract, kidneys, thymus, heart, lungs, and uterus. These receptors drive a wide range of pharmacological effects, mediating nociception, various aspects of nerve signaling, hematopoiesis, blood flow regulation, renal filtration and blood pressure, mucosal integrity regulation, vascular permeability, smooth muscle function, and both pro-inflammatory (vasodilation and recruitment and activation of mast cells, macrophages, and neutrophils) and immunosuppressive immune functions. Functional PGE2 antagonism has therapeutic potential in a wide range of disease settings.

[0005] Different crystalline forms of compounds can result in different properties in terms of solubility, elution rate, filterability, hygroscopicity, fluidity, and stability.

[0006] (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid is available in multiple crystalline forms as well as amorphous forms. It has also been found that these forms can exist. Many of these forms are undesirable from the standpoint of producing pharmaceutically acceptable compositions.

[0007] Therefore, there is still an unmet need for providing a desirable crystalline form of (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid.

[0008] Furthermore, there is a demand for providing processes that prioritize the production of a selected crystal form over other crystal forms and amorphous forms. In particular, it is desirable to obtain the selected crystal form with high purity and / or high yield. Moreover, it is desirable to provide processes for producing the selected crystal form that are suitable for commercial scale, for example, from the standpoint of safety requirements and processability. [Overview of the project]

[0009] In one aspect of the present invention, the present invention relates to formula (1): [ka] The present invention provides a crystalline form of a compound, wherein the crystalline form exhibits a powder X-ray diffraction pattern containing peaks at 2θ = 10.0 ± 0.1° and 15.0 ± 0.1°.

[0010] In another embodiment, the present invention provides a crystalline form of the compound of formula (1) that exhibits a differential scanning calorimetry (DSC) thermogram including an endothermic event at a starting temperature of 171±2°C.

[0011] In certain embodiments, the crystalline form of the compound of formula (1) exhibits a powder X-ray diffraction pattern with peaks at 2θ = 10.0 ± 0.1° and 15.0 ± 0.1°, and a DSC thermogram that includes an endothermic event at a starting temperature of 171 ± 2°C.

[0012] The specific crystalline form of the present invention achieves the desired form by possessing several unexpected properties. The crystalline form of the present invention has been demonstrated to have excellent physical stability, polymorphic stability, and racemization resistance under various test conditions. It has also been shown that the crystalline form of the present invention is nonhygroscopic.

[0013] In another aspect, the present invention provides compositions comprising the crystalline form of the present invention.

[0014] In another aspect, the present invention provides a pharmaceutical composition comprising the crystalline form of the present invention and at least one pharmaceutically acceptable excipient.

[0015] In another aspect, the present invention provides the crystalline form of the present invention for use in medicine, for example, for use in the treatment of cancer.

[0016] In another aspect, the present invention provides a method for producing the crystalline form of the present invention. The method is safe even when carried out on a large scale. Further, by the method, the crystalline form of the present invention can be obtained in a high yield and high purity.

Brief Description of the Drawings

[0017] [Figure 1] Figure 1 is an XRPD spectrum of the crystalline form of the present invention. [Figure 2] Figure 2 is a TGA and DSC plot of the crystalline form of the present invention. [Figure 3] Figure 3 is an FT-IR spectrum of the crystalline form of the present invention. [Figure 4] Figure 4 is an NMR spectrum of the crystalline form of the present invention. [Figure 5] Figure 5 is a DVS adsorption and desorption plot of the crystalline form of the present invention. [Figure 6] Figure 6 is a DVS isotherm plot of the crystalline form of the present invention. [Figure 7] Figure 7 is an XRPD spectrum of a comparative crystalline form. [Figure 8] Figure 8 is a TGA and DSC plot of a comparative crystalline form.

Modes for Carrying Out the Invention

[0018] The compound of formula (1) is also referred to herein as (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamido)cyclopropyl)benzoic acid.

[0019] The crystalline form of the present invention may exhibit a powder X-ray diffraction pattern including peaks at 2θ = 10.0 ± 0.1° and 15.0 ± 0.1°.

[0020] Powder X-ray diffraction patterns may be measured using CuKα radiation.

[0021] The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 18.7 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 20.9 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 14.6 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 10.7 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 17.9 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 17.7 ± 0.09°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 19.8 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 20.1 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 15.2 ± 0.09°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 3.5 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 4.9 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 10.4 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 11.4 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 11.9 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 12.4 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 14.2 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 15.5 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 16.8 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 18.4 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 19.0 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 20.6 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 21.5 ± 0.1°. The crystal form may show a powder X-ray diffraction pattern with a peak at 2θ = 21.8 ± 0.1° The powder X-ray diffraction pattern may include a peak at 2θ = 22.3 ± 0.1°. The crystalline form may show a powder X-ray diffraction pattern with a peak at 2θ = 22.9 ± 0.1°. The crystalline form may show a powder X-ray diffraction pattern with a peak at 2θ = 23.8 ± 0.1°. The crystalline form may show a powder X-ray diffraction pattern with a peak at 2θ = 24.4 ± 0.1°. The crystalline form may show a powder X-ray diffraction pattern with a peak at 2θ = 25.0 ± 0.1°. The crystalline form may show a powder X-ray diffraction pattern with a peak at 2θ = 25.4 ± 0.1°. The crystalline form may show a powder X-ray diffraction pattern with a peak at 2θ = 26.4 ± 0.1°. The crystalline form may show a powder X-ray diffraction pattern with a peak at 2θ = 26.7 ± 0.1°. The crystalline form may exhibit a powder X-ray diffraction pattern with a peak at 2θ = 27.1 ± 0.1°. The crystalline form may exhibit a powder X-ray diffraction pattern with a peak at 2θ = 27.7 ± 0.1°. The crystalline form may exhibit a powder X-ray diffraction pattern with a peak at 2θ = 28.3 ± 0.1°. The crystalline form may exhibit a powder X-ray diffraction pattern with a peak at 2θ = 29.1 ± 0.1°. The crystalline form may exhibit a powder X-ray diffraction pattern with a peak at 2θ = 29.6 ± 0.1°. The crystalline form may exhibit a powder X-ray diffraction pattern with a peak at 2θ = 30.2 ± 0.1°.

[0022] The crystal form may exhibit a powder X-ray diffraction pattern containing peaks at 2θ = 10.0±0.1°, 14.6±0.1°, 15.0±0.1°, 18.7±0.1°, and 20.9±0.1°.

[0023] The crystal form may exhibit a powder X-ray diffraction pattern containing peaks at 2θ = 10.0±0.1°, 10.7±0.1°, 14.6±0.1°, 15.0±0.1°, 17.7±0.09°, 17.9±0.1°, 18.7±0.1°, and 20.9±0.1°.

[0024] The crystal form may exhibit a powder X-ray diffraction pattern containing peaks at 2θ = 10.0±0.1°, 10.7±0.1°, 14.6±0.1°, 15.0±0.1°, 15.2±0.09°, 17.7±0.09°, 17.9±0.1°, 18.7±0.1°, 19.8±0.1°, 20.1±0.1°, and 20.9±0.1°.

[0025] The crystal form may exhibit a powder X-ray diffraction pattern containing peaks at 2θ = 3.5±0.1°, 4.9±0.1°, 10.0±0.1°, 10.7±0.1°, 14.6±0.1°, 15.0±0.1°, 15.2±0.09°, 17.7±0.09°, 17.9±0.1°, 18.7±0.1°, 19.0±0.1°, 19.8±0.1°, 20.1±0.1°, 20.6±0.1°, 20.9±0.1°, and 21.5±0.1°.

[0026] The crystal forms are 2θ = 3.5±0.1°, 4.9±0.1°, 10.0±0.1°, 10.4±0.1°, 10.7±0.1°, 11.9±0.1°, 14.6±0.1°, 15.0±0.1°, 15.2±0.09°, 15.5±0.1°, 16.8±0.1°, 17.7±0.09°, and 17.9±0.1°. The powder X-ray diffraction pattern may show peaks at °, 18.4±0.1°, 18.7±0.1°, 19.0±0.1°, 19.8±0.1°, 20.1±0.1°, 20.6±0.1°, 20.9±0.1°, 21.5±0.1°, 23.8±0.1°, 25.0±0.1°, and 30.2±0.1°.

[0027] The crystal forms are 2θ = 3.5±0.1°, 4.9±0.1°, 10.0±0.1°, 10.4±0.1°, 10.7±0.1°, 11.9±0.1°, 14.2±0.1°, 14.6±0.1°, 15.0±0.1°, 15.2±0.09°, 15.5±0.1°, 16.8±0.1°, 17.7±0.09°, 1 7.9±0.1°, 18.4±0.1°, 18.7±0.1°, 19.0±0.1°, 19.8±0.1°, 20.1±0.1°, 20.6±0.1°, 20.9±0.1°, 21.5±0.1°, 21.8±0.1°, 22.9±0.1°, 23.8±0.1°, 24.4±0.1°, 25.0±0.1°, 2 The powder X-ray diffraction pattern may show peaks at 5.4±0.1°, 26.4±0.1°, 26.7±0.1°, 27.1±0.1°, 27.7±0.1°, 28.3±0.1°, 29.1±0.1°, 29.6±0.1°, and 30.2±0.1°.

