Crystal forms of 4-[(5-chloropyridine-2-yl) methoxy]-1-[3-(propane-2-yl)-1H, 2H, 3H, 4H, 5H-[1, 4] diazacyclohepta [1, 7-a] indol-9-yl]-1, 2-dihydropyridine-2-one and salt thereof, preparation method and application thereof

Abstract

The invention relates to a hydrochloride of 4-[(5-chloropyridine-2-yl) methoxy]-1-[3-(propan-2-yl)-1H, 2H, 3H, 4H, 5H-[1, 4] diazacyclohepta [1, 7-a] indol-9-yl]-1, 2-dihydropyridine-2-one (compound 1), a preparation method of the hydrochloride, and a preparation method of the hydrochloride. The pharmaceutical composition can be used for treating and / or preventing obesity, co-diseases and complications related to obesity, diabetes, metabolic disorders, coronary artery diseases, cerebrovascular diseases, peripheral artery diseases, hypertension, endocrine dyscrasia, mental disorders, personality disorders, eating disorders, sleep-awakening cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, and the like. Potent oral active selective melanin aggregation hormone receptor 1 (MCHR1) antagonists for treating diseases of the gastrointestinal tract, chronic diseases of the musculoskeletal system, osteoporosis, cancer, and one or more symptoms of Prallard-Wili Syndrome (PWS) or PWS. The present invention also relates to crystalline forms of 4-[(5-chloropyridin-2-yl) methoxy]-1-[3-(propan-2-yl)-1H, 2H, 3H, 4H, 5H-[1, 4] diazepane [1, 7-a] indol-9-yl]-1, 2-dihydropyridin-2-one in the form of a free base, different crystalline forms of the hydrochloride thereof, processes for their preparation, pharmaceutical compositions thereof and therapeutic uses thereof.

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]diazepine[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 for treating and / or preventing obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, psychiatric disorders, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic disorders of the musculoskeletal system, osteoporosis, cancer, and Prader-Willi Syndrome (PWS) or one or more symptoms of PWS. The present disclosure also relates to crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in the form of a free base, different crystalline forms of its hydrochloride salt, methods for preparing the same, pharmaceutical compositions thereof, and therapeutic uses thereof. Prior art

[0002] MCHR1 antagonists, including 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in free base form (as shown below, hereinafter referred to as Compound 1) and its maleate salt are reported in WO 2016 / 166684 A1.

[0003]

[0004] 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 attracted much attention for its effects on food intake and body weight, and its receptor MCHR1 remains one of the viable targets for obesity therapy (Pissios P., Peptides 2009, 30(11): 2040-2044). MCH is one of the most potent central stimulants of feeding, regulating 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 caused by the absence of imprinted gene expression in the paternally derived region of chromosome 15q11.2-q13. PWS is the most common syndromic cause of life-threatening obesity, with an estimated incidence of 1 / 10,000 to 1 / 25,000 live births, occurring equally in both males and females, and across all ethnicities. Syndromic obesity caused by severe overeating is derived from the neurodevelopmental consequences of a deletion of the small nucleolar C / D box RNA 116 (SNORD116) cluster that is always involved in cases of paternal copy deletion (as it has been shown to be the smallest deleted region) (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., OpenBiology 2020,10:200195).Overeating, a key behavioral symptom in PWS, has a significant impact on the well-being of patients and caregivers that goes far beyond weight gain alone. Management of overeating is ranked highest among caregivers in the priority of PWS treatment goals. Uncontrolled appetite, weight gain, and impaired reproductive capacity in PWS can be explained by overactive MCH neurons due to a loss of "checks and balances" caused by reduced ORX numbers in the lateral hypothalamus. Preventing MCH overactivity is most likely to improve MCH-ORX balance, which may ultimately help patients reduce eating-related symptoms. According to the latest preclinical reports, the MCH-MCHR1 system is overactive due to impaired ORX control, and PWS patients may benefit from MCHR1 antagonist treatment to 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. Meatabolism 2020, 36: 100977; Linehan et al., J. Physiol 2022, 596: 305-316). Thus, MCHR1 antagonists may be used to treat diseases or conditions associated with melanin concentrating hormone receptor 1 activity, such as obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, psychiatric disorders, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic disorders of the musculoskeletal system, osteoporosis, cancer, as well as for PWS or for one or more symptoms of PWS.

[0005] For the purpose of drug formulation and patient administration, it is necessary to provide Compound 1 in a suitable form. However, solid forms of Compound 1 and its pharmaceutically acceptable salts, such as crystalline forms, cocrystals or pseudo-polymorphs / solvatomorphs, have not been characterized in the prior art.

[0006] Polymorphism is the ability of a compound to exist in two or more different crystalline phases with different molecular arrangements in the crystal lattice (J. Bernstein (2002) Polymorphism in molecular Crystals, Oxford Univ. Press. p. 2-4). Although polymorphs have the same chemical composition, they differ in packing and geometric arrangement and exhibit different physical properties, such as melting point, X-ray diffraction pattern, crystal habit, density, stability, solubility, mechanical properties (such as hardness, compactibility, tableting properties, flowability, blending), rheological parameters, etc.

[0007] Extensive research has been conducted in the pharmaceutical industry to develop different polymorphs of various APIs (R. Hilfiker (ed., 2006) Polymorphism in the Pharmaceutical Industry, Wiley-VCH, pp. 1-15) to obtain suitable polymorphs or pseudopolymorphs with improved performance characteristics. A general requirement for active ingredients in the development of pharmaceutical compositions is that the active ingredients have appropriate physical, physicochemical and chemical parameters. Examples of such parameters include solubility, particularly water solubility. Another important feature to be considered in industrial-scale production is easy handling and good separability, which are extremely important for the economic benefits of the manufacturing process. Another important aspect is that the solid form of the active ingredient has appropriate physical and chemical stability, such as non-hygroscopicity, and no significant degradation. In addition, different polymorphic forms of a given salt may have different solid phase characteristics, physical and chemical stability. To date, there is no reliable method that can clearly predict the actual number of different solid forms that can physically exist in a given compound of a given new chemical entity. This also applies to all the complex physical and chemical properties that need to be considered when predicting drug development for a given form. Therefore, exploring polymorphic morphology of compounds and discovering and making true existing solid forms remain experimental challenges and an important area of ​​invention in the pharmaceutical field.The search for new solid forms of compounds with favorable pharmaceutical properties is highly desirable.

