4-[(5-Chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one and crystalline forms of salts thereof, a process for preparing the same, and uses thereof

Abstract

The present disclosure relates to the hydrochloride salt of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (Compound 1), which is a potent, orally active, selective melanin-concentrating hormone receptor 1 (MCHR1) antagonist useful in the treatment and / or prevention of obesity, obesity-related comorbidities and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, endocrine disorders, psychiatric conditions, personality disorders, eating disorders, sleep-wake cycle disorders, drug abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal disorders, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and also Prader-Willi syndrome (PWS) or one or more symptoms of PWS. The present disclosure also relates to the crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in free base form, different crystalline forms of its hydrochloride salt, methods for producing the same, its pharmaceutical compositions, as well as its therapeutic applications.

Description

Technical Field

[0001] The present disclosure relates to the hydrochloride salt of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (Compound 1), which is a potent, orally active, selective melanin-concentrating hormone receptor 1 (MCHR1) antagonist useful in the treatment and / or prevention of obesity, obesity-related complications and comorbidities, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, endocrine disorders, psychiatric conditions, personality disorders, eating disorders, sleep-wake cycle disorders, drug abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal disorders, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and also Prader-Willi syndrome (PWS) or one or more symptoms of PWS. The present disclosure also relates to the crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in free base form, different crystalline forms of its hydrochloride salt, methods for preparing the same, pharmaceutical compositions thereof, as well as its therapeutic uses.

Background Art

[0002] MCHR1 antagonists containing 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in free base form (represented as follows. Hereinafter referred to as Compound 1) and its maleate salt have been reported in WO2016 / 166684A1.

Chemical Formula

[0003] Melanin-concentrating hormone (MCH) plays a multifaceted role in energy homeostasis and is central to the control of food intake and energy expenditure in the hypothalamus (Pissios et al., Endocr Rev 2006, 27(6):606-620). MCH has received considerable attention because of its effects on food intake and body weight, and its receptor, MCHR1, remains one of the viable targets for the treatment of obesity (Pissios P., Peptides 2009, 30(11):2040-2044). MCH is one of the most potent central stimulants of intake and regulates energy balance and mood (Pissios et al., Endocrinology 2003, 144(8):3514-3523; Pissios et al., Endocr Rev 2006, 27(6):606-620; Forray C., Curr Opin Pharmacol 2003, 3:85-89; Qu et al., Nature 1996, 380:243-47; Hervieu G., Expert Opin Ther Targets 2003, 7:495-511; Chung et al., J Mol Neurosci 2011, 43:115-21). Prader-Willi syndrome (PWS) is a rare, complex neurodevelopmental genetic disorder resulting from the absence of expression of imprinted genes in the paternally derived region of chromosome 15q11.2-q13. PWS is the most common symptomatic cause of life-threatening obesity with an estimated incidence of 1 / 10,000-1 / 25,000 births, occurring equally in both males and females and across all ethnic groups.Syndromic obesity driven by severe overeating has been found to have a deletion of the small nucleolar RNA C / D box 116 (SNORD116) cluster as the minimal deletion region, resulting from the neurodevelopmental consequences of the deletion of the SNORD116 cluster, which is always involved in paternal copy deletion cases (Holm et al., Pediatrics 1993, 91:398 - 402; Gunay - Aygun et al., Pediatrics 2001, 108:E95; Duker et al., Eur. J. Hum. Genet. 2010; 18:1196 - 201; de Smith et al., Hum. Mol. Genet. 2009, 18:3257 - 65; Bieth et al., Eur. J. Human Genet. 2015, 23:252 - 255; Polex - Wolf et al., J. Clin. Invest. 2018, 128:960 - 969; Tan et al., Genes 2020, 11:128; Chung et al., Open Biology 2020, 10:200195). Overeating, an important behavioral symptom in PWS, has a significant impact on the well - being of patients and caregivers, extending far beyond the effect of weight gain alone. Management of overeating is ranked as the highest priority among the goals of PWS treatment among caregivers. Uncontrolled appetite, weight gain, and impaired reproduction in PWS can be explained as a loss of "checks and balances" by hyperactive MCH neurons due to a reduction in the ORX population in the lateral hypothalamic area. Prevention of MCH over - activation is most likely to improve the MCH - ORX balance, which could ultimately help patients in reducing intake - related symptoms. According to the latest pre - clinical reports, the MCH - MCHR1 system is over - activated due to impaired ORX control, and PWS patients would benefit from MCHR1 antagonist treatment and gain control over overeating and obesity (Pace M., JCI Insight 2020, 5:e137495; Pace et al., Hum. Mol. Genet. 2020, 29:2051 - 2064; Linehan et al., Mol. Metabolism 2020, 36:100977; Linehan et al., J. Physiol 2022, 596:305 - 316).Therefore, MCHR1 antagonists may be useful in the treatment of diseases or conditions associated with melanin-concentrating hormone receptor 1 activity, such as obesity, obesity-related complications and comorbidities, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, endocrine disorders, psychiatric conditions, personality disorders, eating disorders, sleep-wake cycle disorders, drug abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal disorders, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and also Prader-Willi syndrome (PWS) or one or more symptoms of PWS.

[0004] For the purposes of pharmaceutical formulation and administration to patients, it is necessary to provide a suitable form of Compound 1. However, the solid forms of Compound 1 and its pharmaceutically acceptable salts, such as crystalline forms, co-crystals or pseudo-polymorphs / solvate forms, have not been characterized in the prior art.

[0005] Polymorphism is the ability of a compound to exist in two or more different crystal phases with different arrangements of molecules within the crystal lattice (J. Bernstein (2002) Polymorphism in molecular Crystals, Oxford Univ. Press. p. 2-4). Polymorphs have the same chemical composition, but they differ in packing and geometric arrangement and exhibit different physical properties, such as melting point, X-ray diffraction pattern, crystal habit, density, stability, dissolution rate, mechanical properties (e.g., hardness, compressibility, tableting properties, flow, blending), rheology parameters, etc.

[0006] Extensive research has been done in the pharmaceutical industry on the development of different polymorphs of various drug substances to obtain suitable polymorphs or pseudopolymorphs with improved performance characteristics (R. Hilfiker (ed. 2006) Polymorphism in Pharmaceutical Industry, Wiley-VCH, p. 1-15). A common requirement for an active ingredient in the development of a pharmaceutical composition is that the active ingredient has appropriate physical, physicochemical and chemical parameters. Examples of such parameters include solubility, especially water solubility. Another important feature that must be taken into account in industrial-scale manufacturing is ease of handling and good isolability, which is extremely important for the economics of the manufacturing process. A further important aspect is that the solid form of the active ingredient has appropriate physical and chemical stability, for example, it is not hygroscopic and does not decompose significantly. Furthermore, different polymorphic forms of a given salt can have different solid-phase characteristics, physical and chemical stability. So far, there is no reliable way to clearly predict the true number of different solid forms in which a given compound can physically exist for a given new chemical entity. This also holds true for predicting all the complex physical and chemical properties that need to be considered when it comes to the pharmaceutical development of a given form. Therefore, the exploration and discovery of the polymorph landscape of a compound, as well as the generation of truly existing solid forms, remains an important area of experimental challenge and invention in the pharmaceutical field. Attempts to find new solid forms of compounds with advantageous pharmaceutical properties are highly desired.

[0007] Pseudopolymorphism is the ability of a compound to coexist with different solvents in two or more different crystal phases. In the crystallization process for generating the compound, it is generally desirable not to use solvents that can form solvates with the specific compound (Hilfiker et al. (2019), Polymorphism in Pharmaceutical Industry: Solid Form and Drug Development; p. 245 - 246; Wiley - VCH). Also, since trace amounts of organic solvents can be harmful, for pharmaceutical development, apart from hydrates, using solvate forms is highly disadvantageous (Bhatia et al. (2018), Dosage form design parameters, chapter 2.2.2: Crystal solvates and hydrates, Elsevier). Moreover, solvate forms are known to exhibit variable composition, potentially causing problems with reproducibility and long - term stability.