[0028] The crystal forms are 2θ = 3.5±0.1°, 4.9±0.1°, 10.0±0.1°, 10.4±0.1°, 10.7±0.1°, 11.4±0.1°, 11.9±0.1°, 12.4±0.1°, 14.2±0.1°, 14.6±0.1°, 15.0±0.1°, 15.2±0.09°, 15.5±0.1°, 16.8±0.1°, 17.7±0.09°, 17.9±0.1°, 18.4±0.1°, 18.7±0.1°, 19.0±0.1°, 19.8±0.1°, 20. The powder X-ray diffraction pattern may show peaks at 1±0.1°, 20.6±0.1°, 20.9±0.1°, 21.5±0.1°, 21.8±0.1°, 22.3±0.1°, 22.9±0.1°, 23.8±0.1°, 24.4±0.1°, 25.0±0.1°, 25.4±0.1°, 26.4±0.1°, 26.7±0.1°, 27.1±0.1°, 27.7±0.1°, 28.3±0.1°, 29.1±0.1°, 29.6±0.1°, and 30.2±0.1°.

[0029] The crystalline form may exhibit peaks and powder X-ray diffraction patterns with substantially the same intensity as those shown in Table 1.

[0030]

Table 1

[0031] The crystalline form may substantially exhibit the powder X-ray diffraction pattern shown in FIG. 1.

[0032] The crystalline form may exhibit a differential scanning calorimetry (DSC) thermogram including an endothermic event at an onset temperature of 171 ± 2 °C. The DSC thermogram may be measured using a heating rate of 10 °C / min.

[0033] The crystalline form may have an infrared spectrum including at least one or all of the following peaks: 3273 ± 2 cm -1 , 2960 ± 2 cm -1 , 2870 ± 2 cm -1 , 1686 ± 2 cm -1 , 1657 ± 2 cm -1 , 1328 ± 2 cm -1 , and 1068 ± 2 cm -1 . The crystalline form may have an infrared spectrum including the following peaks: 3273 ± 2 cm -1 , 1686 ± 2 cm -1 , and 1657 ± 2 cm -1 . The infrared spectrum may be measured using Fourier transform infrared spectroscopy (FT-IR).

[0034] The crystalline form may be substantially a pure crystalline form. Substantially pure crystalline form means that the crystalline form of the present invention is contained at least 95% by weight based on the total weight of the compound of formula (1). Based on the total weight of the compound of formula (1), the crystalline form of the present invention may be contained at least 96% by weight, or at least 97% by weight, or at least 98% by weight, or at least 99% by weight, or at least 99.5% by weight, or at least 99.9% by weight.

[0035] The crystalline form may have a purity of at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% (in the measurement of HPLC area%).

[0036] The crystalline form may have a chiral purity of at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% (measured as HPLC area%).

[0037] In one embodiment, the present invention provides a composition, such as a pharmaceutical composition (or formulation), that contains the crystalline form of the present invention.

[0038] The pharmaceutical composition may contain at least one pharmaceutically acceptable excipient.

[0039] Pharmaceutically acceptable excipients can be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulators, binders, fluidizing agents, coatings, release control agents (e.g., polymers or waxes that inhibit or delay release), binders, disintegrants, lubricants, preservatives, antifungal agents, antibacterial agents, antioxidants, buffers, isotonic agents, thickeners, fragrances, sweeteners, pigments, plasticizers, taste masking agents, stabilizers, vehicles, wetting agents, emulsifiers, suspending agents, fragrances, dispersants, or other excipients commonly used in pharmaceutical compositions.

[0040] Pharmaceutical compositions can be formulated according to known techniques. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0041] The pharmaceutical composition may be in a form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, ophthalmic, ophthalmic, rectal, vaginal, or transdermal administration.

[0042] The pharmaceutical composition may be in the form of, for example, tablets; sugar-coated tablets; powders; elixirs; syrups; liquid formulations such as suspensions; sprays; inhalants; tablets; lozenges; emulsions; liquids; cachets; granules; capsules; and suppositories; as well as liquid formulations for injection, including liposomal formulations.

[0043] Suitable dosage forms for oral administration include tablets (with or without coating), capsules (hard or softshell), caplets, pills, lozenges, syrups, liquids, powders, granules, elixirs, suspensions, sublingual tablets, wafers, or patches such as oral patches.

[0044] The pharmaceutical composition may be a tablet composition. The pharmaceutical composition may be a capsule composition.

[0045] The tablet composition may contain a unit dose of the active compound along with an inert diluent or carrier, examples of which include sugars or sugar alcohols, e.g., lactose, sucrose, sorbitol, or mannitol; and / or non-sugar diluents, e.g., sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, e.g., microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, and starches such as corn starch. The tablets may also contain standard components such as binders and granulators (e.g., polyvinylpyrrolidone), disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate buffer or citrate buffer), and foaming agents such as citrate / bicarbonate mixtures. These excipients are well known and do not need to be discussed in detail here.

[0046] Tablets may be designed to release the drug upon contact with gastric juice (immediate-release tablets), or to release the drug in a controlled manner over a long period of time or at a specific site in the gastrointestinal tract (controlled-release tablets).

[0047] A pharmaceutical composition typically comprises about 1% (w / w) to about 95%, preferably % (w / w), of an active ingredient and 99% (w / w) to 5% (w / w) of pharmaceutically acceptable excipients or combinations of excipients (for example, as defined above). Preferably, a pharmaceutical composition comprises about 20% (w / w) to about 90% (w / w) of an active ingredient and 80% (w / w) to 10% of pharmaceutically acceptable excipients or combinations of excipients. The pharmaceutical composition may also contain about 1% to about 95%, preferably about 20% to about 90%, of an active ingredient. The pharmaceutical composition may be in unit dose form, such as ampoules, vials, suppositories, pre-filled syringes, sugar-coated tablets, powders, tablets, or capsules.

[0048] Tablets and capsules may contain, for example, 0-20% disintegrant, 0-5% lubricant, 0-5% fluidizer, and / or 0-99% (w / w) filler or bulking agent (depending on the drug dose). They may also contain 0-10% (w / w) polymer binder, 0-5% (w / w) antioxidant, and 0-5% (w / w) pigment. Sustained-release tablets typically further contain 0-99% (w / w) controlled-release (e.g., delayed-release) polymer (depending on the dose). Film coatings of tablets or capsules usually contain 0-10% (w / w) polymer, 0-3% (w / w) pigment, and / or 0-2% (w / w) plasticizer.

[0049] Parenteral formulations typically contain 0–20% (w / w) buffering agent, 0–50% (w / w) co-solvent, and / or 0–99% (w / w) water for injection (WFI) (depending on the dose and whether or not it is lyophilized). Intramuscular depot formulations may also contain 0–99% (w / w) oil.

[0050] The pharmaceutical composition may be provided to the patient in a "patient pack" containing the entire course of treatment in a single package. The packaging is usually a blister pack.

[0051] Active compounds are generally supplied in unit dose forms, and therefore typically, the desired level of activity is obtained. The formulation contains a sufficient amount of compound to impart physical activity. For example, the formulation may contain 1 nanogram to 2 grams of the active ingredient, e.g., 1 nanogram to 2 milligrams of the active ingredient. Specific sub-ranges of the compound within these ranges include 0.1 milligrams to 2 grams of the active ingredient (more generally 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example, 1 microgram to 10 milligrams of the active ingredient, e.g., 0.1 milligrams to 2 milligrams).

[0052] For oral compositions, the unit dose may contain 1 milligram to 2 grams of the active compound, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, or for example 100 milligrams to 1 gram.

[0053] The active compound is administered to the patient (e.g., human or animal patient) in an effective dose sufficient to achieve the desired therapeutic effect. The exact amount of each compound administered may be determined by the attending physician according to standard procedures.

[0054] In the compositions or pharmaceutical compositions described herein, the compound of formula (1) may be 50% to 100% crystalline. In the compositions or pharmaceutical compositions described herein, the compound of formula (1) may be at least 50% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, and may be, for example, 100% crystalline.