[0008] Pseudopolymorphism is the ability of a compound to coexist with different solvents in two or more different crystalline phases. It is generally recommended not to use a solvent that can form a solvate with a specific compound during the crystallization process to prepare the compound (Hilfiker et al. (2019), Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; Pages 245-246; Wiley-VCH). In addition, in addition to hydrates for pharmaceutical development, the use of solvated forms is highly disadvantageous because trace organic solvents may be harmful (Bhatia et al. (2018), Dosage form design parameters, Chapter 2.2.2.: Crystal solvates and hydrates, Elsevier). In addition, it is known that solvate forms show variable compositions, which may lead to reproducibility and long-term stability problems.

[0009] International patent application WO 2016 / 166684 provides a method for preparing a maleate salt of Compound 1. Reproduction of Example 20(b) of WO 2016 / 166684 confirmed that the isolated crystalline solid was an ethanol solvate, which was not suitable for drug development.

[0010] Additional experiments confirmed that the maleate salt of compound 1 showed an increased tendency to form solvated forms, showing various pseudo-polymorphs in different organic solvents such as methanol, ethanol, dichloromethane, dimethyl sulfoxide, etc. The common feature of such solvated forms is the increased solvent content (higher than 1% by thermogravimetric analysis (TGA)). The increased tendency to form new polymorphs, especially solvates, represents the risk of polymorph transformation or composition change during storage or drug formulation. Thus, it is unfavorable to use the maleate salt of compound 1 in drug products. Therefore, it is desirable to provide an improved form of compound 1 suitable for drug formulation and administration to humans.

[0011] International patent application WO 2016 / 166684 also provides for the separation of compound 1 as a free base. Re-experimental studies have shown that the product of Example 20 (a) in WO 2016 / 166684 is a crystalline form with unfavorable stability properties, i.e., it is a metastable crystalline form (Form B) of a base that is not suitable for drug development. Form B of compound 1 tends to undergo polymorphic transformation when in contact with most solvents and when exposed to heating. Therefore, the use of Form B of compound 1 in a drug product is disadvantageous and does not meet the demand for a suitable solid form of compound 1 for drug formulation and for effective inhibition of MCHR1 and patient-tolerable treatment.

[0012] Apart from the unfavorable maleate and base forms, no other solid forms of Compound 1 have been described in the prior art.

[0013] Therefore, it would be desirable to discover new solid forms of Compound 1 or pharmaceutically acceptable salts thereof that are suitable for drug development and for administration to patients in need of treatment for diseases or conditions associated with melanin concentrating hormone receptor 1 activity and that are tolerable to such patients. Summary of the invention

[0014] The present disclosure is directed to the hydrochloride salt of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[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 for treating and / or preventing obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, psychiatric disorders, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic disorders of the musculoskeletal system, osteoporosis, cancer, and 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, to stable crystalline forms of its hydrochloride salt, methods of making the same, pharmaceutical compositions thereof, and therapeutic uses thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 1.

[0016] Figure 2 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 2.

[0017] Figure 3 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 3.

[0018] Figure 4 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 4.

[0019] Figure 5 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 5.

[0020] Figure 6 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 6.

[0021] Figure 7 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 7.

[0022] Figure 8 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 8.

[0023] Fig. 9 The figure shows the X-ray diffraction pattern of the maleate salt of Compound 1 obtained in Reference Example 9.

[0024] Fig.10 The figure shows the TGA thermogram of the maleate salt of Compound 1 obtained in Reference Example 1.

[0025] Fig.11 The figure shows the TGA thermogram of the maleate salt of Compound 1 obtained in Reference Example 2.

[0026] Fig.12 The figure shows the TGA thermogram of the maleate salt of Compound 1 obtained in Reference Example 3.

[0027] Fig.13 The figure shows the TGA thermogram of the maleate salt of Compound 1 obtained in Reference Example 4.

[0028] Fig.14 The figure shows the TGA thermogram of the maleate salt of Compound 1 obtained in Reference Example 5.

[0029] Fig.15 The figure shows the TGA thermogram of the maleate salt of Compound 1 obtained in Reference Example 6.

[0030] Fig.16 The figure shows the TGA thermogram of the maleate salt of Compound 1 obtained in Reference Example 7.

[0031] Fig.17 The figure shows the TGA thermogram of the maleate salt of Compound 1 obtained in Reference Example 8.

[0032] Fig.18 The figure shows the X-ray diffraction pattern of Compound 1 hydrochloride Form A.

[0033] Fig.19 The figure shows the infrared spectrum of Compound 1 hydrochloride Form A.

[0034] Fig. 20 The figure shows the Raman spectrum of Compound 1 hydrochloride Form A.

[0035] Fig.21 The figure shows the DSC recording curve of Compound 1 hydrochloride type A.

[0036] Fig. 22The figure shows the TGA thermogram of Compound 1 hydrochloride Form A.

[0037] Fig.23 The figure shows the X-ray diffraction pattern of Compound 1 free base Form A.

[0038] Fig.24 The figure shows the infrared spectrum of compound 1 free base form A.

[0039] Fig.25 The figure shows the Raman spectrum of Compound 1 free base Form A.

[0040] Fig.26 The figure shows the DSC curve of the free base form A of compound 1.

[0041] Fig. 27 The figure shows the TGA thermogram of compound 1 free base form A.

[0042] Fig.28 The figure shows the X-ray diffraction pattern of Compound 1 free base Form B.

[0043] Fig.29 The figure shows the infrared spectrum of compound 1 free base form B.

[0044] Fig.30 The figure shows the Raman spectrum of compound 1 free base form B.

[0045] Fig.31 The figure shows the DSC curve of the free base form B of compound 1.

[0046] Fig.32 The figure shows the X-ray diffraction pattern of Compound 1 free base Form C.

[0047] Fig.33 The figure shows the DSC curve of the free base form C of compound 1.

[0048] Fig.34 The figure shows the TGA thermogram of compound 1 free base Form C.

[0049] Fig.35 The figure shows the X-ray diffraction pattern of Compound 1 free base D-form.

[0050] Fig.36 The figure shows the infrared spectrum of the free base D-form of compound 1.

[0051] Fig.37 The figure shows the Raman spectrum of the free base D-form of compound 1.

[0052] Fig.38 The figure shows the DSC curve of the free base D form of compound 1.

[0053] Fig.39The figure shows the TGA thermogram of compound 1 free base D-form.

[0054] Fig.40 The figure shows the X-ray diffraction pattern of the free base of Compound 1 obtained in Reference Example 10.

[0055] Fig.41 The figure shows the X-ray diffraction pattern of the free base of Compound 1 obtained in Example 3. DETAILED DESCRIPTION

[0056] As outlined above, Compound 1 maleate has been found to be disadvantageous for pharmaceutical formulation and for treatment that effectively inhibits MCHR1 and is tolerable to patients.