[0008] WO2016 / 166684 provides a preparation method for Compound 1 maleate. According to the reproducibility experiment of Example 20(b) of WO2016 / 166684, it was revealed that the isolated crystalline solid is an ethanol solvate that is not suitable for pharmaceutical development.

[0009] Further experiments have proven that maleate of Compound 1 has a strong tendency to form solvate forms showing various pseudopolymorphisms in different organic solvents such as methanol, ethanol, dichloromethane, dimethyl sulfoxide, etc. A common feature of these solvate forms is the increase in solvent content (exceeding 1% by thermogravimetric analysis (TGA)). The increased tendency to form new polymorphs, especially solvates, indicates the risk of polymorphic transformation or composition change during storage or in pharmaceutical formulations. As a result, it is disadvantageous to use maleate of Compound 1 in pharmaceutical products. Therefore, it is desirable to provide an improved form of Compound 1 suitable for pharmaceutical formulations and human administration.

[0010] WO2016 / 166684 also proposes isolating Compound 1 as the free base. Reproducibility experiments have demonstrated that the product of Example 20(a) of WO2016 / 166684 is a crystalline form with unfavorable stability characteristics, namely the metastable crystalline form (Form B) of the base that is not suitable for pharmaceutical development. Form B of Compound 1 tends to undergo polymorphic transformation when in contact with most solvents and when exposed to heat. Therefore, the use of Compound 1 Form B in pharmaceutical products is disadvantageous and does not meet the requirements for a suitable solid form of Compound 1 for pharmaceutical formulations and for the treatment of effectively inhibiting MCHR1 and showing tolerance in patients.

[0011] Other than the disadvantageous maleate and base forms, no other solid forms of Compound 1 have been described in the prior art to date.

[0012] Therefore, it is desirable to find a new solid form of Compound 1 or a pharmaceutically acceptable salt thereof that is suitable for pharmaceutical development and for administration to patients in need of treatment of diseases or conditions related to melanin-concentrating hormone receptor 1 activity and is tolerable by such patients. SUMMARY OF THE INVENTION

[0013] The present disclosure relates to the hydrochloride salt of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (Compound 1), which is a potent, orally active, selective melanin-concentrating hormone receptor 1 (MCHR1) antagonist useful in the treatment and / or prevention of obesity, obesity-related complications and comorbidities, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, endocrine disorders, psychiatric conditions, personality disorders, eating disorders, sleep-wake cycle disorders, drug abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal disorders, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and also Prader-Willi syndrome (PWS) or one or more symptoms of PWS. The present disclosure also relates to stable crystalline forms of Compound 1 in free base form, stable crystalline forms of its hydrochloride salt, methods for producing its solid forms, its pharmaceutical compositions, as well as its therapeutic applications.

Brief Description of the Drawings

[0014]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 31

Figure 32

Figure 33

Figure 34

Figure 35

Figure 36

Figure 37

Figure 38

Figure 39

Figure 40

Figure 41

Mode for Carrying Out the Invention

[0015] As summarized above, it was found that Compound 1 maleate is disadvantageous for pharmaceutical formulations and effectively inhibits MCHR1, which is unacceptable for patient treatment.

[0016] WO2016 / 166684 discloses a method for preparing Compound 1 maleate (Reference Example 1). The sample was reported to be crystalline by XRPD (Figure 1), but a significant weight loss of 3.9% was detected by TGA. Reproduction experiments of Example 20(b) - Reference Example 2 - of WO2016 / 166684 revealed that the isolated crystalline solid was an ethanol solvate (TGA: 5.1%).

[0017] Since trace amounts of organic solvents can be harmful, for pharmaceutical development, apart from hydrates, using solvated forms is highly disadvantageous (Bhatia et al. (2018), Dosage form design parameters, Chapter 2.2.2: Crystal solvates and hydrates, Elsevier). Also, solvated forms are known to have variable compositions, potentially causing problems in reproducibility and long-term stability. As a result, solvates are generally not suitable for pharmaceutical development, so it is also generally desirable not to use solvents that can form solvates with a particular compound in the crystallization process for producing that compound (Hilfiker et al. (2019), Polymorphism in Pharmaceutical Industry: Solid Form and Drug Development; p. 245 - 246; Wiley-VCH).

[0018] Further experiments led to the discovery of suitable polymorphs of Compound 1 maleate for pharmaceutical development. Recrystallization experiments from various solvents (e.g., methanol, ethanol, dichloromethane, dimethyl sulfoxide) and by various crystallization methods (e.g., suspension stirring, cooling, evaporation) were designed and carried out to identify solvent-free polymorphs of Compound 1 maleate (Reference Examples 2-9). In these experiments, several crystal forms were identified (Figures 1-9), but the residual solvent content (determined by TGA) exceeded the acceptable limit in all of these experiments, indicating that they were solvates (Figures 10-17). A number of new pseudopolymorphs combined with a high residual solvent content (above 1% by TGA) indicate a risk of polymorphic transformation or compositional change during storage or pharmaceutical formulation. As a result, the use of maleate of Compound 1 in pharmaceutical products is disadvantageous, and there is a need for different, more stable solid forms.

[0019] As summarized above, the present invention relates to stable crystalline free bases and crystalline hydrochlorides of Compound 1 that are acceptable for pharmaceutical development. This specification also relates to the identification of said crystal forms and methods for their preparation.

[0020] The crystalline solid phase can be identified by X-ray diffraction, and the positions of the powder X-ray diffraction pattern or one or more diffraction peaks are characteristic of the crystalline material. Alternatively, vibrational spectroscopy, such as IR and Raman spectroscopy, is also a suitable and widely used method for differentiating different polymorphs / pseudopolymorphs / amorphous forms. Vibrational spectroscopy mainly examines local short-range order (intramolecular vibrations), but the vibrational frequencies are also affected by the surrounding environment, and these frequencies are affected not only by the conformational polymorphism but also by the way the molecules are packed. As a result, different polymorphs typically have different vibrational spectra under conditions where they are measured with sufficiently high wavenumber resolution (Hilfiker et al. (2019), p. 418). Therefore, each crystalline form of the free base and hydrochloride salt of Compound 1 of the present invention can be identified and distinguished from other crystalline forms by one or more of the following solid-state analytical characteristics: characteristic XRPD diffraction peaks, IR absorption bands, or Raman peaks.

[0021] One aspect of the present invention is the hydrochloride salt of Compound 1. The salt can exist in various forms such as oily or solid. The solid can be amorphous, crystalline, or a mixture of both.

[0022] In another aspect, the present invention provides a method for the preparation of the hydrochloride salt of Compound 1, comprising: a) preparing a solution of Compound 1 in any suitable solvent; b) mixing the solution of step a) with a hydrochloric acid solution; c) stirring the resulting slurry; d) isolating the hydrochloride salt of Compound 1 and providing a method.

[0023] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0024] The solvent used in step b) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0025] Step c) involves agitating the slurry by any suitable method including a stir bar, stir rod, or shaker at any suitable temperature including reflux, room temperature, 0 - 5 °C, or any other suitable temperature.

[0026] Isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0027] Another aspect of the present invention is the stable anhydrous form A of the hydrochloride salt of compound 1.

[0028] A further aspect of the present invention is the hydrochloride of Compound 1, comprising at least 5%, at least 10%, at least 20%, at least 40%, at least 60%, at least 80%, at least 90%, at least 95%, at least 99% of Compound 1 hydrochloride A-type.