[0055] The composition or pharmaceutical composition may contain a mixture of crystalline forms of the compound of formula (1), or may contain substantially pure crystalline forms of the present invention. The composition or pharmaceutical composition may contain at least 5% by weight, or at least 50% by weight, or at least 90% by weight, of the crystalline forms of the present invention relative to the total weight of the compound of formula (1). The composition or pharmaceutical composition may contain at least 95% by weight, of the crystalline forms of the present invention relative to the total weight of the compound of formula (1). The composition or pharmaceutical composition may contain at least 96% by weight, or at least 97% by weight, or at least 98% by weight, or at least 99% by weight, or at least 99.5% by weight, or at least 99.9% by weight, of the crystalline forms of the present invention relative to the total weight of the compound of formula (1).

[0056] In one embodiment, the present invention provides a combination product comprising a crystalline form of the present invention, or a pharmaceutical composition containing the crystalline form of the present invention, and at least one immune checkpoint inhibitor.

[0057] In one embodiment, the present invention provides a kit comprising a crystalline form of the present invention, or a pharmaceutical composition containing the crystalline form of the present invention, and at least one immune checkpoint inhibitor.

[0058] In the combination products and kits of the present invention, the immune checkpoint inhibitor may be any immune checkpoint inhibitor. The immune checkpoint inhibitor may be an antibody. The immune checkpoint inhibitor may be in the form of an injectable antibody.

[0059] Combinations of immune checkpoint inhibitors may be used in the combination products and kits of the present invention. The at least one immune checkpoint inhibitor may include, or may be an inhibitor of, PD-1, PD-L1, CTLA4, LAG-3, TIM-3, NKG2A, PVRIG, CEACAM1, CEACAM5 / 6, LIF, CD47, or CSF-1. The at least one immune checkpoint inhibitor may include, or may be an inhibitor of, a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA4 inhibitor. The at least one immune checkpoint inhibitor may include, or may be an anti-CTLA4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody. It's okay to have it.

[0060] The aforementioned at least one immune checkpoint inhibitor may include an anti-PD-1 antibody selected from nivolumab (Opdivo), pembrolizumab (Keytruda), semiprimab (Libtayo), dostallimab (Jemperli), tripalimab (Tuoyi), cintilimab (Tyvyt), camrelizumab (AiRuiKa), sasanlimab, and letifanlimab, or may be said anti-PD-1 antibody.

[0061] The aforementioned at least one immune checkpoint inhibitor may include an anti-PD-L1 antibody selected from atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), or may be said anti-PD-L1 antibody.

[0062] The aforementioned at least one immune checkpoint inhibitor may include ipilimumab (Yervoy), or it may be ipilimumab (Yervoy).

[0063] The crystalline form, pharmaceutical composition, combination product, or kit of the present invention may be intended for medical use.

[0064] The crystalline form, pharmaceutical composition, combination product, or kit of the present invention may be used for the treatment, prevention, improvement, control, or risk reduction of diseases or disorders involving the EP4 receptor.

[0065] The crystalline form or pharmaceutical composition of the present invention may be used for the manufacture of pharmaceuticals for the treatment, prevention, improvement, control, or risk reduction of diseases or disorders involving the EP4 receptor.

[0066] The crystalline form or pharmaceutical composition of the present invention may be used for the treatment of abdominal aortic aneurysm (AAA), ankylosing spondylitis (AS), Alzheimer's disease (AD), atherosclerosis, cancer including epithelial carcinoma (in the GBD tumor classification, colon and rectum, lips and oral cavity, nasopharynx, other pharyngeal tissues, gallbladder and biliary tract, pancreas, non-melanomatous skin, ovaries, testes, kidneys, bladder, thyroid, mesothelioma, esophagus, stomach, liver, larynx, trachea, bronchi and lungs, breast, cervix, uterus, prostate), diabetic nephropathy, endometriosis, inflammatory bowel disease, migraine, multiple sclerosis (MS), osteoarthritis (OA), and rheumatoid arthritis.

[0067] The crystalline form, pharmaceutical composition, combination product, or kit of the present invention may be for use in the treatment of cancer. Accordingly, the present invention includes a method for treating cancer, the method comprising administering a therapeutically effective amount of the crystalline form or pharmaceutical composition of the present invention to a subject in need thereof. The present invention also provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of the crystalline form of the present invention and a therapeutically effective amount of an immune checkpoint inhibitor to a subject in need thereof.

[0068] The cancer may be an epithelial carcinoma. The cancer may be a carcinoma. The cancer may be a sarcoma. The cancer may be a lymphoma.

[0069] The aforementioned cancers include lung cancers such as non-small cell lung cancer, small cell lung cancer (SCLC), and squamous cell carcinoma of the lung; renal cancers such as renal cell carcinoma and urothelial carcinoma; Hodgkin lymphomas such as classical Hodgkin lymphoma; head and neck cancers such as head and neck squamous cell carcinoma (HNSCC), lip cancer, oral cancer, nasopharyngeal cancer, and other pharyngeal cancers; colon cancer; rectal cancer; colorectal cancers (CRCs) such as microsatellite-unstable high-grade colorectal cancer (MSI-H CRC), mismatch-repair-deficient colorectal cancer (dMMR CRC), and microsatellite-stable colorectal cancer (MSS CRC); and liver cancers such as hepatocellular carcinoma. ; may be selected from: gastric cancer; gastroesophageal cancer such as esophageal squamous cell carcinoma and gastroesophageal junction cancer; esophageal cancer; cervical cancer; breast cancer such as triple-negative breast cancer; melanoma; non-melanoma skin cancer such as Merkel cell carcinoma and cutaneous squamous cell carcinoma; pancreatic cancer; prostate cancer such as castration-resistant prostate cancer and metastatic castration-resistant prostate cancer (mCRPC); endometrial cancer; gallbladder cancer; biliary tract cancer; ovarian cancer; testicular cancer; thyroid cancer; laryngeal cancer; tracheal cancer; bronchial cancer; mesothelioma; bladder cancer; sarcoma; or pheochromocytoma.

[0070] The cancers include melanoma, non-small cell lung cancer, small cell lung cancer (SCLC), renal cell carcinoma, classic Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, colorectal cancer (CRC), microsatellite instability-high colorectal cancer (MSI-H CRC), and mismatch repair-deficient colorectal cancer (dMMR). The following may be selected from CRC, hepatocellular carcinoma, gastric cancer, cervical cancer, Merkel cell carcinoma, cutaneous squamous cell carcinoma, triple-negative breast cancer, gastroesophageal cancer, pancreatic cancer, prostate cancer, esophageal cancer, endometrial cancer, colon cancer, rectal cancer, colorectal cancer, lip cancer, oral cancer, nasopharyngeal cancer, other pharyngeal cancers, gallbladder cancer, biliary tract cancer, non-melanoma skin cancer, ovarian cancer, testicular cancer, thyroid cancer, liver cancer, laryngeal cancer, tracheal cancer, bronchial cancer, breast cancer, esophageal squamous cell carcinoma, lung squamous cell carcinoma, kidney cancer, mesothelioma, lung cancer, bladder cancer, microsatellite-stable colorectal cancer (MSS CRC), castration-resistant prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), sarcoma, pheochromocytoma, head and neck cancer, gastroesophageal junction cancer, or Hodgkin lymphoma.

[0071] The aforementioned cancers may be selected from melanoma, non-small cell lung cancer, small cell lung cancer (SCLC), renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, colorectal cancer (CRC) (MSI-H or dMMR), hepatocellular carcinoma, gastric cancer, cervical cancer, Merkel cell carcinoma, cutaneous squamous cell carcinoma, triple-negative breast cancer, gastroesophageal cancer, pancreatic cancer, prostate cancer, esophageal cancer, or endometrial cancer.

[0072] The aforementioned cancers may be epithelial cancers (in the GBD tumor classification, including colorectal and rectal cancer, lip and oral cavity cancer, nasopharynx, other pharyngeal cancers, gallbladder and biliary tract cancers, pancreatic cancer, non-melanomatous skin cancer, ovarian cancer, testicular cancer, kidney cancer, bladder cancer, thyroid cancer, mesothelioma cancer, esophageal cancer, stomach cancer, liver cancer, larynx cancer, trachea cancer, bronchi and lung cancer, breast cancer, cervical cancer, uterine cancer, and prostate cancer).

[0073] The aforementioned cancers may be selected from colorectal cancer, microsatellite-stable colorectal cancer (MSS CRC), gastroesophageal cancer, head and neck squamous cell carcinoma (HNSCC), prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), pancreatic cancer, lung cancer, bladder cancer, mesothelioma, cervical cancer, kidney cancer, sarcoma, or pheochromocytoma.

[0074] The aforementioned cancers may be selected from microsatellite-stable colorectal cancer (MSS CRC), gastroesophageal junction cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), sarcoma, pheochromocytoma, melanoma, renal cell carcinoma, Hodgkin lymphoma, classical Hodgkin lymphoma, urothelial carcinoma, microsatellite-instability-high (MSI-H) colorectal cancer, mismatch-defective-mixed-millennial (dMMR) colorectal cancer, hepatocellular carcinoma, and Merkel cell carcinoma.