[0057] International patent application WO 2016 / 166684 provides a method for preparing the maleate salt of compound 1 (reference example 1). By XRPD ( Figure 1 ) The sample was found to be crystalline, but a significant weight loss of 3.9% was detected by TGA. The re-experiment of Example 20(b) of WO2016 / 166684, i.e., Reference Example 2, confirmed that the isolated crystalline solid was an ethanol solvate (TGA: 5.1%).

[0058] In addition to hydrates for drug development, the use of solvated forms is highly disadvantageous because trace amounts of solvents can be harmful (Bhatia et al. (2018), Dosage form design parameters, Chapter 2.2.2.: Crystal solvates and hydrates, Elsevier). Moreover, it is known that solvate forms show variable compositions, which may lead to reproducibility and long-term stability problems. Thus, solvates are generally not suitable for drug development, and it is generally recommended not to use solvents that can form solvates with a particular compound during crystallization to prepare the compound (Hilfiker et al. (2019), Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; Pages 245-246; Wiley-VCH).

[0059] Additional experiments were performed to find suitable polymorphs of the maleate salt of Compound 1 for drug 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 performed to identify stable and solvent-free polymorphs of the maleate salt of Compound 1 (Reference Examples 2-9). Several crystalline forms ( Figure 1-9) However, the residual solvent content (determined by TGA) in all these experiments was above the acceptable limit, indicating that they were solvates ( Figure 10-17 ). The large number of new pseudo-polymorphs combined with the high residual solvent content (higher than 1% by TGA) represent a risk of polymorph conversion or composition changes during storage or pharmaceutical formulation. Therefore, the use of maleate salts of Compound 1 in pharmaceutical products is disadvantageous and a need for different more stable solid forms has emerged.

[0060] As summarized above, the present invention relates to stable crystalline free base and crystalline hydrochloride salts of Compound 1 that are acceptable for pharmaceutical development. The present specification also relates to methods for the identification and preparation of said crystalline forms.

[0061] The crystalline solid phase can be identified by X-ray diffraction: the powder X-ray diffraction pattern or the position of one or more diffraction peaks is characteristic of the crystalline material. Alternatively, vibrational spectroscopy, such as IR and Raman spectroscopy, is also a suitable and widely used method for distinguishing different polymorphic / pseudo-polymorphic / amorphous forms. Although vibrational spectroscopy mainly detects local, short-range order (intramolecular vibrations), the vibrational frequencies are also affected by their surroundings, so that these frequencies represent not only conformational polymorphisms, but also the way the molecules are stacked. Therefore, if measured with sufficiently high wavenumber resolution, different polymorphs typically have different vibrational spectra (Hilfiker et al. (2019), p. 418). Therefore, each crystalline form of the free base and hydrochloride 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 features: characteristic XRPD diffraction peaks, IR absorption bands or Raman peaks.

[0062] One aspect of the present invention is the hydrochloride salt of compound 1. The salt can exist in various forms such as oil or solid. The solid can be amorphous, crystalline or a mixture of the two.

[0063] In another aspect, the present invention provides a method for preparing a hydrochloride salt of Compound 1, comprising:

[0064] a) providing a solution of compound 1 in any suitable solvent;

[0065] b) mixing the solution in step a) with a hydrochloric acid solution;

[0066] c) stirring the slurry; and

[0067] d) Isolating Compound 1 hydrochloride.

[0068] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0069] The solvent used in step b) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0070] Step c) involves stirring the slurry by means of any suitable technique, including a stir bar, a stirring rod or a shaker at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature.

[0071] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0072] Another aspect of the present invention is a stable anhydrate form of the hydrochloride salt of Compound 1, Form A.

[0073] Another aspect of the invention is a hydrochloride salt 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 Form A.

[0074] The X-ray diffraction pattern of Compound 1 hydrochloride type A is shown in Fig.18 The detailed peak list is shown in Table 1. The most characteristic peaks of Compound 1 hydrochloride type A are at 9.2, 12.5, 14.5, 15.1, 15.8, and 17.4 ± 0.2° 2θ.

[0075] Table 1 X-ray diffraction peaks of Compound 1 hydrochloride type A

[0076]

[0077] Compound 1 hydrochloride type A can also be characterized by its FT-IR spectrum. The infrared spectrum of compound 1 hydrochloride type A is shown in Fig.19The absorption bands of Compound 1 hydrochloride type A are shown in detail in Table 2. The most characteristic absorption bands of Compound 1 hydrochloride type A are at 2474, 2524, 1668, 1479 and 1222±4 cm -1 Place.

[0078] Table 2 Infrared absorption bands of Compound 1 hydrochloride type A

[0079]

[0080]

[0081] Compound 1 hydrochloride type A can also be characterized by its Raman spectrum. The Raman spectrum of compound 1 hydrochloride type A is shown in Fig. 20 The detailed list of Raman peaks of Compound 1 Hydrochloride Form A is shown in Table 3. The most characteristic Raman peaks of Compound 1 Hydrochloride Form A are at 1549, 1344, 1303, 1257 and 747 cm -1 Place.

[0082] Table 3 Raman peaks of Compound 1 hydrochloride type A

[0083]

[0084]

[0085] Compound 1 hydrochloride Form A can also be characterized by its differential scanning calorimetry (DSC) thermogram. A typical DSC thermogram of Compound 1 hydrochloride Form A is shown in Fig.21 Compound 1 hydrochloride Form A melts during decomposition with a broad endothermic DSC peak with a peak maximum between 250 and 300 °C.

[0086] Compound 1 hydrochloride type A is prepared by Fig. 22 Its thermogravimetric (TGA) thermogram shown here confirms the true anhydrate form. The weight loss of Compound 1 hydrochloride Form A is less than 1.0% (up to 175°C).

[0087] The chemical stability of Compound 1 HCl Form A was evaluated via a set of forced stability studies as shown in Table 4. Samples of Compound 1 HCl Form A were stored for 10 days under different controlled conditions (50°C dry, 75°C dry, and 50°C 85% RH) and analyzed using the same method as the initial samples.

[0088] Table 4 Forced stability results of Compound 1 hydrochloride type A under different conditions

[0089]

[0090] The impurity profile, loss on drying, and polymorph form of samples of Compound 1 HCl Form A did not change during the mandatory stability study, demonstrating that Compound 1 HCl Form A is stable at 50°C, 75°C, and at 50°C 85% RH for 10 days.