[0029] The X-ray diffraction pattern of Compound 1 hydrochloride A-type is shown in Figure 18. A detailed list of peaks is shown in Table 1. The most characteristic peaks of Compound 1 hydrochloride A-type are 9.2, 12.5, 14.5, 15.1, 15.8, 17.4 ± 0.2° 2θ.

[0030] [Table 1]

[0031] Compound 1 hydrochloride A-type can also be characterized by its FT-IR spectrum. The infrared spectrum of Compound 1 hydrochloride A-type is shown in Figure 19. A detailed list of absorption bands of Compound 1 hydrochloride A-type is shown in Table 2. The most characteristic absorption bands of Compound 1 hydrochloride A-type are 2474, 2524, 1668, 1479 and 1222 ± 4 cm -1 -1.

[0032] [Table 2] TIFF2025523414000004.tif172170

[0033] Compound 1 hydrochloride A-type can also be characterized by its Raman spectrum. The Raman spectrum of Compound 1 hydrochloride A-type is shown in Figure 20. A detailed list of Raman peaks of Compound 1 hydrochloride A-type is shown in Table 3. The most characteristic Raman peaks of Compound 1 hydrochloride A-type are 1549, 1344, 1303, 1257 and 747 cm -1 -1.

[0034] [Table 3] TIFF2025523414000006.tif97170

[0035] Compound 1 hydrochloride A type can also be characterized by its differential scanning calorimetry (DSC) thermogram. A typical DSC thermogram of Compound 1 hydrochloride A type is shown in Figure 21. Compound 1 hydrochloride A type melts during decomposition with a broad endothermic DSC peak at a peak maximum of 250 - 300 °C.

[0036] Compound 1 hydrochloride A type is in a true anhydrous form, as evidenced by its thermogravimetric analysis (TGA) thermogram shown in Figure 22. The weight loss of Compound 1 hydrochloride A type is less than 1.0% (up to 175 °C).

[0037] The chemical stability of Compound 1 hydrochloride A type was evaluated by a series of forced stability studies as shown in Table 4. Samples of Compound 1 hydrochloride A type were stored for 10 days under different controlled conditions (drying at 50 °C, drying at 75 °C, and 85% RH at 50 °C) and analyzed in the same manner as the initial samples.

[0038]

Table 4

[0039] The impurity profile, reduction in drying, and polymorphic form of the samples of Compound 1 hydrochloride A type did not change during the forced stability studies, and it was found that Compound 1 hydrochloride A type is stable for 10 days at 50 °C, 75 °C, and 85% RH at 50 °C.

[0040] The term solubility is used to measure the amount (μmol) of Compound 1 hydrochloride that can be dissolved in 1 L of the simulated solvent. Examples of the simulated solvent include FaSSiF (simulated intestinal fluid in the fasting state) and FeSSiF (simulated intestinal fluid in the fed state). The parent substance is considered to be very soluble according to the Biopharmaceutics Classification System (BCS) when the highest strength dissolves in an aqueous medium of 250 mL or less within the pH range of 1 to 6.8 at 37 ± 1 °C (Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on Biopharmaceutics Classification System, Guidance for Industry, December 2017, https: / / www.gmp-compliance.org).

[0041] Table 5 shows the solubility data of Compound 1 HCl Form A in FaSSiF and FeSSiF solutions. In the simulated liquids (FaSSiF and FeSSiF), Compound 1 HCl Form A is very soluble at a strength of up to 20 mg.

[0042]

Table 5

[0043] The analytical and physical characteristics described above demonstrate that Compound 1 hydrochloride Form A is a stable anhydrous polymorph of Compound 1 hydrochloride that is very soluble in the simulated medium. This is not hygroscopic under normal conditions (up to 70% RH), but some precautions are required at high humidity. The analysis results indicate that the solid form is suitable for pharmaceutical development.

[0044] In another aspect, the present invention is a method for the preparation of Compound 1 hydrochloride Form A, comprising: a) preparing a solution of Compound 1 hydrochloride in any suitable solvent; and b) evaporating a part of the solvent to obtain a suspension; c) stirring the slurry; d) isolating Compound 1 hydrochloride A-type and provides a method.

[0045] The solution prepared in step a) may be prepared by dissolving Compound 1 hydrochloride or by mixing Compound 1 with hydrochloric acid in an appropriate amount of solution.

[0046] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0047] Step b) includes evaporation of the solvent by any suitable technique including a rotary evaporation device, such as a rotary evaporator, an open reactor or any other suitable technique. Evaporation can be induced by increasing the temperature, or by reducing the pressure, or by a combination thereof.

[0048] Step c) includes stirring the slurry by any suitable technique including a stirrer, a stirring rod or a shaker at any suitable temperature including reflux, room temperature, 0 to 5 °C or any other suitable temperature.

[0049] Isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0050] In another aspect, the present invention is a method for the preparation of Compound 1 hydrochloride A-type, comprising a) Preparing a solution of Compound 1 hydrochloride in any suitable solvent; b) Cooling the solution to obtain a slurry; c) Stirring the slurry; d) Isolating Compound 1 hydrochloride Form A and providing a method comprising the same.

[0051] The solution prepared in step a) may be prepared by dissolving Compound 1 hydrochloride or by mixing Compound 1 with hydrochloric acid in a suitable amount of solvent.

[0052] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0053] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50 °C, 40 °C, room temperature, etc.

[0054] Step b) includes cooling the solution to a lower temperature than in step a), such as room temperature or 0 to 5 °C, or any suitable temperature.

[0055] Step c) includes stirring the slurry by any suitable technique including a stir bar, stirring rod or shaker at the temperature set in step b) or a lower temperature.

[0056] The isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0057] In another aspect, the present invention provides a method for the preparation of Compound 1 Hydrochloride Form A, comprising: a) preparing a solution of Compound 1 Hydrochloride in any suitable solvent; b) mixing the solution with a poor solvent to obtain a slurry; c) stirring the slurry; d) isolating Compound 1 Hydrochloride Form A and providing a method.

[0058] The solvent used in step a) and the poor solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0059] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50 °C, 40 °C, room temperature, etc.

[0060] The mixing of the solution in step b) can be carried out by adding the solution to the poor solvent or by adding the poor solvent to the solution. The addition may be uncontrolled or controlled by any suitable technique.

[0061] Step c) includes stirring the slurry by any suitable technique including a stirrer, a stirring rod or a shaker at the temperature set in step b) or a lower temperature.

[0062] The isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0063] International Patent Application WO2016 / 166684 also provides the isolation of compound 1 as a free base. Reference Example 10 demonstrated that the evaporation of the eluent described in Example 20(a) of WO2016 / 166684 produced the crystalline form B of compound 1 free base. The analytical characteristics of compound 1 Form B, particularly DSC analysis, revealed that this form undergoes a polymorphic transition at high temperature and forms a new form with a melting point of 200 - 210 °C. These DSC results indicate that compound 1 free base Form B may not be a stable polymorph for compound 1 free base.

[0064] According to Ostwald's law of stages (Ostwald, 1897), in crystallization, the system moves from an initial high-energy state to equilibrium with a minimum change in free energy, thus implying that the least stable polymorph should be separated first in any crystallization (Jonathan C. Burley, Melinda J. Duer, Robin S. Stein, Ranko M. Vrcelj, European Journal of Pharmaceutical Sciences, Volume 31, Issue 5, August 2007, pages 271 - 276). To obtain a more stable polymorph, additional crystallization experiments (e.g., Example 3) were designed and conducted using a more controlled crystallization process that applied an additional resuspension step instead of rapid evaporation of the eluent. In Example 3, a new polymorph of compound 1 free base Form A was obtained along with some trace amounts of Form B. In further crystallization experiments, pure Form A was prepared and characterized.