[0075] The aforementioned cancers may be selected from microsatellite-stable colorectal cancer (MSS CRC), gastroesophageal junction cancer, head and neck squamous cell carcinoma (HNSCC), castration-resistant prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), sarcoma, and pheochromocytoma.

[0076] The aforementioned cancers may be selected from microsatellite-stable colorectal cancer (MSS CRC), gastroesophageal junction cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), sarcoma, and pheochromocytoma.

[0077] The aforementioned cancer may be a solid tumor. A solid tumor is a blood-related cancer such as leukemia or lymphoma. This refers to all types of cancer other than lymphatic cancer. The aforementioned cancers may be progressive solid tumors. Progressive solid tumors are solid tumors that are refractory to treatment, continue to grow despite treatment, recur after treatment, or have metastasized from the primary site to other parts of the body.

[0078] The crystalline form of the present invention and the immune checkpoint inhibitor may be administered by any feasible route of administration. In some embodiments, the crystalline form of the present invention may be administered orally and the immune checkpoint inhibitor may be administered intravenously. The crystalline form of the present invention and the immune checkpoint inhibitor may be administered simultaneously, sequentially, or separately.

[0079] Therapeutic doses may vary depending on the patient's needs, the severity of the condition being treated, and the compound used. Determining the appropriate dose in a particular situation is within the scope of the skill of those skilled in the art. Generally, treatment is started with a low dose below the optimal dose of the compound. The dose is then gradually increased until the optimal effect is achieved in that situation. For convenience, the entire daily dose may be divided and administered in multiple doses per day, if desired.

[0080] Generally, the daily dose may be about 10 μg to about 30 mg per kg of body weight of humans and non-human animals, preferably about 50 μg to about 30 mg per kg of body weight of humans and non-human animals, for example, about 50 μg to about 10 mg per kg of body weight of humans and non-human animals, for example, about 100 μg to about 30 mg per kg of body weight of humans and non-human animals, for example, about 100 μg to about 10 mg per kg of body weight of humans and non-human animals, and most preferably about 100 μg to about 1 mg per kg of body weight of humans and non-human animals.

[0081] In one embodiment, the present invention provides a method for producing the crystal form of the present invention. The method is: (a) To provide a solution containing the compound of formula (1) in a polar organic solvent at a temperature of 60 to 90°C; and (b) Add water to the solution to induce crystallization of the crystalline form and obtain a suspension; Includes.

[0082] The solution in step (a) may contain the polar organic solvent and water in a volume ratio of 1:3 to 3:1, or 1:3 to 2:1, or 1:3 to 1:1, or 1:2 to 1:1.

[0083] The solution in step (a) may have a pH of 3.5 or less. The solution in step (a) may have a pH of 1 to 3.5, or a pH of 2 to 3.5, or a pH of 3 to 3.5. Preferably, the pH of the solution in step (a) is about 3.5.

[0084] Examples of polar organic solvents include alcohols, ketones, esters, ethers, and polyethers. Polar organic solvents may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, heptanol, octanol, acetone, cyclohexanone, toluene, cyclohexanone, methylbutanone, methyl isobutyl ketone, methyl acetate, ethyl acetate, propyl acetate, tetrahydrofuran (THF), diethyl ether, propylene oxide, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, and mixtures thereof. Polar organic solvents may be selected from the group consisting of methanol, tetrahydrofuran, and isopropanol.

[0085] The polar organic solvent may be a protic solvent.

[0086] Preferably, the polar organic solvent is isopropanol.

[0087] The solution in step (a) may be provided at a temperature of 75-85°C, or about 80°C.

[0088] Step (b) may include maintaining the solution at a temperature of 60–90°C, 75–85°C, or about 80°C during the addition of water. Step (b) may include adding water to the solution over a period of 30–90 minutes.

[0089] The volume ratio of polar organic solvent to water after step (b) may be 1:1.5 to 1:10, or 1:1.5 to 1:9, or 1:1.5 to 1:8, or 1:1.5 to 1:7, or 1.15 to 1:6, or 1:1.5 to 1:5, or 1:1.5 to 1:4.

[0090] The method is, (c) Stirring the suspension for at least 16 hours, preferably 36 hours or less, at a temperature of 60-90°C, 75-85°C, or about 80°C; It may further include the following.

[0091] The method is, (d) A step of adjusting the temperature of the suspension to 15-25°C, or about 20°C; It may further contain the following. The temperature of the suspension may be adjusted over a period of 2 to 4 hours. The suspension may be stirred at 15 to 25°C for 30 to 90 minutes.

[0092] The method may further include filtering the suspension to obtain a filter cake containing the crystalline form. The filter cake may be rinsed with water at least once, for example, three times.

[0093] The method may further include drying the filtered cake to obtain a crystalline form.

[0094] Step (a) is, (a)(i) In the presence of a polar organic solvent, formula (2): [ka] Hydrolysis of the ester of the compound; It may include.

[0095] The compound of formula (2) is also referred to herein as (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)methyl benzoate.

[0096] The aforementioned hydrolysis proceeds at a faster rate in the presence of a polar organic solvent.

[0097] Hydrolysis may be catalyzed by an acid or a base. Preferably, the ester of the compound of formula (2) is hydrolyzed using an aqueous base.

[0098] Suitable bases include any base that is soluble in water and forms hydroxide ions. The base may be an alkali metal hydroxide or an alkaline earth metal hydroxide. The base may be selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, and mixtures thereof. Preferably, the base is sodium hydroxide.

[0099] The reaction mixture in step (a)(i) may be stirred at a temperature of 55-65°C or about 60°C. The reaction mixture in step (a)(i) may be stirred at a temperature of 55-65°C or about 60°C for 4 hours or more, for example, 4-8 hours. A reaction temperature of 55-65°C provides a good balance between reaction rate and purity profile.

[0100] Step (a) further, (a)(ii) The pH of the reaction mixture may be adjusted to a pH of 3.5 or less, for example, about 3.5. This may provide a solution containing the compound of formula (1) in a polar organic solvent and water.

[0101] The pH of the reaction mixture may be adjusted by any suitable method, for example, by adding an acid. The pH of the reaction mixture may be adjusted using any suitable acid, such as hydrochloric acid or citric acid. Preferably, the pH of the reaction mixture is adjusted using citric acid.

[0102] Step (a)(ii) may include maintaining the reaction mixture at a temperature of 60-90°C or 60-70°C while adjusting the pH of the reaction mixture to pH 3.5 or lower, for example, about 3.5. This is preferable when adjusting the pH of the reaction mixture using citric acid, because maintaining a temperature above 60°C prevents the precipitation of citric acid.

[0103] The reaction mixture may be stirred at 60-90°C or 60-70°C for 10-30 minutes or about 20 minutes after adjusting the pH to 3.5 or below.

[0104] After adjusting the pH to 3.5 or lower, the solution temperature may be adjusted to 60-90°C, 75-85°C, or approximately 80°C to provide a solution containing the compound of formula (1) in a polar organic solvent and water.

[0105] The method is, (a) To provide a solution containing the compound of formula (1) in a polar organic solvent at a temperature of 60 to 90°C, wherein the solution may be a solution of polar organic solvent and water in a volume ratio of 1:3 to 3:1, and / or the pH of the solution may be 3.5 or less; (b) Adding water to the solution to induce crystallization of the crystalline form and obtain a suspension, wherein the solution may be maintained at a temperature of 60-90°C, 75-85°C, or about 80°C while adding water, and / or the volume ratio of polar organic solvent to water after the addition of water may be 1:1.5-1:10, 1:1.5-1:9, 1:1.5-1:8, 1:1.5-1:7, 1.15-1:6, 1:1.5-1:5, or 1:1.5-1:4; (c) Stir the suspension for at least 16 hours, preferably 36 hours or less, at a temperature of 60-90°C, 75-85°C, or about 80°C; (d) Adjust the temperature of the suspension to 15-25°C, or approximately 20°C; Filtering the suspension to obtain a filter cake containing the crystalline form; and The filtered cake is dried to obtain the crystalline form; It may include.