[0091] The term solubility is used to measure the amount of compound 1 hydrochloride that can be dissolved in 1L of simulated solvent (in μmol). Simulated solvents include FaSSiF (fasted state simulated intestinal fluid) and FeSSiF (fed state simulated intestinal fluid). When the highest concentration is soluble in 250mL or less of an aqueous medium with a pH range of 1-6.8 at 37±1°C, the drug substance is considered to be highly soluble according to the Biopharmaceutics Classification System (BCS) (Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, Guidance for Industry, December 2017, https: / / www.gmp-compliance.org).

[0092] The solubility data of Compound 1 HCl Form A in FaSSiF and FeSSiF solutions are shown in Table 5. In the simulated fluids (FaSSiF and FeSSiF), Compound 1 HCl Form A is highly soluble up to a concentration of 20 mg.

[0093] Table 5 Solubility of Compound 1 HCl Form A

[0094]

[0095] The analysis and physical characterization described above confirm that Compound 1 hydrochloride Form A is a stable anhydrate polymorph of Compound 1 hydrochloride that is highly soluble in simulated media. It is not hygroscopic under normal conditions (up to 70% RH), but requires some protective measures at high humidity. The analytical results indicate that the solid form is suitable for drug development.

[0096] In another aspect, the present invention provides a method for preparing Compound 1 hydrochloride Form A, comprising:

[0097] a) providing a solution of Compound 1 hydrochloride in any suitable solvent;

[0098] b) evaporating part of the solvent to obtain a suspension; and

[0099] c) stirring the slurry; and

[0100] d) Isolation of Compound 1 hydrochloride Form A.

[0101] The solution provided in step a) can be provided by dissolving Compound 1 hydrochloride or by mixing Compound 1 with an appropriate amount of hydrochloric acid in a solution.

[0102] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0103] Step b) involves evaporating the solvent by means of any suitable technique, including a rotary distillation apparatus, such as a rotary evaporator, an open reactor or any other suitable technique. The evaporation may be initiated by increasing the temperature or by reducing the pressure or a combination thereof.

[0104] Step c) involves stirring the slurry by means of any suitable technique, including a stir bar, a stirring rod or a shaker at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature.

[0105] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0106] In another aspect, the present invention provides a method for preparing Compound 1 hydrochloride Form A, comprising:

[0107] a) providing a solution of Compound 1 hydrochloride in any suitable solvent;

[0108] b) cooling the solution to obtain a slurry; and

[0109] c) stirring the slurry; and

[0110] d) Isolation of Compound 1 hydrochloride Form A.

[0111] The solution provided in step a) can be provided by dissolving Compound 1 hydrochloride or by mixing Compound 1 with an appropriate amount of hydrochloric acid in a solution.

[0112] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0113] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50° C., 40° C., room temperature, and the like.

[0114] Step b) involves cooling the solution to a temperature lower than that in step a), for example to room temperature or 0-5°C or any suitable temperature.

[0115] Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique including a stirring bar, stirring rod or shaker.

[0116] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0117] In another aspect, the present invention provides a method for preparing Compound 1 hydrochloride Form A, comprising:

[0118] a) providing a solution of Compound 1 hydrochloride in any suitable solvent;

[0119] b) mixing the solution with an anti-solvent to obtain a slurry; and

[0120] c) stirring the slurry; and

[0121] d) Isolation of Compound 1 hydrochloride Form A.

[0122] The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0123] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50° C., 40° C., room temperature, and the like.

[0124] Mixing the solutions in step b) can be carried out by metering the solution into the antisolvent or by metering the antisolvent into the solution. The metering can be uncontrolled or controlled by means of any suitable technique.

[0125] Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique including a stirring bar, stirring rod or shaker.

[0126] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0127] International patent application WO 2016 / 166684 also provides for the separation of compound 1 as a free base. Reference Example 10 demonstrates that the evaporation of the eluent as described in Example 20(a) of WO 2016 / 166684 prepares a crystalline form of compound 1 free base, Form B. Analytical characterization of Compound 1 Form B, in particular DSC analysis, reveals that the form undergoes a polymorphic transition at higher temperatures and forms a new form having a melting point between 200 and 210°C. These DSC results indicate that Compound 1 Free Base Form B may not be a stable polymorph of Compound 1 Free Base.

[0128] According to Ostwald's rule of stages (Ostwald, 1897), in crystallization, the system moves from the initial high energy state to equilibrium by the smallest change in free energy, thus suggesting that the least stable polymorph in any crystallization should be separated first (Jonathan C. Burley, Melinda J. Duer, Robin S. Stein, Ranko M. Vrcelj, European Journal of Pharmaceutical Sciences, Vol. 31, No. 5, August 2007, pp. 271-276). In order to obtain more stable polymorphs, further crystallization experiments (e.g., Example 3) were designed and performed using a more controlled crystallization process: an additional resuspension step was applied instead of rapid evaporation of the eluent. In Example 3, a new polymorph A of the free base of Compound 1 was obtained with some traces of Form B. In further crystallization experiments, pure Form A was prepared and characterized.

[0129] Another aspect of the present invention is a stable anhydrate form of the free base of Compound 1, Form A.

[0130] Another aspect of the invention is a crystalline solid form of Compound 1 free base 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 free base Form A.

[0131] The X-ray diffraction pattern of compound 1 free base type A is shown in Fig.23 The detailed peak list is shown in Table 6. The most characteristic peaks of Compound 1 free base Form A are at 5.9, 17.7, 18.1, 19.8 and 22.2° 2θ.

[0132] Table 6 X-ray diffraction peaks of free base type A of compound 1

[0133]

[0134]

[0135] Compound 1 free base Form A can also be characterized by its FT-IR spectrum. The infrared spectrum of Compound 1 free base Form A is shown in Fig.24 The detailed list of absorption bands of Compound 1 free base type A is shown in Table 7. The most characteristic absorption bands of Compound 1 free base type A are at 1663, 1478, 1220, 860, 795 and 766±4 cm -1 Place.

[0136] Table 7 Infrared absorption bands of compound 1 free base type A

[0137]

[0138]

[0139]

[0140] Compound 1 free base Form A can also be characterized by its Raman spectrum. The Raman spectrum of Compound 1 free base Form A is shown in Fig.25 The detailed list of Raman peaks of Compound 1 free base Form A is shown in Table 8. The most characteristic Raman peaks of Compound 1 free base Form A are at 1554, 1345, 1267, 1260 and 750±4 cm -1 Place.