[0065] Another aspect of the present invention is the stable anhydrous form of compound 1 free base Form A.

[0066] A further aspect of the present invention is a crystalline solid form of the free base of Compound 1, comprising at least 5%, at least 10%, at least 20%, at least 40%, at least 60%, at least 80%, at least 90%, at least 95%, at least 99% of the free base A form of Compound 1.

[0067] The X-ray diffraction pattern of the free base A form of Compound 1 is shown in Figure 23. A detailed list of the peaks is shown in Table 6. The most characteristic peaks of the free base A form of Compound 1 are at 5.9, 17.7, 18.1, 19.8 and 22.2° 2θ.

[0068] [Table 6] TIFF2025523414000010.tif138170

[0069] The free base A form of Compound 1 can also be characterized by its FT-IR spectrum. The infrared spectrum of the free base A form of Compound 1 is shown in Figure 24. A detailed list of the absorption bands of the free base A form of Compound 1 is shown in Table 7. The most characteristic absorption bands of the free base A form of Compound 1 are at 1663, 1478, 1220, 860, 795 and 766 ± 4 cm -1 are.

[0070] [Table 7] TIFF2025523414000012.tif235170TIFF2025523414000013.tif63170

[0071] The free base A form of Compound 1 can also be characterized by its Raman spectrum. The Raman spectrum of the free base A form of Compound 1 is shown in Figure 25. A detailed list of the Raman peaks of the free base A form of Compound 1 is shown in Table 8. The most characteristic Raman peaks of the free base A form of Compound 1 are at 1554, 1345, 1267, 1260 and 750 ± 4 cm -1 are.

[0072]

Table 8

[0073] Compound 1 free base A form can also be characterized by its DSC thermogram. A typical DSC thermogram of Compound 1 free base A form is shown in Figure 26. Compound 1 free base A form shows a single melting endotherm with an onset temperature value of 200 - 210 °C.

[0074] Compound 1 free base A form is a true anhydrous form as evidenced by its TGA thermogram shown in Figure 27. The weight loss of Compound 1 free base A form is less than 0.5% (up to 215 °C).

[0075] The chemical stability of Compound 1 free base A form was evaluated by a series of forced stability studies as shown in Table 9. Samples of Compound 1 free base A form were stored for 10 days under different controlled conditions (50 °C drying, 75 °C drying, and 50 °C at 85% RH) and analyzed in the same manner as the initial samples.

[0076]

Table 9

[0077] The impurity profile, reduction on drying and polymorphic form of the samples of Compound 1 free base A form did not change during the forced stability studies, indicating that Compound 1 free base A form is stable at 50 °C, 75 °C, and 50 °C at 85% RH for 10 days.

[0078] The solubility of Compound 1 free base A form in PBS, FaSSiF and FeSSiF solutions is shown in Table 10. Compound 1 A form is very soluble with a maximum strength of 9 mg, and its solubility is even higher in more acidic media.

[0079]

Table 10

[0080] The analytical and physical characteristics described above demonstrate that the compound 1 free base A form is a stable, non-hygroscopic anhydrous polymorph of the compound 1 free base that exhibits acceptable solubility in the simulated medium. The analysis results indicate that the solid form is suitable for pharmaceutical development.

[0081] In another aspect, the present invention provides a method for the preparation of the compound 1 free base A form, comprising: a) preparing a solution of the compound 1 free base in any suitable solvent; b) evaporating a portion of the solvent to obtain a suspension; c) stirring the slurry; d) isolating the compound 1 free base A form and providing a method.

[0082] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0083] Step b) includes evaporation of the solvent by any suitable technique, including a rotary evaporation device, such as a rotary evaporator, an open reactor, or any other suitable technique. The evaporation can be induced by an increase in temperature, or a decrease in pressure, or a combination thereof.

[0084] Step c) involves stirring the slurry by any suitable technique including a reflux, room temperature, any suitable temperature including 0 to 5 °C or any other suitable temperature, using any suitable stirrer, stir bar or shaker.

[0085] Isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0086] In another aspect, the present invention provides a method for the preparation of Compound 1 free base A type, comprising: a) preparing a solution of Compound 1 free base in any suitable solvent; b) cooling the solution to obtain a slurry; c) stirring the slurry; d) isolating Compound 1 free base A type and providing a method.

[0087] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or a mixture thereof.

[0088] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50 °C, 40 °C, room temperature, etc.

[0089] Step b) involves cooling the solution to a lower temperature than in step a), such as room temperature or 0 to 5 °C, or any suitable temperature.

[0090] Step c) involves stirring the slurry by any suitable technique including a stir bar, a stirring rod, or a shaker at the temperature set in step b) or a temperature below it.

[0091] Isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0092] In another aspect, the present invention provides a method for the preparation of compound 1 free base type A, comprising: a) preparing a suspension of the solid form of compound 1 free base in any suitable solvent; b) stirring the slurry; c) isolating compound 1 type A and providing a method.

[0093] In step a), the solid form of compound 1 free base may be type B or type D or type A, or any mixture thereof. The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0094] Step b) involves stirring the slurry by any suitable technique including a stir bar, a stirring rod, or a shaker at any suitable temperature including reflux, room temperature, 0 to 5 °C, or any other suitable temperature.

[0095] The isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0096] In another aspect, the present invention provides a method for the preparation of Compound 1 free base A-type, comprising: a) preparing a solution of Compound 1 free base in any suitable solvent; b) mixing the solution with a poor solvent to obtain a slurry; c) stirring the slurry; d) isolating Compound 1 free base A-type. The solvent used in step a) and the poor solvent in step b) are selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0097] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50 °C, 40 °C, room temperature, etc.

[0098] The mixing of the solution in step b) can be carried out by adding the solution to the poor solvent or by adding the poor solvent to the solution. The addition may be uncontrolled or controlled by any suitable technique.

[0099] Step c) includes stirring the slurry by any suitable technique including a stir bar, stir rod or shaker at the temperature set in step b) or below.

[0100] ​

[0101] The isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0102] In another aspect, the present invention is a method for the preparation of the free base B form of Compound 1, comprising: a) preparing a solution of the free base of Compound 1 in any suitable solvent; b) mixing the solution with a poor solvent to obtain a slurry; d) isolating the B form of Compound 1 and providing a method.

[0103] The solvent used in step a) and the poor solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof.

[0104] The temperature of the solution can be any suitable temperature, e.g., the reflux temperature of the solvent, 50 °C, 40 °C, room temperature, etc.

[0105] The mixing of the solution in step b) can be carried out by adding the solution to the poor solvent or by adding the poor solvent to the solution. The addition may be uncontrolled or controlled by any suitable technique.

[0106] The isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0107] The X-ray diffraction pattern of Form B of Compound 1 is shown in Figure 28. A detailed list of the peaks is shown in Table 11. The most characteristic peaks of Form B of Compound 1 are 6.1, 16.0, 18.0, 19.2 and 21.5 ± 0.2° 2θ.

[0108] [Table 11] TIFF2025523414000019.tif44170

[0109] Form B of Compound 1 can also be characterized by its FT-IR spectrum. The infrared spectrum of Form B is shown in Figure 29. A detailed list of the absorption bands of Form B of Compound 1 is shown in Table 12.

[0110] [Table 12] TIFF2025523414000021.tif254170

[0111] Form B of Compound 1 can also be characterized by its Raman spectrum. The Raman spectrum of Form B of Compound 1 is shown in Figure 30. A detailed list of the Raman peaks of Form B of Compound 1 is shown in Table 13.