[0106] The method is, (a)(i) Hydrolysis of the ester of the compound of formula (2) in the presence of a polar organic solvent, wherein an aqueous base may be used for the hydrolysis, and the hydrolysis may be carried out with stirring at a reaction mixture temperature of 55-65°C or about 60°C; (a)(ii) Adjusting the pH of the reaction mixture to pH 3.5 or less (or about 3.5), and providing a solution containing the compound of formula (1) in a polar organic solvent and water, wherein the reaction mixture may be maintained at a temperature of 60-90°C or about 60-70°C while adjusting the pH of the reaction mixture to pH 3.5 or less, and the volume ratio of the polar organic solvent to water may be 1:3-3:1, or 1:3-2:1, or 1:3-1:1, or 1:2-1:1. The temperature of the solution may be adjusted to 60-90°C, 75-85°C, or approximately 80°C to provide a solution containing the compound of formula (1) in a polar organic solvent and water; (b) Adding water to the solution to induce crystallization of the crystalline form and obtain a suspension, wherein the solution may be maintained at a temperature of 60-90°C, 75-85°C, or about 80°C during the addition of water, and / or the volume ratio of polar organic solvent to water after the addition of water may be 1:1.5-1:10, 1:1.5-1:9, 1:1.5-1:8, 1:1.5-1:7, 1.15-1:6, 1:1.5-1:5, or 1:1.5-1:4; (c) Stir the suspension for at least 16 hours, preferably 36 hours or less, at a temperature of 60-90°C, 75-85°C, or about 80°C; (d) Adjust the temperature of the suspension to 15-25°C, or approximately 20°C; Filtering the suspension to obtain a filter cake containing the crystalline form; and The filtered cake is dried to obtain the crystalline form; It may include.

[0107] definition Unless otherwise specified, the following definitions apply to this application.

[0108] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that, within the bounds of appropriate medical judgment, is suitable for use in contact with the tissue of a subject (e.g., a human subject) and that does not cause problems or complications such as excessive toxicity, irritation, or allergic reactions, and that has a reasonable benefit-to-risk ratio. Each excipient must also be “acceptable” in the sense that it is compatible with the other components of the formulation.

[0109] As used herein in relation to the compounds, the term “treatment” is used to describe any form of intervention involving the administration of the compound to a subject who is suffering from, at risk of suffering from, or potentially suffering from the disease or disorder in question. Therefore, the term “treatment” encompasses both preventive treatment and treatment in the event that measurable or detectable symptoms of the disease or disorder are present.

[0110] As used herein (for example, in relation to methods of treating a disease or condition), the terms “effective dose” and “therapeutic effective dose” refer to the amount of a compound that is effective in producing the desired therapeutic effect. For example, if the condition is pain, the therapeutic effective dose is the amount sufficient to produce the desired level of pain relief. The desired level of pain relief may be, for example, complete elimination of pain or reduction in the severity of pain.

[0111] Unless otherwise specified, all chemical terms are used in their conventional sense (for example, as defined in the IUPAC Gold Book).

[0112] As used herein, the terms “administer” or “to administer” mean the route of administration of the compounds disclosed herein. Examples of routes of administration include, but are not limited to, oral, intravenous, intraperitoneal, intra-arterial, and intramuscular administration. The preferred route of administration may vary depending on various factors, such as the components of the pharmaceutical composition containing the compounds disclosed herein, the site of the potential or actual disease, and the severity of the disease.

[0113] In this specification, the terms “subject” and “patient” are used interchangeably. These terms refer to humans or other mammals (e.g., mice, rats, rabbits, dogs, cats, cattle, pigs, sheep, horses, or primates) that are susceptible to or prone to a disease or disorder, but do not necessarily have the disease or disorder. The subject is preferably a human.

[0114] The compounds of the present invention may be disclosed by name or chemical structure. In the event of any discrepancy between the name of a compound and its associated chemical structure, the chemical structure shall prevail. [Examples]

[0115] The present invention will be described below with reference to examples, but the present invention is not limited thereto. Biological data relating to the compound of formula (1), (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid, are provided in International Publication No. 2021 / 069927.

[0116] Apparatus and Method nuclear magnetic resonance (NMR) 1 ¹H NMR spectra may be acquired using a Bruker 400MHz instrument equipped with an autosampler and controlled by a DRX400 console. Unless otherwise specified, samples were prepared in DMSO-d6 solvent. Automated experiments were performed using the ICON-NMR settings in the Topspin software and the standard experimental settings on the Bruker. 1The analysis was performed using H). Offline analysis was performed using the ACDSpectrus Processor.

[0117] Fourier transform infrared spectroscopy (FT-IR) A Perkin-Elmer Spectrum One can be fitted with a universal ATR sampling accessory, and data may be acquired using a single-bounce diamond / ZnSe crystal. The spectrum should be from 4000 to 650 cm⁻¹. -1 Data was collected in 16 scans within the specified range. The data was collected using Spectrum software and ACD. Processed using a Spectrus Processor.

[0118] Powder X-ray diffraction (XRPD) Bruker AXS D8 advance XRPD diffractograms may be acquired using a Bruker D8 diffractometer equipped with a θ-2θ goniometer and a Ge monochromator, using CuKα light (40kV, 40mA). The incident beam passes through a 2.0mm divergent slit, followed by a 0.2mm anti-scattering slit and a knife edge. The diffracted beam passes through an 8.0mm receiving slit with a 2.5° solar slit, and then to the Lynxeye detector. The software used for data acquisition and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively.

[0119] The samples were measured as flat plates using the obtained powder directly under room temperature conditions. The samples were prepared by lightly pressing them onto a flat surface or filling them into a cut cavity on a polished zero-background (510) silicon wafer. The samples were rotated within their own plane.

[0120] Details of the data collection method are as follows: • Angle range: 2~42° 2θ Step width: 0.05° 2θ • Collection time: 0.5 seconds / step (Total collection time: 6.40 minutes)

[0121] Capillary XRPD The XRPD diffractogram may be acquired using a PANalytical Empyrean diffractometer employing CuKα radiation (45kV, 40mA) via transmission. A 0.5° slit, a 0.04rad solar slit, and a focusing mirror were used on the incident beam side. The sample was prepared in a 0.7mm borosilicate glass capillary, with a knife edge positioned directly above the sample. A PIXcel was placed on the diffraction beam side. 3D The detector was equipped with a light-receiving slit and a 0.04 rad solar slit.

[0122] The samples were prepared by filling capillaries with solid material and analyzed according to the following details. • Angle range: 2.5~42.0° 2θ • Step width: 0.013° 2θ • Collection time: 95.6 seconds / step (Total collection time: 20 minutes 26 seconds)

[0123] The software used for data collection was X'Pert Data Collector, and Diffrac Plus EVA was used for data analysis and display.

[0124] Variable temperature XRPD (VT-XRPD) XRPD diffractograms were collected using a PANalytical Empyrean diffractometer employing CuKα (45kV, 40mA) reflection. This instrument is equipped with an Anton Paar CHC plus+ stage featuring a graphite / Kapton window and air cooling with a proUmid MHG32 Modular Humidity Generator. A programmable divergent slit (automatic mode) was used on the incident beam side, along with a 10mm fixed incident beam mask, a Ni filter, and a 0.04rad solar slit. A PIXcel was positioned on the diffracted beam side. 3DThe detector is equipped with a programmable anti-scattering slit (automatic mode) and a 0.04 rad solar slit.

[0125] The software used for data collection was X'Pert Data Collector, and Diffrac Plus EVA or Highscore was used for data analysis and display. I used Plus.

[0126] In the variable temperature (VT-XRPD) experiment, Anton with a silicon wafer insert was used. Samples were prepared and analyzed in a Paar chromium-plated sample holder. Isothermal holding was performed for 2 minutes before measurement, with a heating / cooling rate of 10°C / min. The measurement parameters are as follows: • Angle range: 2.5~32.0° 2θ Step width: 0.0130° 2θ • Collection time: 12.75 seconds / step (Total collection time: 2.07 minutes)

[0127] Measurements were taken at various temperatures.

[0128] Differential Scanning Calorimetry (DSC) DSC data may be acquired using a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5–3 mg of each sample in a pinhole-punched aluminum pan was heated from 25°C to 275°C at a rate of 10°C / min. A 50 mL / min dry nitrogen purge was maintained over the sample.

[0129] The device control software used was Advantage for Q Series and Thermal Advantage, and the data was analyzed using Universal Analysis or TRIOS.

[0130] Thermogravimetric analysis (TGA) TGA data may be acquired using a TA Instruments Q500 TGA equipped with a 16-position autosampler. Typically, 5–10 mg of each sample was placed in a tare-filled aluminum DSC pan and heated from room temperature to 350°C at a rate of 10°C / min. A nitrogen purge of 60 mL / min was maintained over the sample.

[0131] The device control software used was Advantage for Q Series and Thermal Advantage, and the data was analyzed using Universal Analysis or TRIOS.

[0132] Dynamic vapor adsorption (DVS) DVS testing is performed by Surface Measurement Systems' DVS This may be done using Resolution (with video module, device number 3441). The software used for data collection is DVS Control Software. This is for 21 CFR Part 11 v1.0.3.0. Data analysis will be performed using DVS Standard Analysis Suite v7.2.0.9 (Standard).