[0141] Table 8 Raman peaks of type A of compound 1

[0142]

[0143]

[0144] Compound 1 free base Form A can also be characterized by its DSC thermogram. A typical DSC thermogram of Compound 1 free base Form A is shown in Fig.26 Compound 1 free base Form A exhibits a single melting endotherm with an onset temperature value between 200 and 210 °C.

[0145] Compound 1 free base type A is prepared by Fig. 27 Its TGA thermogram is shown to confirm the true anhydrate form. The weight loss of Compound 1 free base Form A was less than 0.5% (up to 215°C).

[0146] The chemical stability of Compound 1 Free Base Form A was evaluated via a set of mandatory stability studies as shown in Table 9. Samples of Compound 1 Free Base Form A were stored under different controlled conditions (50°C dry, 75°C dry, and 50°C 85% RH) for 10 days and analyzed in the same manner as the initial samples.

[0147] Table 9 Forced stability results of compound 1 free base type A under different conditions

[0148]

[0149] The impurity profile, loss on drying, and polymorph form of samples of Compound 1 Free Base Form A did not change during the mandatory stability study, demonstrating that Compound 1 Free Base Form A is stable at 50°C, 75°C, and 85% RH at 50°C for 10 days.

[0150] The solubility of Compound 1 free base Form A in PBS, FaSSiF, and FeSSiF solutions is shown in Table 10. Compound 1 Form A is highly soluble up to a concentration of 9 mg, but in more acidic media, the solubility is even higher.

[0151] Table 10 Solubility of Form A of Compound 1

[0152]

[0153] The analytical and physical characterizations described above demonstrate that Compound 1 Free Base Form A is a stable, non-hygroscopic anhydrate polymorph of Compound 1 Free Base that exhibits acceptable solubility in simulated media. The analytical results indicate that the solid form is suitable for pharmaceutical development.

[0154] In another aspect, the present invention provides a method for preparing Compound 1 free base Form A, comprising:

[0155] a) providing a solution of Compound 1 free base in any suitable solvent;

[0156] b) evaporating part of the solvent to obtain a suspension; and

[0157] c) stirring the slurry; and

[0158] d) Isolation of Compound 1 free base Form A.

[0159] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0160] Step b) involves evaporating the solvent by means of any suitable technique, including a rotary distillation apparatus, such as a rotary evaporator, an open reactor or any other suitable technique. The evaporation may be initiated by increasing the temperature or by reducing the pressure or a combination thereof.

[0161] Step c) involves stirring the slurry by means of any suitable technique, including a stir bar, a stirring rod or a shaker at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature.

[0162] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0163] In another aspect, the present invention provides a method for preparing Compound 1 free base Form A, comprising:

[0164] a) providing a solution of Compound 1 free base in any suitable solvent;

[0165] b) cooling the solution to obtain a slurry; and

[0166] c) stirring the slurry; and

[0167] d) Isolation of Compound 1 free base Form A.

[0168] The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0169] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50° C., 40° C., room temperature, and the like.

[0170] Step b) involves cooling the solution to a temperature lower than that of step a), for example to room temperature or 0-5°C or any suitable temperature.

[0171] Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique including a stirring bar, stirring rod or shaker.

[0172] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0173] In another aspect, the present invention provides a method for preparing Compound 1 free base Form A, comprising:

[0174] a) providing a suspension of a solid form of Compound 1 free base in any suitable solvent;

[0175] b) stirring the slurry; and

[0176] c) Isolation of Form A of Compound 1.

[0177] In step a), the solid form of the free base of compound 1 can 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, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0178] Step b) involves stirring the slurry by means of any suitable technique, including a stir bar, a stirring rod or a shaker at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature.

[0179] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0180] In another aspect, the present invention provides a method for preparing Compound 1 free base Form A, comprising:

[0181] a) providing a solution of Compound 1 free base in any suitable solvent;

[0182] b) mixing the solution with an anti-solvent to obtain a slurry; and

[0183] c) stirring the slurry; and

[0184] d) Isolation of Compound 1 free base Form A.

[0185] The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0186] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50° C., 40° C., room temperature, and the like.

[0187] Mixing the solutions in step b) can be carried out by metering the solution into the antisolvent or by metering the antisolvent into the solution. The metering can be uncontrolled or controlled by means of any suitable technique.

[0188] Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique including a stirring bar, stirring rod or shaker.

[0189] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0190] In another aspect, the present invention provides a method for preparing Compound 1 free base Form B, comprising:

[0191] a) providing a solution of Compound 1 free base in any suitable solvent;

[0192] b) mixing the solution with an anti-solvent to obtain a slurry; and

[0193] d) Isolation of Form B of Compound 1.

[0194] The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

[0195] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50° C., 40° C., room temperature, and the like.

[0196] Mixing the solutions in step b) can be carried out by metering the solution into the antisolvent or by metering the antisolvent into the solution. The metering can be uncontrolled or controlled by means of any suitable technique.

[0197] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0198] The X-ray diffraction pattern of Form B of Compound 1 is shown in Fig.28 The detailed peak list is shown in Table 11. The most characteristic peaks of Form B of Compound 1 are at 6.1, 16.0, 18.0, 19.2 and 21.5 ± 0.2° 2θ.

[0199] Table 11 X-ray diffraction peaks of type B of compound 1

[0200]

[0201]

[0202] Form B of compound 1 can also be characterized by its FT-IR spectrum. The infrared spectrum of Form B is shown in Fig.29 The detailed list of absorption bands of Form B of Compound 1 is shown in Table 12.

[0203] Table 12 Infrared absorption bands of Type B of Compound 1

[0204]

[0205]

[0206]

[0207] 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 Fig.30 The detailed list of Raman peaks of Form B of Compound 1 is shown in Table 13.

[0208] Table 13 Raman peaks of type B of compound 1

[0209]

[0210]

[0211] 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 Fig.31 Form B of Compound 1 exhibits a broad exotherm between 100 and 200 °C prior to a melting endotherm that begins between 200 and 210 °C.

[0212] In another aspect, the present invention provides a method for preparing a pyridine solvate of Compound 1 Free Base Form C by suspending Compound 1 maleate in pyridine, stirring and isolating Compound 1 Free Base Form C in the form of a white or off-white solid. Stirring involves stirring the slurry by any suitable technique, including a stirring bar, a stirring rod or an oscillator at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature.

[0213] The X-ray diffraction pattern of compound 1 free base type C is shown in Fig.32 The detailed peak list is shown in Table 14. The most characteristic peaks of Compound 1 free base Form C are at 2.6, 5.3, 16.0, 19.4 and 24.7 ± 0.2° 2θ.