[0112] [Table 13] TIFF2025523414000023.tif95170

[0113] Form B of Compound 1 can also be characterized by its DSC thermogram. A typical DSC thermogram of Form B of Compound 1 is shown in Figure 31. Form B of Compound 1 shows a broad endotherm from 100 to 200 °C before the melting endotherm that starts at 200 - 210 °C.

[0114] In another aspect, the present invention provides a method for preparing the pyridine solvate C form of the free base of Compound 1 by suspending Compound 1 maleate in pyridine, stirring, and isolating the free base of Compound 1 in the form of a white or off-white solid as the C form. Stirring includes stirring the slurry by any suitable technique including a stir bar, stirring rod, or shaker at any suitable temperature including reflux, room temperature, 0 - 5 °C, or any other suitable temperature.

[0115] The X-ray diffraction pattern of the free base of Compound 1 in the C form is shown in Figure 32. A detailed list of peaks is shown in Table 14. The most characteristic peaks of the free base of Compound 1 in the C form are 2.6, 5.3, 16.0, 19.4, and 24.7 ± 0.2 °2θ.

[0116] [Table 14] TIFF2025523414000025.tif111170

[0117] The free base of Compound 1 in the C form can also be characterized by its DSC thermogram. A typical DSC thermogram of the free base of Compound 1 in the C form is shown in Figure 33. The free base of Compound 1 in the C form shows a broad endotherm from 50 - 150 °C prior to the melting endotherm that starts at 200 - 210 °C.

[0118] A typical TGA thermogram of the free base of Compound 1 in the C form is shown in Figure 34. The weight loss of the C form is approximately 10% up to 120 °C.

[0119] Another aspect of the present invention is the hydrate form D of the free base of Compound 1.

[0120] A further aspect of the present invention is a crystalline solid form of the free base of Compound 1 comprising at least 5%, at least 10%, at least 20%, at least 40%, at least 60%, at least 80%, at least 90%, at least 95%, at least 99% of the free base of Compound 1 in the D form.

[0121] The X-ray diffraction pattern of Compound 1 free base D form is shown in Figure 35. A detailed list of peaks is shown in Table 15. The most characteristic peaks of Compound 1 free base D form are 8.1, 18.4, 18.8, 19.0 and 20.4 ± 0.2° 2θ.

[0122] [Table 15] TIFF2025523414000027.tif247170

[0123] Compound 1 free base D form can also be characterized by its FT-IR spectrum. The infrared spectrum of the D form is shown in Figure 36. A detailed list of the absorption bands of Compound 1 free base D form is shown in Table 16. The most characteristic absorption bands of Compound 1 free base D form are 3515, 3243, 2869, 2829 and 1650 ± 4 cm -1 -1.

[0124] [Table 16] TIFF2025523414000029.tif254170TIFF2025523414000030.tif58170

[0125] Compound 1 free base D form can also be characterized by its Raman spectrum. The Raman spectrum of the D form is shown in Figure 37. A detailed list of the Raman peaks of Compound 1 free base D form is shown in Table 17. The most characteristic Raman peaks of Compound 1 free base D form are 1644, 1552, 1539, 1301, 1257 ± 4 cm -1 -1.

[0126] [Table 17] TIFF2025523414000032.tif179170

[0127] The D-form of the free base of Compound 1 can also be characterized by its DSC thermogram. A typical DSC thermogram of the D-form of the free base of Compound 1 is shown in Figure 38. The D-form of the free base of Compound 1 shows a broad endotherm from 50 to 110 °C prior to the melting endotherm that starts at 200 to 210 °C.

[0128] The D-form of the free base of Compound 1 is in the hydrated form, and its TGA thermogram shows a characteristic weight loss of 4.1% at 50 to 110 °C. A typical TGA thermogram of the D-form of the free base of Compound 1 is shown in Figure 39. The water content of the sample was confirmed by Karl Fischer titration (4.6%).

[0129] In another aspect, the present invention provides a method for the preparation of the D-form of the free base of Compound 1, comprising: a) preparing a solution of the free base of Compound 1 in any suitable solvent; b) mixing the solution with water to obtain a slurry; c) stirring the slurry; d) isolating the D-form of the free base of Compound 1 and providing a method.

[0130] The solvent used in step a) is selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, acetone, butanone, 2-pentanone, 3-pentanone, acetonitrile, tetrahydrofuran, 2-methoxyethanol, or mixtures thereof.

[0131] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50 °C, 40 °C, room temperature, etc.

[0132] The mixing of the solution in step b) can be carried out by administering the solution to the poor solvent or by administering the poor solvent to the solution. The administration may be uncontrolled or controlled by any suitable technique.

[0133] Step c) involves stirring the slurry by any suitable technique including a stir bar, stirring rod or shaker at a temperature set in step b) or below.

[0134] Isolation of the product may be carried out under ambient conditions or in an inert atmosphere (e.g., nitrogen). The product is a white or off-white solid.

[0135] For analytical studies, the following experimental conditions were used.

[0136] Parameters of FT-IR spectroscopic measurement : Equipment: Thermo-Nicolet 6700 Phase: KBr tablet Spectral resolution: 4 cm -1 Detector: DTGS Beam splitter: XT-KBr Mirror movement speed: 0.6329 Number of scans: 100

[0137] Parameters of FT-Raman spectroscopic measurement: Equipment: Thermo-Nicolet NXR9650 Measurement range: 3500~200 cm -1 Spectral resolution: 4 cm -1 Detector: Ge Beam splitter: CaF2 Mirror movement speed: 0.1581 Number of scans: 256 Laser performance: 500 mW

[0138] Parameters of powder X-ray diffraction measurement: Equipment: PANanalytical X’Pert PRO MPD Irradiation: CuKα Accelerating voltage: 40 kV Anode current: 40 mA Goniometer: PW3050 / 60 Scanning speed: 0.0305 seconds Increment: 0.0131° Sample holder: PW1818 / 25&40 (transmission, sample between foils) Sample holder spinner: PW3064 / 60 (reflection / transmission spinner) Rotation speed of the sample holder: 1 rotation / second Detector: PIXcel (PW3018 / 00) Uncertainty of 2θ measurement: ±0.2°

[0139] Parameters of TGA measurement: Instrument: TA Instruments TGA Q5000 or Discovery TGA 5500 Heating rate: 10 °C / min Sample weight: approximately 2 - 10 mg Atmosphere: N2 at 60 mL / min

[0140] Parameters of DSC measurement: Instrument: TA Instruments DSC Q1000 or Discovery DSC 2500 Heating rate: 10 °C / min Sample weight: approximately 1 - 3 mg Type of pan: open Al pan Atmosphere: N2 at 50 mL / min

[0141] Analysis method of solubility Approximately 2 - 2 mg (N = 5) of the test substance was weighed into a transparent test container, and 300 μL of solvent was added thereto. The test container was placed on a mechanical shaker and shaken during an incubation time of 24 hours at 37 °C, filtered, and the concentration of Compound 1 in the filtrate was determined by HPLC - MS (6410 QQQ - MS, Agilent1200 liquid chromatograph equipped with a Kinetex EVO C18 column).

[0142] HPLC method for purity analysis Approximately 10 to 10 mg of the test substance was weighed into a 10 mL volumetric flask and dissolved in a mixture of formic acid, acetonitrile, and water. 1 mL of this solution was diluted to 100 mL using the solvent mixture in a 100 mL volumetric flask. The diluted solution was then injected into a Waters Acquity H-Class UPLC instrument using an Acquity CSH column.

[0143] The physicochemical and biopharmaceutical characteristics of the active substance are important from the perspective of in vivo and in vitro behavior. Ideally, for oral solid dosage forms, water-soluble, non-hygroscopic, stable, and easily processable crystalline compounds are preferred for development purposes. The physicochemical and formulation-related characteristics of the compounds 1 and their hydrochloride salts and crystalline forms disclosed herein can be further characterized by the following methods.