[0133] Moisture absorption, USP <1241> Measurements were taken according to the following procedure: The sample was equilibrated at 0% relative humidity (RH) for 6 hours. Subsequently, the %RH was increased in 10% increments every hour until it reached 95%RH. The relative humidity was then reduced to 0%RH at the same rate. This cycle was repeated once.

[0134] exterior Observe the sample of the active pharmaceutical ingredient (API) in terms of its physical shape and color. Provide a qualitative description of the API's visual appearance. The acceptance criterion was set as a white to off-white powder.

[0135] polymorphism The crystallinity of the active pharmaceutical ingredient (API) is monitored using XRPD. The diffractogram of the API is recorded and compared with that in Figure 1.

[0136] Assays and related substances The method for measuring related substances by w / w% assay and area % is reversed-phase gradient HPLC using a Waters Xselect CSH C18 150mm × 4.6mm × 3.5μm column or equivalent. Column temperature: 40℃; Flow rate: 1.0 mL / min; Mobile phase A = 95 / 5 / 0.1 water / acetonitrile / trifluoroacetic acid; Mobile phase B = 5 / 95 / 0.1 water / acetonitrile / trifluoroacetic acid; Gradient [Time (min) / Mobile phase A (v / v%) / Mobile phase B (v / v%)]: 0.0 / 100 / 0, 19.0 / 0 / 100, 25.0 / 0 / 100, 25.1 / 100 / 0, 30.0 / 100 / 0; Injection volume :5 μL; UV detection: 248 nm. Sample and standard solutions are prepared at a concentration of 0.4 mg / mL in acetonitrile / water = 50 / 50.

[0137] (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid is quantified by a w / w% assay against a suitable standard sample, and the relevant substance is quantified as area % of the total peak area relative to the total peak area of ​​all peaks exceeding 0.05% in the sample chromatogram.

[0138] In the assay, the content of (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid in the active pharmaceutical ingredient was measured using HPLC. The acceptance criterion for the assay was 97.0-103.0% (w / w) on an anhydrous, solvent-free basis.

[0139] For related substances, the content of these substances in the active pharmaceutical ingredient is measured using HPLC. The acceptable standard for chemical purity is ≥97.0 area%.

[0140] Total impurities are controlled to a limit of ≤3.0 area%.

[0141] Chiral purity The chiral purity is measured using a normal-phase gradient HPLC method with a Phenomenex Lux Amylase-2 250mm × 4.6mm × 3μm column or equivalent. Column temperature: 40°C; Flow rate: 1.0 mL / min; Mobile phase: 15 / 85 / 0.1 ethanol / n-heptane / trifluoroacetic acid; Injection volume: 5 μL; UV detection: 248 nm. The sample solution is prepared at a concentration of 1.0 mg / mL in ethanol / n-heptane = 15 / 85.

[0142] The chiral purity of (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)benzoic acid is quantified on an area-based basis, calculated as the percentage of the peak area of ​​the desired enantiomer relative to the sum of the peak areas of both the desired and undesired enantiomers.

[0143] The amount of undesirable (S) enantiomers in the active pharmaceutical ingredient was quantified as area percentage to determine the chiral purity value. The acceptable chiral purity standard was set at 98.0 area percentage or higher.

[0144] moisture content The moisture content of the active pharmaceutical ingredient is specified in the USP <921> Measurement was performed by Karl Fischer analysis in accordance with PH.Eur 2.5.12. The acceptance criterion was set at 2.0% (w / w) or less.

[0145] DSCt (onset) The crystallinity of the active pharmaceutical ingredient (API) is monitored using DSC. A thermogram of the API is recorded and compared with that shown in Figure 2.

[0146] Example 1 The crystalline form of the present invention may be produced from (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)methyl benzoate according to the following method.

[0147] [ka]

[0148] A method for producing (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)methyl benzoate is disclosed in International Publication No. 2021 / 069927.

[0149] Saponification In a 5L jacketed reactor equipped with a mechanical stirrer, thermometer, dropping funnel, and reflux partition with condenser, (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)methyl benzoate (145.2 g; 0.32 mol; 1.0 equivalent) was added to isopropanol (300 mL; 2.0 rel. vol.), and 33% sodium hydroxide aqueous solution (58.1 g; 0.48 mol; 1.5 equivalents) was added via a dosing funnel. Purified water (300 mL; 2 rel. vol.) was added, and the solution was heated to 60±5°C. The solution was stirred at 60±5°C for 4 hours.

[0150] Without organic solvents, the reaction proceeded very slowly, taking 24 hours to reach complete conversion in water. The reaction proceeded well in a mixture of water with methanol, tetrahydrofuran, or isopropanol.

[0151] The reaction temperature was investigated through screening experiments. The reaction was carried out at 20, 40, and 60°C. Complete conversion was observed within 1-2 hours at 60°C and within 4.5 hours at 40°C, but it took several days at 20°C. The in situ purity profile at the reaction endpoint was similar at all temperatures. Therefore, it is preferable to use a reaction temperature of 55-65°C, or approximately 60°C, in this process.

[0152] Isolation A 1N citric acid solution was prepared by dissolving 198.8 g of citric acid in 510 mL of purified water and 510 mL of isopropanol. The reaction mixture was adjusted to pH 3.5 by adding 1105 g of this 1N citric acid solution. The mixture was stirred at 60°C for a further 20 minutes to obtain a concentrated suspension.

[0153] Next, heat the mixture to 80°C to dissolve the entire volume, then add purified water (1750 mL; 12.0 (rel.vol.) was added within 1 hour. Crystallization occurred after adding one-third of the water. The suspension was stirred at 80°C for a further 16 hours, then cooled to 20°C over 3.5 hours. After stirring for another hour at 20°C, the suspension was filtered. The cake was rinsed three times with purified water (3 × 300 mL; 3 × 2.0 rel.vol.) and air-dried to obtain the crystalline form of the present invention as a white powder (125.5 g; 96%). HPLC purity: 99.9 area%.

[0154] The isolation of the crystalline form of the present invention was optimized.

[0155] Initially, acidification was carried out using an aqueous hydrochloric acid solution, but this was replaced with an aqueous citric acid solution to prevent the formation of isopropyl chloride. Therefore, it is preferable to perform acidification using citric acid.

[0156] To prevent the compound of formula (1) from crystallizing during the acidification process, it is preferable to maintain the reaction mixture at a temperature of 60-70°C during the acidification step.

[0157] After acidifying the reaction mixture with isopropanol / water, water was added, and the compound of formula (1) precipitated.

[0158] If water is added at a temperature significantly below 80°C, the compound of formula (1) may precipitate too quickly, potentially resulting in an unagitable suspension or a rubber ball-like substance. Therefore, it is preferable to provide the solution at a temperature of 75-85°C (approximately 80°C). Furthermore, it is preferable to maintain the solution at a temperature of 75-85°C, or approximately 80°C, while adding water.

[0159] This optimized procedure allowed the crystalline form of the present invention to be obtained directly from the reaction mixture in high purity.

[0160] Characteristic evaluation Table 2 shows a list of XRPD peaks for the aforementioned crystal form. Figure 1 shows the XRPD spectrum of the aforementioned crystal form. Figure 2 shows the TGA and DSC plots of the aforementioned crystal form. Figure 3 shows the FT-IR spectrum of the aforementioned crystal form. Figure 4 shows the NMR spectrum of the aforementioned crystal form.

[0161] The TGA thermogram of the aforementioned crystal form showed that the mass did not decrease prior to decomposition at approximately 280°C. 1 The 1H-NMR spectrum was consistent with the proposed structure, and no residual solvent was observed. 1 Since no solvent was detected by 1H-NMR and no weight loss was observed by TGA, the crystalline form is considered to be an anhydrous form.

[0162] [Table 2]

[0163] Example 2 In a calorimeter reactor (RC-1), the reaction described in Example 1 was carried out on a 28g scale using the starting material (R)-4-(1-(3-methyl-2-((4-(trifluoromethyl)benzyl)oxy)butanamide)cyclopropyl)methyl benzoate. The reaction at 60°C following the addition of sodium hydroxide generated 100.3 kJ / mol of heat, which corresponds to an adiabatic temperature rise of 8.4 K. Acidification with citric acid solution at 60°C generated 65.0 kJ / mol of heat, which corresponds to an adiabatic temperature rise of 2.2 K. Crystallization occurred during the addition of water at 80°C, generating 222.2 kJ / mol of heat, which corresponds to an adiabatic temperature rise of 3.8 K. This process is safe to carry out on a large scale.

[0164] Example 3 The crystalline form was packed into a double-lined antistatic LDPE bag, secured with cable ties, and placed inside a sealed HDPE drum.

[0165] The stability of the crystalline form of the present invention was evaluated under long-term conditions of 25°C / 60% relative humidity (RH) for 18 months, and under accelerated conditions of 40°C / 75%RH for 6 months.

[0166] Detailed data on the stability of the crystal form is shown in Table 3 (40°C / 75%RH) and Table 4 (25°C / 60%RH).