[0214] Table 14 X-ray diffraction peaks of compound 1 free base type C

[0215]

[0216]

[0217]

[0218] Compound 1 free base Form C can also be characterized by its DSC thermogram. A typical DSC thermogram of Compound 1 free base Form C is shown in Fig.33 Compound 1 free base Form C exhibits a broad endotherm between 50 and 150 °C prior to a melting endotherm that starts between 200 and 210 °C.

[0219] The typical TGA thermogram of compound 1 free base type C is shown in Fig.34 The weight loss of Form C at 120°C is about 10%.

[0220] Another aspect of the present invention is the free base hydrate form of Compound 1, Form D.

[0221] Another aspect of the invention is a crystalline solid form of Compound 1 free base 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 free base Form D.

[0222] The X-ray diffraction pattern of compound 1 free base D is shown in Fig.35The detailed peak list is shown in Table 15. The most characteristic peaks of Compound 1 free base D-form are at 8.1, 18.4, 18.8, 19.0 and 20.4 ± 0.2° 2θ.

[0223] Table 15 X-ray diffraction peaks of free base D-type of compound 1

[0224]

[0225]

[0226]

[0227] Compound 1 free base D-form can also be characterized by its FT-IR spectrum. The infrared spectrum of D-form is shown in Fig.36 The detailed list of absorption bands of the free base D-type of Compound 1 is shown in Table 15. The most characteristic absorption bands of the free base D-type of Compound 1 are at 3515, 3243, 2869, 2829 and 1650±4 cm -1 .

[0228] Table 16 Infrared absorption bands of compound 1 free base D

[0229]

[0230]

[0231]

[0232] Compound 1 free base D-form can also be characterized by its Raman spectrum. The Raman spectrum of D-form is shown in Fig.37 The detailed list of Raman peaks of the free base D-type of compound 1 is shown in Table 17. The most characteristic Raman peaks of the free base D-type of compound 1 are at 1644, 1552, 1539, 1301, 1257±4 cm -1 .

[0233] Table 17 Raman peaks of compound 1 free base D

[0234]

[0235]

[0236] Compound 1 free base D-form can also be characterized by its DSC thermogram. A typical DSC thermogram of compound 1 free base D-form is shown in Fig.38 Compound 1 free base Form D exhibits a broad endotherm between 50 and 110 °C prior to a melting endotherm that starts between 200 and 210 °C.

[0237] Compound 1 free base Form D is a hydrate, and its TGA thermogram shows a characteristic weight loss of 4.1% between 50 and 110°C. A typical TGA thermogram of Compound 1 free base Form D is shown in Fig.39 The water content of the sample was confirmed by Karl Fisher titration (4.6%).

[0238] In another aspect, the present invention provides a method for preparing compound 1 free base form D, comprising:

[0239] a) providing a solution of Compound 1 free base in any suitable solvent;

[0240] b) mixing the solution with water to obtain a slurry; and

[0241] c) stirring the slurry; and

[0242] d) Isolation of compound 1 free base form D.

[0243] 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 a mixture thereof.

[0244] The temperature of the solution can be any suitable temperature, such as the reflux temperature of the solvent, 50° C., 40° C., room temperature, and the like.

[0245] Mixing the solutions in step b) can be carried out by metering the solution into the antisolvent or by metering the antisolvent into the solution. The metering can be uncontrolled or controlled by means of any suitable technique.

[0246] Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique including a stirring bar, stirring rod or shaker.

[0247] Isolation of the product can be carried out under ambient conditions or in an inert atmosphere (eg nitrogen). The product is a white or off-white solid.

[0248] For analytical studies, the following experimental conditions were used:

[0249] Parameters measured by FT-IR spectroscopy:

[0250] Instrument: Thermo-Nicolet 6700

[0251] Phase: KBr ingot

[0252] Spectral resolution: 4cm -1

[0253] Detector: DTGS

[0254] Spectrum splitter: XT-KBr

[0255] Mirror moving speed: 0.6329

[0256] Scan times: 100

[0257] Parameters measured by FT-Raman spectroscopy:

[0258] Instrument: Thermo-Nicolet NXR9650

[0259] Measuring range: 3500 to 200cm -1

[0260] Spectral resolution: 4cm -1

[0261] Detector: Ge

[0262] Spectrum splitter: CaF2

[0263] Mirror moving speed: 0.1581

[0264] Scan times: 256

[0265] Laser performance: 500mW

[0266] Parameters of X-ray powder diffraction measurement:

[0267] Instrument: PANanalytical X'Pert PRO MPD

[0268] Radiation: CuKα

[0269] Accelerating voltage: 40 kV

[0270] Anode current: 40mA

[0271] Goniometer: PW3050 / 60

[0272] Scan speed: 0.0305s

[0273] Increment: 0.0131°

[0274] Sample holder: PW1818 / 25&40 (transmission, sample between foils)

[0275] Sample holder rotator: PW3064 / 60 (reflection / transmission rotator)

[0276] Sample holder rotation speed: 1 rpm

[0277] Detector: PIXcel (PW3018 / 00)

[0278] Uncertainty of 2θ measurement: ±0.2°

[0279] Parameters measured by TGA:

[0280] Instrument: TA Instruments TGA Q5000 or Discovery TGA 5500

[0281] Heating rate: 10℃ / min

[0282] Sample weight: ~2 to 10 mg

[0283] Atmosphere: 60mL / min N2

[0284] Parameters measured by DSC:

[0285] Instrument: TA Instruments DSC Q1000 or Discovery DSC 2500

[0286] Heating rate: 10℃ / min

[0287] Sample weight: ~1 to 3 mg

[0288] Pan type: open Al pan Atmosphere: 50mL / min N2

[0289] Solubility analysis method

[0290] About 2-2 mg (N = 5) of the test substance was weighed into transparent test containers and 300 μL of solvent was added to them. The test container was placed on a mechanical shaker and shaken at 37° C. for an incubation time of 24 h, filtered and the concentration of compound 1 in the filtrate was determined by HPLC-MS (Agilent 1200 liquid chromatograph, coupled with 6410 QQQ-MS, Kinetex EVO C18 column).

[0291] HPLC Method for Purity Analysis

[0292] Approximately 10-10 mg of the test substance was weighed into a 10 mL volumetric flask and dissolved in a mixture of formic acid, acetonitrile and water. Using a 100 mL volumetric flask, 1 mL of the solution was diluted to 100 mL with the solvent mixture. The diluted solution was then injected into a Waters Acquity H-Class UPLC instrument with an Acquity CSH column.