[0144] Crystal habit: Crystalline polymorphic materials can exist in several shapes or forms (sometimes called "habits") depending on the method and solvent used for the final crystallization. This can range from very angular crystals of an elongated shape, needle-shaped crystals, and flat plate-like forms to more spherical habits. Those shapes can affect the flowability of the bulk powder, for example, during discharge from a container / hopper, due to mechanical and physical interactions or adhesion between the particles. The shape of drug particles can be characterized, for example, by polarized light microscopy (PLM).

[0145] Particle size distribution: A narrow range and single-modal particle size distribution of the drug substance are advantageous from the perspective of drug formulations. The measurement of the particle size distribution can be performed, for example, by laser diffraction and polarized light microscopy.

[0146] The specific surface area of the solid form can be determined by gas absorption (e.g., BET) or gas permeability methods.

[0147] Dissolution: Solubility is important for selecting salt forms or specific crystalline or polymorphic forms that can affect the dissolution rate, which is the most important parameter. Dissolution is the process by which a substance forms a solution. Dissolution tests measure the extent and rate of solution formation from dosage forms such as tablets, capsules, ointments, etc. The dissolution of a drug is important for its bioavailability and therapeutic efficacy. Dissolution and drug release are terms used interchangeably. Differences in solubility and dissolution between polymorphs can have a significant impact on the oral bioavailability of pharmaceuticals (dissolution and absorption from the GI tract).

[0148] Flowability: The two most common solid dosage forms, tablets and capsules, have their own specific requirements but also have similarities. Both require the accurate flow of the weight of the material into a specific volume. Good flow characteristics are essential for the success of the manufacture of both tablets and powder-filled hard gelatin capsules or sachets. The European Pharmacopoeia (Ph.Eur.) includes tests for the flowability of powders based on how the powder flows vertically from a funnel. There are several different methods available for determining the flow characteristics of powders, and there are examples in the literature of corrections between test methods and demonstrating the manufacturing characteristics of formulations.

[0149] Bulk density is an essential parameter for pharmaceutical product and process development, as well as for the manufacture of solid dosage forms. It is used in determining the amount of powder that can fill a space such as a blender or hopper in a tablet press or capsule filling machine. It is used to determine the amount of powder that can be filled into a capsule of a specific volume.

[0150] The tapped bulk density, or simply the tap density, is the maximum packing density of a powder (or blend of powders) achieved under the influence of a well-defined externally applied force. The minimum packed volume thus achieved depends on several factors including particle size distribution, true density, particle shape, and adhesion due to surface forces including moisture. Thus, the tap density of a material can be used to predict both its flow characteristics and its compressibility.

[0151] The term "disease or condition associated with MCHR1 activity" refers to obesity, obesity-related complications and comorbidities, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, endocrine disorders, psychiatric conditions, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal disorders, chronic conditions of the musculoskeletal system, osteoporosis, and cancer.

[0152] A parallel patent application filed by the applicant under the name "MCHR1 antagonists for the treatment of Prader-Willi syndrome" is hereby incorporated by reference herein, which discloses a method for treating Prader-Willi syndrome using a compound of formula (I) as described in WO2016 / 166684A1, for example, compound 1 in free form or in pharmaceutically acceptable salt form, such as its hydrochloride salt.

[0153] The term "pharmaceutical composition" refers to a mixture of compound 1 A-type, compound 1 D-type, compound 1 hydrochloride, crystalline form of compound 1 hydrochloride, or compound 1 hydrochloride A-type with other chemical components, such as pharmaceutically acceptable excipients, such as diluents or carriers. The pharmaceutical composition facilitates the administration of the compound to the subject.

[0154] The term "excipient" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.

[0155] The pharmaceutical compositions of the present invention can be formulated in many ways, for example, as tablets, capsules, powders, granules, suspensions, emulsions, solutions, syrups, aerosols (with solid or liquid carriers), soft or hard gelatin capsules, suppositories, and sterile forms of injectables. Preferably, the pharmaceutical compositions are formulated as tablets or capsules.

[0156] The pharmaceutical composition can be a single dosage form containing a given amount of active ingredient.The dosage can contain a therapeutically effective amount or a given percentage of the therapeutically effective amount of compound 1 type A, compound 1 type D, compound 1 hydrochloride, compound 1 hydrochloride in crystalline form, or compound 1 hydrochloride type A, in such a way that these single dosage forms for repeated administration can be administered over a given period of time to reach a desired therapeutically effective dose.Preferred single dosage forms are those that contain a daily dose or divided dose, or a given percentage of the active ingredient as described above.Furthermore, these pharmaceutical compositions can be prepared by methods known in the art.

[0157] The term "therapeutically effective amount" refers to an amount of active ingredient that results in the treatment, cure, prevention, reduction or amelioration of one or more symptoms of a disease, condition, side effect, disease, such as overeating, for maintaining or reducing body weight, or reducing food intake, or for inhibiting or delaying the progression of one or more symptoms of a disease, condition, or disease, such as overeating, compared to a subject not receiving such amount. This term also includes the effective amount required to improve normal physiological function. In therapeutic applications, Compound 1 Type A, Compound 1 Type D, Compound 1 Hydrochloride, Compound 1 Hydrochloride in crystalline form, or Compound 1 Hydrochloride Type A can be administered in a therapeutically effective amount as an unformulated bulk, or the active ingredient can be formulated as a pharmaceutical. The exact therapeutically effective amount of such a compound depends on several factors, including, but not limited to, the age and weight of the subject (patient) being treated, the type and severity of the disease being treated, the type of pharmaceutical composition / medicine, and the method of administration.

[0158] The term "daily dose" refers to the amount of free base administered per day. In the case of administering a pharma-ceutically acceptable salt, the daily dose is also expressed as the equivalent amount of free base.

[0159] In certain embodiments, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, a crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride Form A is a daily dose of at least about 2.5 mg.

[0160] In another embodiment, a therapeutically effective amount of Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type is a daily dosage of about 2.5 mg to about 22.5 mg.

[0161] In a preferred embodiment, a therapeutically effective amount of Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type is a daily dosage of about 2.5 mg to about 7.5 mg.

[0162] In a particularly preferred embodiment, a therapeutically effective amount of Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type is a daily dosage of about 2.5 mg, about 5 mg or about 7.5 mg.

[0163] The term "effective amount" refers to the amount of a drug or active ingredient that is sufficient to elicit a biological or medical response of a tissue, system, animal (including human), as desired by, for example, a researcher or clinician, in the subject to which it is administered.

[0164] The term "subject" refers to a patient who requires any one of Methods 1.1 to 1.7 as defined below in this specification.

[0165] Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type can be administered by any suitable route, for example, orally, transdermally, percutaneous, subcutaneously, topically, intravenously, intramuscularly, or intranasally. The preferred route of administration is oral.