[0167] [Table 3]

[0168] [Table 4]

[0169] Example 4 DVS analysis was performed on the crystalline form of the present invention. The DVS adsorption and desorption plots are shown in Figure 5. The DVS isothermal plot is shown in Figure 6.

[0170] During drying in DVS at 0% RH, a mass loss of 0.03 wt% was observed. Subsequently, sustained uptake was observed as RH increased, reaching 0.06 wt% at 70% RH. Above 70% RH, the uptake became steeper, increasing to 0.16 wt% at 95% RH. The total mass uptake was less than 0.2 wt%, and therefore, the crystalline form of the present invention does not meet the criteria of hygroscopicity according to the European Pharmacopoeia. The second adsorption and desorption cycles showed similar behavior. Therefore, the cycle is reversible and reproducible.

[0171] XRPD was performed on the sample after DVS analysis to confirm that the sample was the crystalline form of the present invention.

[0172] Comparative Example Comparative crystalline forms of the compound of formula (1) were prepared according to the following method.

[0173] 500 mg of the compound of formula (1) was treated with dimethyl sulfoxide (DMSO) (3 Vol) at room temperature to obtain a clear solution. Water (3 Vol) was added to this solution. The resulting suspension was vigorously stirred at room temperature for 2 hours. A precipitate formed. This substance was isolated by Buchner filtration, washed with an excess of water, and dried by vacuum for 1 hour. The sample was then further dried in a vacuum oven (RT) for 2 hours.

[0174] Table 5 provides a list of XRPD peaks for the comparative crystal form. Figure 7 shows the XRPD spectrum of the comparative crystal form. Figure 8 shows the TGA and DSC plots of the comparative crystal form. 1 The 1H-NMR spectrum was consistent with the proposed structure, and residual DMSO was observed.

[0175] This comparative form is the crystalline DMSO solvate. The stability of the comparative form was evaluated under accelerated conditions of 40°C / 75%RH, and it was found to be unstable after 7 days of static storage. VT-XRPD analysis also showed that the comparative crystalline form is unstable above 100°C. The comparative crystalline form is slightly hygroscopic.

[0176] [Table 5]

[0177] Numbered Embodiments 1. Equation (1): [ka] The crystalline form of the compound, (i) The crystal form exhibits a powder X-ray diffraction pattern with peaks at 2θ = 10.0 ± 0.1° and 15.0 ± 0.1°; and / or (ii) The crystalline form shows a differential scanning calorimetry (DSC) thermogram that includes an endothermic event at a starting temperature of 171±2°C; Crystal form. 2. The crystal form according to Embodiment 1, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 18.7 ± 0.1°. 3. A crystal form according to any one of Embodiments 1 to 2, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 20.9 ± 0.1°. 4. A crystal form according to any one of Embodiments 1 to 3, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 14.6 ± 0.1°. 5. A crystal form according to any one of Embodiments 1 to 4, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 10.7 ± 0.1°. 6. A crystal form according to any one of Embodiments 1 to 5, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 17.9 ± 0.1°. 7. A crystal form according to any one of Embodiments 1 to 6, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 17.7 ± 0.09°. 8. A crystal form according to any one of Embodiments 1 to 7, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 19.8 ± 0.1°. 9. A crystal form according to any one of Embodiments 1 to 8, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 20.1 ± 0.1°. 10. A crystal form according to any one of Embodiments 1 to 9, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 15.2 ± 0.09°. 11. A crystal form according to any one of embodiments 1 to 10, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 3.5 ± 0.1°. 12. A crystal form according to any one of Embodiments 1 to 11, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 4.9 ± 0.1°. 13. A crystal form according to any one of Embodiments 1 to 12, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 10.4 ± 0.1°. 14. A crystal form according to any one of embodiments 1 to 13, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 11.4 ± 0.1°. 15. A crystal form according to any one of Embodiments 1 to 14, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 11.9 ± 0.1°. 16. A crystal form according to any one of Embodiments 1 to 15, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 12.4 ± 0.1°. 17. A crystal form according to any one of embodiments 1 to 16, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 14.2 ± 0.1°. 18. A crystal form according to any one of Embodiments 1 to 17, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 15.5 ± 0.1°. 19. A crystal form according to any of Embodiments 1 to 18, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 16.8 ± 0.1°. 20. A crystal form according to any one of Embodiments 1 to 19, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 18.4 ± 0.1°. 21. A crystal form according to any one of Embodiments 1 to 20, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 19.0 ± 0.1°. 22. A crystal form according to any one of Embodiments 1 to 21, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 20.6 ± 0.1°. 23. A crystal form according to any one of Embodiments 1 to 22, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 21.5 ± 0.1°. 24. A crystal form according to any one of Embodiments 1 to 23, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 21.8 ± 0.1°. 25. A crystal form according to any one of Embodiments 1 to 24, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 22.3 ± 0.1°. 26. A crystal form according to any one of Embodiments 1 to 25, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 22.9 ± 0.1°. 27. A crystal form according to any one of Embodiments 1 to 26, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 23.8 ± 0.1°. 28. A crystal form according to any one of Embodiments 1 to 27, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 24.4 ± 0.1°. 29. A crystal form according to any of Embodiments 1 to 28, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 25.0 ± 0.1°. 30. A crystal form according to any one of Embodiments 1 to 29, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 25.4 ± 0.1°. 31. A crystal form according to any one of Embodiments 1 to 30, which exhibits a powder X-ray diffraction pattern including a peak at 2θ = 26.4 ± 0.1°. 32. A crystal form according to any one of Embodiments 1 to 31, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 26.7 ± 0.1°. 33. A crystal form according to any one of Embodiments 1 to 32, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 27.1 ± 0.1°. 34. A crystal form according to any one of embodiments 1 to 33, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 27.7 ± 0.1°. 35. A crystal form according to any one of Embodiments 1 to 34, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 28.3 ± 0.1°. 36. A crystal form according to any one of Embodiments 1 to 35, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 29.1 ± 0.1°. 37. A crystal form according to any one of embodiments 1 to 36, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 29.6 ± 0.1°. 38. A crystal form according to any one of Embodiments 1 to 37, exhibiting a powder X-ray diffraction pattern with a peak at 2θ = 30.2 ± 0.1°. 39. A crystal form according to any one of Embodiments 1 to 38, which exhibits the peaks shown in the table below and a powder X-ray diffraction pattern having substantially the same intensity as those shown in the table below. [Table 6] 40. Embodiments 1 to 39, which substantially show the powder X-ray diffraction patterns shown in Figure 1 The crystal form described below. 41. Crystal form according to any of Embodiments 1 to 40, having an infrared spectrum containing at least one or all of the following peaks: 3273±2 cm⁻¹ -1 , 2960±2cm -1 , 2870±2cm -1 , 1686±2cm-1 , 1657±2cm -1 , 1328±2cm -1 , and 1068±2cm -1 . 42. A composition comprising the crystalline form described in any of Embodiments 1 to 41. 43. A pharmaceutical composition comprising the crystalline form described in any one of Embodiments 1 to 41 and at least one pharmaceutically acceptable excipient. 44. The crystalline form according to any one of Embodiments 1 to 41 for use in medical applications. 45. The crystalline form according to Embodiment 44 for use in the treatment of cancer. 46. ​​The cancers mentioned above include lung cancers such as non-small cell lung cancer, small cell lung cancer (SCLC), and squamous cell carcinoma of the lung; renal cancers such as renal cell carcinoma and urothelial carcinoma; Hodgkin lymphomas such as classical Hodgkin lymphoma; head and neck cancers such as head and neck squamous cell carcinoma (HNSCC), lip cancer, oral cancer, nasopharyngeal cancer, and other pharyngeal cancers; colon cancer; rectal cancer; microsatellite-unstable high-grade colorectal cancer (MSI-H CRC), mismatch-repair-deficient colorectal cancer (dMMR CRC), and microsatellite-stable colorectal cancer (MSS Crystalline forms for use as described in Embodiment 45, selected from colorectal cancer (CRC) such as CRC; liver cancer such as hepatocellular carcinoma; gastric cancer; gastroesophageal cancer such as squamous cell carcinoma and gastroesophageal junction cancer; esophageal cancer; cervical cancer; breast cancer such as triple-negative breast cancer; melanoma; non-melanoma skin cancer such as Merkel cell carcinoma and cutaneous squamous cell carcinoma; pancreatic cancer; prostate cancer such as castration-resistant prostate cancer and metastatic castration-resistant prostate cancer (mCRPC); endometrial cancer; gallbladder cancer; biliary tract cancer; ovarian cancer; testicular cancer; thyroid cancer; laryngeal cancer; tracheal cancer; bronchial cancer; mesothelioma; bladder cancer; sarcoma; or pheochromocytoma. 47. A method for producing the crystal form described in any one of Embodiments 1 to 41, (a) At a temperature of 60-90°C, in a polar organic solvent, formula (1): [ka] To provide a solution containing the compound; and (b) Add water to the solution to induce crystallization of the crystalline form and obtain a suspension; Methods that include... 48. The method according to Embodiment 47, wherein the solution in step (a) contains the polar organic solvent and water in a volume ratio of 1:3 to 3:1, or 1:3 to 2:1, or 1:3 to 1:1, or 1:2 to 1:1. 49. The method according to Embodiment 47 or 48, wherein the pH of the solution in step (a) is pH 3.5 or less. 50. The method according to any one of embodiments 47 to 49, wherein the polar organic solvent is isopropanol. 51. Provide the solution from step (a) at a temperature of 75-85°C, or approximately 80°C. The method described in any one of the following states 47-50. 52. The method according to any one of Embodiments 47 to 51, wherein step (b) comprises maintaining the solution at a temperature of 60 to 90°C, 75 to 85°C, or about 80°C while water is being added. 53. (c) A step of stirring the suspension at a temperature of 75-85°C, or about 80°C, for at least 16 hours, and preferably 36 hours or less; The method according to any one of embodiments 47 to 52, further comprising: 54. (d) A step of adjusting the temperature of the suspension to 15-25°C, or about 20°C; The method according to any one of embodiments 47 to 53, further including the method described above. 55. The method according to any one of embodiments 47 to 54, further comprising filtering the suspension to obtain a filter cake containing the crystalline form. 56. The method according to embodiment 55, further comprising drying the filtered cake to obtain the crystalline form. 57. Process (a) is, (a)(i) In the presence of a polar organic solvent, formula (2): [ka] Hydrolysis of the ester of the compound; A method according to any one of embodiments 47 to 56, including the method described above. 58. The method according to Embodiment 57, wherein the ester of the compound of formula (2) is hydrolyzed using an aqueous base. 59. The method according to Embodiment 58, wherein the base is sodium hydroxide. 60. The method according to any one of embodiments 57 to 59, wherein the reaction mixture of step (a)(i) is stirred at a temperature of 55 to 65°C, or about 60°C. 61. (a)(ii) A step of adjusting the pH of the reaction mixture to pH 3.5 or lower; The method according to any one of embodiments 57 to 60, further including the method described above. 62. The method according to Embodiment 61, wherein the pH of the reaction mixture is adjusted using citric acid. 63. The method according to Embodiment 61 or 62, wherein step (a)(ii) involves maintaining the reaction mixture at a temperature of 60-70°C while adjusting the pH of the reaction mixture to pH 3.5 or less.