[0293] The physicochemical and biopharmaceutical characteristics of the active substance are crucial in terms 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 properties of the salts and crystalline forms of Compound 1 and its hydrochloride disclosed herein can be further characterized by the following methods:

[0294] Crystal habit: Crystalline polymorphic materials may exist in a number of shapes or forms (sometimes referred to as "crystal habit") depending on the method and solvent used for final crystallization. This can range from highly angular crystals with elongated shapes, needle-like crystals and flat plate-like forms to more spherical crystal habits. Their shape can affect the flow properties of bulk powders, e.g., during discharge from a container / hopper, etc., due to particle-particle mechanical and physical interactions or cohesion. The shape of drug particles can be characterized, e.g., by polarized light microscopy (PLM).

[0295] Particle size distribution: A narrow and monomodal particle size distribution of the active pharmaceutical ingredient is advantageous from a pharmaceutical formulation aspect. The measurement of particle size distribution can be performed, for example, by laser diffraction and polarized light microscopy.

[0296] The specific surface area of ​​the solid form can be determined by gas absorption (eg BET) or gas permeability methods.

[0297] Dissolution: Solubility is important for selecting salt forms or specific crystalline or polymorphic forms that may affect the dissolution rate, and it is the most critical parameter. Dissolution is the process in which a substance forms a solution. Dissolution tests measure the extent and rate at which a solution is formed by a dosage form such as a tablet, capsule, ointment, etc. The dissolution of a drug is important for its bioavailability and therapeutic effectiveness. Dissolution and drug release are terms that are used interchangeably. The differences in solubility and dissolution rate between polymorphs can have a significant impact on the oral bioavailability (dissolution and absorption from the GI tract) of a drug.

[0298] Flowability: Although tablets and capsules, the two most common solid dosage forms, have their own unique requirements, there are similarities between them. They both require the correct weight of material to flow into a specific volume. Good flow properties are a prerequisite for the successful manufacture of both tablets and powder-filled hard gelatin capsules or sachets. The European Pharmacopoeia (Ph.Eur.) contains a test for the flowability of powders based on how the powder flows vertically out of a funnel. There are several different methods that can be used to determine the flow properties of powders, and there are many literature examples illustrating the correlation between the test methods and the manufacturing properties of the formulation.

[0299] Bulk density is an essential parameter for pharmaceutical product and process development and solid dosage form manufacturing. It is used to determine the amount of powder that can be packed into a space such as a mixer or hopper on a tablet press or capsule filling machine. It can also be used to determine the amount of powder that can be packed into a capsule of a specific volume.

[0300] The tapped bulk density, or tap density for short, is the maximum bulk density of a powder (or blend of powders) achieved under the influence of a well-defined externally applied force. The minimum bulk volume therefore depends on many factors, including particle size distribution, true density, particle shape and cohesion due to surface forces including moisture. Therefore, the tap density of a material can be used to predict its flow properties as well as its compressibility.

[0301] The term "disease or condition associated with MCHR1 activity" refers to obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, psychiatric disorders, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic disorders of the musculoskeletal system, osteoporosis, cancer.

[0302] Reference is made herein to a parallel patent application entitled “MCHR1 antagonists for the treatment of Prader-Willi syndrome” filed by the present applicant, which discloses a method for treating Prader-Willi syndrome using a compound of formula (I) according to WO 2016 / 166684A1, such as compound 1 in free form or in the form of a pharmaceutically acceptable salt, e.g., its hydrochloride salt.

[0303] The term "pharmaceutical composition" refers to a mixture of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A with other chemical components, such as pharmaceutically acceptable excipients, e.g., diluents or carriers. Pharmaceutical compositions facilitate administration of the compound to a subject.

[0304] The term "excipient" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.

[0305] The pharmaceutical composition of the present invention can be formulated in many ways, for example, in the form of tablets, capsules, powders / powders, granules, suspensions, emulsions, solutions, syrups, aerosols (with solid or liquid carriers), soft or hard gelatin capsules, suppositories, injections in sterile form. Preferably, the pharmaceutical composition is formulated as tablets or capsules.

[0306] The pharmaceutical composition can be in a single dosage form containing a predetermined amount of active ingredient. The dosage form can contain a 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 or a given percentage of therapeutically effective amount, so that these single dosage forms for repeated administration can be administered within a given time period, thereby achieving the desired therapeutically effective dose. A preferred single dosage form is an active ingredient containing a daily dose or sub-dose or a given percentage as mentioned above. In addition, these pharmaceutical compositions can be manufactured by methods known in the art.

[0307] The term "therapeutically effective amount" refers to the amount of active ingredient that leads to treatment, cure, prevention, alleviation or improvement of a disease, pathological condition, side effect, one or more symptoms of a disease such as overeating, to maintain or reduce body weight or reduce food intake, or to inhibit or delay the progression of a disease, a pathological condition of a disease such as overeating, or one or more symptoms, compared to a subject who has not received such an amount. The term also includes the effective amount required to improve normal physiological function. In therapeutic applications, Form A of Compound 1, Form D of Compound 1, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Form A of Compound 1 hydrochloride can be administered in a therapeutically effective amount as an unformulated bulk drug, or the active ingredient can be formulated as a drug. The exact therapeutically effective amount of such a compound depends on several factors, including but not excluding the age and weight of the subject (patient) being treated, the type and severity of the disease to be treated, the type of pharmaceutical composition / drug, and the mode of administration.

[0308] The term "daily dose" means the amount of free base administered per day. In the case of administration of a pharmaceutically acceptable salt, the daily dose is also expressed in terms of the equivalent amount of the free base.

[0309] In one embodiment, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 HCl, Compound 1 HCl in crystalline form, or Compound 1 HCl Form A is a daily dose of at least about 2.5 mg.

[0310] In another embodiment, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A is a daily dose of about 2.5 mg to about 22.5 mg.

[0311] In preferred embodiments, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride Form A is a daily dose of about 2.5 mg to about 7.5 mg.

[0312] In preferred embodiments, the therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride Form A is a daily dose of about 2.5 mg, about 5 mg, or about 7.5 mg.

[0313] The term "effective amount" refers to the amount of a drug or active ingredient sufficient to elicit the biological or medicinal response of a tissue, system, animal (including human) that is being sought, for example, by a researcher or clinician, in the subject to which it is administered.

[0314] The term "subject" refers to a patient in need of any of methods 1.1 to 1.7 defined below.

[0315] Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A can be administered by any appropriate route, such as oral, rectal, transdermal, subcutaneous, topical, intravenous, intramuscular or intranasal. The preferred route of administration is oral.

[0316] In a series of further specific or alternative embodiments, the present invention provides:

[0317] 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 Form A of Compound 1, Form D of Compound 1, Compound 1 hydrochloride, a crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride Form A as defined herein.