[0166] In a further series of more specific or alternative embodiments, the present invention provides the following. 1.1. A method for treating a disease or condition associated with MCHR1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 Type A, Compound 1 Type D, Compound 1 Hydrochloride, the crystalline form of Compound 1 Hydrochloride, or Compound 1 Hydrochloride Type A as defined herein. 1.2. A method for treating Prader-Willi syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 Type A, Compound 1 Type D, Compound 1 Hydrochloride, the crystalline form of Compound 1 Hydrochloride, or Compound 1 Hydrochloride Type A as defined herein. 1.3. A method for improving, alleviating, or delaying the progression of one or more symptoms of PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 Type A, Compound 1 Type D, Compound 1 Hydrochloride, the crystalline form of Compound 1 Hydrochloride, or Compound 1 Hydrochloride Type A as defined herein. 1.4. A method for maintaining body weight in a patient suffering from PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 Type A, Compound 1 Type D, Compound 1 Hydrochloride, the crystalline form of Compound 1 Hydrochloride, or Compound 1 Hydrochloride Type A as defined herein. 1.5. A method for reducing body weight in a patient suffering from PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 Type A, Compound 1 Type D, Compound 1 Hydrochloride, the crystalline form of Compound 1 Hydrochloride, or Compound 1 Hydrochloride Type A as defined herein. 1.6. A method for reducing food intake in a patient suffering from PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 Type A, Compound 1 Type D, Compound 1 Hydrochloride, the crystalline form of Compound 1 Hydrochloride, or Compound 1 Hydrochloride Type A as defined herein. 1. A method for treating binge eating in patients suffering from 1.6.PWS, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type as defined herein. 1.7. The method as set forth above, wherein Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type is administered once daily. A pharmaceutical composition for use in any one of Methods 1.1 - 1.7, comprising Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type as defined herein, together with one or more pharmaceutically acceptable excipients. Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type as defined herein, for use in any one of Methods 1.1 - 1.7. Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type as defined herein, for use in the preparation of a medicament for any one of Methods 1.1 - 1.7. Use of Compound 1 A-type, Compound 1 D-type, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride A-type as defined herein, for any one of Methods 1.1 - 1.7.

[0167] In particular, Compound 1 hydrochloride A-type as described herein is useful for treating binge eating in patients suffering from PWS.

[0168] Without in any way limiting the scope of protection of the present invention to the above-described examples, further details of our invention are shown in the following examples. Unless specifically indicated in each individual example, the starting materials for the following examples were prepared according to Example 20(a) - Compound 1 free base, or 20(b) - Compound 1 maleate of WO2016 / 166684.

Examples

[0169] Reference Example Reference Example 1 Compound 1 maleate solvate derived from ethanol To a solution of 0.47 g (1.015 mmol) of Compound 1 (Example 20 / a of WO2016 / 166684) in a 10:1 mixture of dichloromethane and methanol, 0.13 g (1.117 mmol) of maleic acid was added and the mixture was concentrated. The residue was triturated with ethanol, stirred for 1 hour, then the solid product was filtered, washed with ethanol and dried to give 0.57 g (96%) of the title compound. The XRPD pattern of the product is shown in Figure 1. TGA: 3.9% (Figure 10).

[0170] Reference Example 2 Compound 1 maleate solvate derived from ethanol 99.11 mg of Compound 1 maleate was dissolved in 5 ml of ethanol (jacket temperature 70 °C), filtered, the filtrate was cooled to 25 °C, stirred for 30 minutes, filtered, and left to dry at room temperature for 4 days. The XRPD pattern of the product is shown in Figure 2. TG: 5.1% (Figure 11)

[0171] Reference Example 3 Compound 1 maleate solvate derived from dichloromethane / ethanol Dissolve 0.231 kg of 4-[(5-chloropyridin-2-yl)methoxy]-l-{lH,2H,3H,4H,5H-[l,4]diazepino[l,7-a]indol-9-yl}-l,2-dihydropyridin-2-one (Example 4 of WO2016 / 166684) in 20 l of acetonitrile, add 0.3 kg of K2CO3 and 520 ml of 2-iodopropane, stir at reflux for 10 hours, and isolate the product by evaporation of the solvent (100 mbar, 40 - 45 °C). Dissolve the crude product in 1.1 L of dichloromethane, wash with 3 × 1 l of water, and isolate the crude base by evaporation of the solvent (100 mbar, 40 - 45 °C). Dissolve the solid in 1.5 l of dichloromethane and add thereto a solution of 65 g of maleic acid in 3.6 l of ethanol. Concentrate the suspension by evaporating 3.1 l of the solvent, add 2 l of ethanol, evaporate a further 1.5 l, stir the resulting suspension at 20 - 25 °C for 1 hour, cool to 10 - 12 °C, stir for 1 hour, filter, wash with 2 × 0.5 l of ethanol, and dry at 75 - 80 °C for 7 hours to obtain 0.197 kg of a white solid. The XRPD pattern of the product is shown in Figure 3. TGA: 4.1% (Figure 12).

[0172] Reference Example 4 Compound 1 maleate solvate derived from methanol Suspend 40 mg of the maleate of Compound 1 in 1 ml of methanol, stir for 1 week, filter, and dry under ambient conditions. The XRPD pattern of the product is shown in Figure 4. TGA: 5.5% (Figure 13).

[0173] Reference Example 5 Compound 1 maleate solvate derived from ethanol Suspend 40 mg of the maleate of Compound 1 in 1 ml of ethanol, stir for 1 week, filter, and analyze by XRPD. The XRPD pattern of the product is shown in Figure 5. TGA: 4.7% (Figure 14)

[0174] Reference Example 6 Compound 1 maleate solvate derived from ethanol A solution of 0.47 g (1.015 mmol) of Compound 1 in a 10:1 mixture of 5 ml of dichloromethane and methanol was added to a solution of 0.13 g of maleic acid in 3.5 ml of the same solvent, and the mixture was evaporated by a Rotavapor (500 - 350 mbar, 40 °C). To the solid residue, 1.9 ml of ethanol was added, stirred for 1 hour, filtered, and left to dry at room temperature. The XRPD pattern of the product is shown in Figure 6. TGA: 1.9% (Figure 15).

[0175] Reference Example 7 Compound 1 maleate solvate derived from methanol 50 mg of the maleate of Compound 1 was dissolved in 1 ml of methanol, and the solvent was evaporated at room temperature. The XRPD pattern of the solid is shown in Figure 7. TGA: 4.3% (Figure 16).

[0176] Reference Example 8 Compound 1 maleate solvate derived from methanol 101 mg of the maleate of Compound 1 was suspended in 2.5 ml of methanol, stirred for 1 week, filtered, and analyzed by XRPD. The XRPD pattern of the product is shown in Figure 8. The sample was dried at 40 °C overnight. TGA: 2.7% (Figure 17).

[0177] Reference Example 9 Compound 1 maleate solvate derived from DMSO 272 mg of the maleate of Compound 1 was suspended in 0.75 ml of DMSO and stirred at room temperature for 1 week. The solid was filtered and analyzed by XRPD. The XRPD pattern of the product is shown in Figure 9.

[0178] Reference Example 10 0.6 g of Compound 1 was dissolved in a 95:5:0.1 mixture of 5 ml of dichloromethane, methanol and ammonia. The solvent was evaporated by a Rotavapor (40 °C, 500 mbar) to obtain 0.6 g of an off - white powder. Yield: 100%. The XRPD of the product is shown in Figure 40.

[0179] Example Example 1 To a solution of 30 mg of the free base of Compound 1 in 1.2 ml of acetone, 7.5 μl of 37% hydrochloric acid was added dropwise, stirred for 3 hours, filtered, and dried at 40 °C / vacuum. Yield: N / A. The XRPD pattern of the product followed Figure 18, and the moisture content by TGA was 0.6% (up to 200 °C).

[0180] Example 2 To a solution of 3 g of the free base of Compound 1 in 36 ml of dichloromethane, a solution of 0.6 ml of concentrated hydrochloric acid in 36 ml of acetone was added. The resulting suspension was cooled to 0 °C and stirred for 3 hours. The solid was filtered, washed with acetone, and dried at 60 °C to obtain 3.10 g of Compound 1 hydrochloride. Yield: 96%. The XRPD pattern, FT-IR and FT-Raman spectra, DSC, and TGA curves of the product are shown in Figures 18 - 22.