Claims

1. Formula (1): 【Chemistry 1】 The crystalline form of the compound, (i) The crystal form exhibits a powder X-ray diffraction pattern with peaks at 2θ = 10.0 ± 0.1° and 15.0 ± 0.1°; and / or (ii) The crystal form shows a differential scanning calorimetry (DSC) thermogram including an endothermic event at a starting temperature of 171 ± 2°C; Crystal form.

2. The aforementioned crystal forms are 2θ = 18.7±0.1°; 20.9±0.1°; 14.6±0.1°; 10.7±0.1°; 17.9±0.1°; 17.7±0.09°; 19.8±0.1°; 20.1±0.1°; 15.2±0.09°; 3.5±0.1°; 4.9±0.1°; 10.4±0.1°; 11.4±0.1°; 11.9±0.1°; 12.4±0.1°; 14.2±0.1°; 15.5±0.1°; 16.8±0.1°; 18.4±0.1°; 19.0±0.1°; 20.6±0.1 The crystal form according to claim 1, which exhibits a powder X-ray diffraction pattern including at least one peak selected from the group consisting of °; 21.5±0.1°; 21.8±0.1°; 22.3±0.1°; 22.9±0.1°; 23.8±0.1°; 24.4±0.1°; 25.0±0.1°; 25.4±0.1°; 26.4±0.1°; 26.7±0.1°; 27.1±0.1°; 27.7±0.1°; 28.3±0.1°; 29.1±0.1°; 29.6±0.1°; and / or 30.2±0.1°.

3. The crystal form according to claim 1 or 2, which exhibits the peaks shown in the table below and a powder X-ray diffraction pattern having substantially the same intensity as those shown in the table below. Table 1

4. A powder X-ray diffraction pattern substantially shown in Figure 1, according to any one of claims 1 to 3. The crystal form described.

5. The crystal form according to any one of claims 1 to 4, having an infrared spectrum including at least one or all of the following peaks: 3273 ± 2 cm⁻¹ －１ , 2960±2cm －１ , 2870±2cm －１ , 1686±2cm －１ , 1657±2cm －１ , 1328±2cm －１ , and 1068±2cm －１ .

6. A composition comprising the crystalline form described in any one of claims 1 to 5.

7. A pharmaceutical composition comprising the crystalline form described in any one of claims 1 to 5 and at least one pharmaceutically acceptable excipient.

8. A crystalline form according to any one of claims 1 to 5 for use in medical treatment, preferably for use in the treatment of cancer, wherein the cancer is a lung cancer such as non-small cell lung cancer, small cell lung cancer (SCLC), and squamous cell carcinoma of the lung; a renal cancer such as renal cell carcinoma and urothelial carcinoma; a Hodgkin lymphoma such as classical Hodgkin lymphoma; a head and neck cancer such as head and neck squamous cell carcinoma (HNSCC), lip cancer, oral cancer, nasopharyngeal cancer, and other pharyngeal cancers; a colon cancer; a rectal cancer; a microsatellite instability high colorectal cancer (MSI-H CRC), a mismatch repair defect colorectal cancer (dMMR) Crystalline form may be selected from colorectal cancer (CRC), such as colorectal cancer (CRC) and microsatellite-stable colorectal cancer (MSS-CRC); liver cancer such as hepatocellular carcinoma; gastric cancer; gastroesophageal cancer such as esophageal squamous cell carcinoma and gastroesophageal junction cancer; esophageal cancer; cervical cancer; breast cancer such as triple-negative breast cancer; melanoma; non-melanoma skin cancer such as Merkel cell carcinoma and cutaneous squamous cell carcinoma; pancreatic cancer; prostate cancer such as castration-resistant prostate cancer and metastatic castration-resistant prostate cancer (mCRPC); endometrial cancer; gallbladder cancer; biliary tract cancer; ovarian cancer; testicular cancer; thyroid cancer; laryngeal cancer; tracheal cancer; bronchial cancer; mesothelioma; bladder cancer; sarcoma; or pheochromocytoma.

9. A method for producing the crystal form described in any one of claims 1 to 5, (a) At a temperature of 60 to 90°C, in a polar organic solvent, formula (1): 【Chemistry 2】 To provide a solution containing the compound; and (b) Add water to the solution to induce crystallization of the crystalline form and obtain a suspension; Methods that include...

10. (i) The solution of step (a) comprises the polar organic solvent and water in a volume ratio of 1:3 to 3:1, or 1:3 to 2:1, or 1:3 to 1:1, or 1:2 to 1:1; and / or (ii) The pH of the solution in step (a) is 3.5 or less; and / or (iii) The polar organic solvent is isopropanol; and / or (iv) The solution of step (a) is provided at a temperature of 75 to 85°C, or about 80°C; and / or (v) Step (b) includes maintaining the solution at a temperature of 60 to 90°C, or 75 to 85°C, or about 80°C during the addition of water; The method according to claim 9.

11. (c) A step of stirring the suspension at a temperature of 75 to 85°C, or about 80°C, for at least 16 hours, and preferably 36 hours or less; The method according to claim 9 or 10, further comprising:

12. (d) A step of adjusting the temperature of the suspension to 15 to 25°C, or about 20°C; The method according to any one of claims 9 to 11, further comprising:

13. The method according to any one of claims 9 to 12, further comprising: filtering the suspension to obtain a filter cake containing the crystalline form; and drying the filter cake to obtain the crystalline form.

14. Step (a) is, (a)(i) In the presence of a polar organic solvent, formula (2): 【Transformation 3】 Hydrolysis of the ester of the compound; Includes, Preferably, the ester of the compound of formula (2) is hydrolyzed using an aqueous base; the base may be sodium hydroxide; and / or, the reaction mixture of step (a)(i) may be stirred at a temperature of 55 to 65°C, or about 60°C; The method according to any one of claims 9 to 13.

15. (a) (ii) A step of adjusting the pH of the reaction mixture to pH 3.5 or less; It further includes, Preferably, the pH of the reaction mixture is adjusted using citric acid; and / or, Preferably, step (a)(ii) includes maintaining the reaction mixture at a temperature of 60-70°C while adjusting the pH of the reaction mixture to pH 3.5 or lower; The method according to claim 14.

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