[0181] Example 3 5.23 g of crude Compound 1 free base was dissolved in a mixture of 30 ml of dichloromethane, 15 ml of ethanol, and 15 ml of toluene and concentrated by evaporation. The product was purified by column chromatography using Kieselgel 60 (0.040 - 0.063 mm) as the adsorbent and a 95:5:0.1 mixture of dichloromethane, methanol, and concentrated NH3 solution as the eluent. The eluent was removed (Rotavapor), the product was resuspended in ethanol, dried, resuspended in diethyl ether, and filtered to obtain 1.24 g of white crystals. The XRPD pattern of the product, which was found to be a mixture of Compound 1 Form B and Compound 1 Form A, is shown in Figure 41.

[0182] Example 4 100 mg of the free base of Compound 1, which is a mixture of Form A and Form B, was suspended in 2 ml of ethanol and stirred at room temperature for 1 week. The solid was filtered and identified as Compound 1 Form A by XRPD.

[0183] Example 5 96.76 mg of Compound 1 was dissolved in 11 ml of ethanol under reflux, cooled, and stirred for approximately 3 days to obtain a white precipitate identified as Compound 1 free base A-type. The XRPD pattern of the product followed that of Figure 23.

[0184] Example 6 83.5 mg of Compound 1 free base was dissolved in 15 ml of acetonitrile, stirred in an open vial for 2 days, and the solid was filtered to obtain a white to off-white precipitate identified as Compound 1 free base A-type. The XRPD pattern of the product followed that of Figure 23.

[0185] Example 7 1.17 g of Compound 1 free base was dissolved in 13.2 ml of dichloromethane, 2 ml of the solution was added to 2 ml of tetrahydrofuran, and stirred overnight to obtain a white precipitate identified as Compound 1 free base A-type. The XRPD pattern of the product followed that of Figure 23.

[0186] Example 8 1.17 g of Compound 1 free base was dissolved in 13.2 ml of dichloromethane, 2 ml of the solution was added to 2 ml of methyl tert-butyl ether to obtain a white precipitate identified as Compound 1 free base B-type. The XRPD pattern of the product followed that of Figure 28.

[0187] Example 9 51.20 mg of Compound 1 maleate was suspended in 1.5 ml of pyridine and stirred for 1 week. The solid was filtered and dried in vacuo at 40 °C to obtain Compound 1 free base C-type. The XRPD pattern of the sample is shown in Figure 32. TGA: 10.3% (Figure 34). NMR: Compound 1 having 0.4 mol of pyridine and 0.15 mol of maleic acid was confirmed. Melting of A-type was detected by DSC (Figure 33).

[0188] Example 10 131.5 g of Compound 1 free base was dissolved in 18.5 ml of dichloromethane, and 1.2 ml of this solution was added to 1 ml of n-hexane containing 17 μl of concentrated HCl. The solid was filtered and dried at 40 °C. The XRPD pattern of the sample was confirmed as Compound 1 D-form according to Figure 35. TGA: 4.1% (215 °C).

[0189] Example 11 A solution of 1 g of Compound 1 free base in 50 ml of tetrahydrofuran under reflux was added to 150 ml of water, stirred for 1 hour, filtered, and washed with water. The XRPD pattern of the sample follows Figure 35.

[0190] Preparation of pharmaceutical composition The following formulation examples show representative pharmaceutical compositions of the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0191] A) Solid oral dosage forms Tablets or capsules or filled sachets Active substance 0.005 - 90% Filler 0.1 - 99.9% Binder 0 - 20% Disintegrant 0 - 20% Lubricant 0 - 10% Glidant 0 - 10% Other specific excipients 0 - 50%

[0192] B) Parenteral dosage forms Intravenous injection Active substance 0.001 - 50% Solvent 10 - 99.9% Cosolvent 0 - 99.9% Osmotic agent 0 - 50% Buffer q.s.

[0193] C) Other dosage forms Suppositories Active substance 0.0003 - 50% Suppository base 1 - 99.9% Surfactant 0 - 20% Lubricant 0 - 20% Preservative q.s.

Claims

1. 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one hydrochloride, It contains 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one hydrochloride type A, and the following analytical properties in the solid state: a. Characteristic XRPD peaks are present at 9.2, 12.5, 14.5, 15.1, 15.8 and 17.4°²θ (±0.2°) when measured at CuKα wavelength, and / or b. Characteristic peaks in its Raman spectrum are at 1549, 1344, 1303, 1257, and 747 cm⁻¹. －１ ±4cm －１ The values ​​in the range exist, and / or c. Characteristic absorption bands are located at 2474, 2524, 1668, 1479, and 1222 cm⁻¹ in its infrared spectrum. －１ (±4cm) －１ ) exists within the range of values A salt characterized by one or more of the following.

2. The salt according to claim 1, wherein the salt is in a crystalline form.

3. The salt according to claim 1, wherein the salt contains at least 5% of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one hydrochloride type A.

4. The salt according to claim 1, wherein the salt contains at least 20% of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one hydrochloride type A.

5. The salt according to claim 1, wherein the salt contains at least 60% of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one hydrochloride type A.

6. The salt according to claim 1, wherein the salt contains at least 80% of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one hydrochloride type A.

7. The salt according to claim 1, wherein the salt comprises at least 95% of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one hydrochloride type A.

8. A pharmaceutical composition comprising the hydrochloride salt solid form of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one according to claims 1 to 7, and a pharmaceutically acceptable carrier.

9. A method for preparing the salt according to any one of claims 1 to 7, a) the step of preparing a solution of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one in any suitable solvent; b) a step of mixing the solution from step a) with an HCl solution; c) The step of stirring the resulting slurry; d) A step to isolate 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one hydrochloride Includes, The solvent used in steps a) and b) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene chloride, ethylene chloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof. method.

10. A method for preparing the salt according to any one of claims 1 to 7, a) the step of preparing a solution of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one HCl salt in any suitable solvent; b) A step of evaporating a portion of the solvent to obtain a suspension; c) The step of stirring the resulting slurry; d) A step to isolate 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one HCl salt type A and Includes, The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene chloride, ethylene chloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof. method.

11. A method for preparing the salt according to any one of claims 1 to 7, a) the step of preparing a solution of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one HCl salt in any suitable solvent; b) A step of cooling the solution to obtain a slurry; c) The step of stirring the slurry; d) A step to isolate 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one HCl salt type A and Includes, The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene chloride, ethylene chloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof. method.

12. A method for preparing the salt according to any one of claims 1 to 7, a) the step of preparing a solution of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one HCl salt in any suitable solvent; b) The step of mixing the solution with a poor solvent to obtain a slurry; c) The step of stirring the slurry; d) A step to isolate 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one HCl salt type A and Includes, The solvent used in step a) and the poor solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene chloride, ethylene chloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl t-butyl ether, or mixtures thereof. method.

13. A solid form of 4-[(5-chloropyridine-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole-9-yl]-1,2-dihydropyridine-2-one or its hydrochloride salt, as described in any one of claims 1 to 7, for use in the treatment / prevention of diseases or conditions associated with melanin-concentrating hormone receptor 1 activity.

14. The solid form according to claim 13, wherein the disease or condition associated with the melanin-concentrating hormone receptor 1 activity is selected from the group consisting of obesity, obesity-related complications and conditions, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, endocrine disorders, psychiatric conditions, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal disorders, chronic musculoskeletal conditions, osteoporosis, cancer, and Prader-Willi syndrome.

15. The solid substance according to claim 14, wherein the disease or condition associated with the melanin-concentrating hormone receptor 1 activity is Prader-Willi syndrome, preferably improving one or more symptoms of Prader-Willi syndrome, and preferably one or more symptoms of Prader-Willi syndrome is overeating.

Images