[0318] 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 Form A of Compound 1, Form D of Compound 1, Compound 1 hydrochloride, a crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride Form A as defined herein.

[0319] 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 Form A of Compound 1, Form D of Compound 1, Compound 1 hydrochloride, a crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride Form A as defined herein.

[0320] 1.4. A method for maintaining the body weight of a patient with PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form A of Compound 1, Form D of Compound 1, Compound 1 hydrochloride, a crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride Form A as defined herein.

[0321] 1.5. A method for reducing body weight in a patient with PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form A of Compound 1, Form D of Compound 1, Compound 1 hydrochloride, a crystalline form of Compound 1 hydrochloride, or Compound 1 hydrochloride Form A as defined herein.

[0322] 1.6. A method for reducing food intake in a patient with PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Form A of Compound 1, Form D of Compound 1, Compound 1 HCl, a crystalline form of Compound 1 HCl, or Compound 1 HCl Form A as defined herein.

[0323] 1.6. A method for treating binge eating disorder in a patient with PWS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1 Form A, Compound 1 Form D, Compound 1 HCl, a crystalline form of Compound 1 HCl, or Compound 1 HCl Form A as defined herein.

[0324] 1.7. A method as described above, wherein 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 administered once daily.

[0325] 2. A pharmaceutical composition for use in any of Methods 1.1 to 1.7, comprising Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A as defined herein together with one or more pharmaceutically acceptable excipients.

[0326] 4. Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A as defined herein, for use in any one of methods 1.1 to 1.7.

[0327] 5. Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A as defined herein for use in the preparation of a medicament for use in any one of Methods 1.1 to 1.7.

[0328] 6. Use of Compound 1 Form A, Compound 1 Form D, Compound 1 hydrochloride, Compound 1 hydrochloride in crystalline form, or Compound 1 hydrochloride Form A as defined herein for use in any one of methods 1.1 to 1.7.

[0329] In particular, Compound 1 HCl Form A as described herein may be used to treat binge eating in patients suffering from PWS.

[0330] Further details of the present invention are presented in the following examples, the scope of protection of the present invention is not limited in any way to the examples mentioned. Unless explicitly indicated in a single example, the starting materials of the following examples are prepared according to WO2016 / 166684 Example 20 (a) - Compound 1 free base or 20 (b) - Compound 1 maleate.

[0331] Reference example

[0332] Reference Example 1

[0333] Compound 1 maleate solvate from ethanol

[0334] To a solution of 0.47 g (1.015 mmol) of compound 1 (WO 2016 / 166684 Example 20 / a) in a 10:1 mixture of dichloromethane and methanol was added 0.13 g (1.117 mmol) of maleic acid, and the mixture was concentrated. The residue was triturated with ethanol, and after 1 h of stirring, the solid product was filtered, washed with ethanol, and dried to obtain 0.57 g (96%) of the title compound. The XRPD pattern of the product is shown in Figure 1 Medium. TGA: 3.9% ( Fig.10 ).

[0335] Reference Example 2

[0336] Compound 1 maleate solvate from ethanol

[0337] 99.11 mg of Compound 1 maleate was dissolved in 5 ml of ethanol (jacket temperature 70°C), filtered and the filtrate was cooled to 25°C, stirred for 30 min, filtered and left at room temperature for 4 days to dry. The XRPD pattern of the product is shown in Figure 2 Medium. TG: 5.1% ( Fig.11 )

[0338] Reference Example 3

[0339] Compound 1 maleate solvate from dichloromethane / ethanol

[0340] 0.231kg ​​4-[(5-chloropyridin-2-yl)methoxy]-l-{lH,2H,3H,4H,5H-[l,4]diazepine [l,7-a] indol-9-yl}-l,2-dihydropyridin-2-one (Example 4 in WO 2016 / 166684) was dissolved in 20l acetonitrile, 0.3kg K2CO3 and 520ml 2-iodopropane were added and stirred for 10h under reflux, and the product was isolated by evaporating the solvent (100mbar, 40-45°C). The crude product was dissolved in 1.1L dichloromethane and washed with 3×1l water, and the crude base was isolated by evaporating the solvent (100mbar, 40-45°C). The solid was dissolved in 1.5l dichloromethane and a solution of 65g maleic acid in 3.6l ethanol was added thereto. The suspension was concentrated by evaporating 3.1 l of solvent, 2 l of ethanol was added and another 1.5 l was evaporated, and the resulting suspension was stirred at 20-25 ° C for one hour, cooled to 10-12 ° C, stirred for one hour, filtered, washed with 2×0.5 l of ethanol and dried 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 Medium. TGA: 4.1% ( Fig.12 ).

[0341] Reference Example 4

[0342] Compound 1 maleate solvate from methanol

[0343] 40 mg of the maleate salt of compound 1 was suspended in 1 ml of methanol, stirred for one week, filtered and dried under ambient conditions. The XRPD pattern of the product is shown in Figure 4 . TGA: 5.5%( Fig.13 ).

[0344] Reference Example 5

[0345] Compound 1 maleate solvate from ethanol

[0346] 40 mg of the maleate salt of compound 1 was suspended in 1 ml of ethanol, stirred for one week, filtered and analyzed by XRPD. The XRPD pattern of the product is shown in Figure 5 Medium. TGA: 4.7% ( Fig.14 )

[0347] Reference Example 6

[0348] Compound 1 maleate solvate from ethanol

[0349] To a solution of 0.47 g (1.015 mmol) of compound 1 in 5 ml of a 10:1 mixture of dichloromethane and methanol was added a solution of 0.13 g of maleic acid in 3.5 ml of the same solvent, and the mixture was evaporated with the aid of a Rotavapor (500-350 mbar, 40° C.). 1.9 ml of ethanol was added to the solid residue, stirred for one hour, filtered and left to dryness at room temperature. The XRPD pattern of the product is shown in Figure 6 Medium. TGA: 1,9% ( Fig.15 )

[0350] Reference Example 7

[0351] Compound 1 maleate solvate from methanol

[0352] 50 mg of the maleate salt 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%( Fig.16 ).

[0353] Reference Example 8

[0354] Compound 1 maleate solvate from methanol

[0355] 101 mg of the maleate salt of compound 1 was suspended in 2.5 ml of methanol, stirred for one 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% ( Fig.17 ).

[0356] Reference Example 9

[0357] Compound 1 maleate solvate from DMSO

[0358] 272 mg of the maleate salt of compound 1 was suspended in 0.75 ml of DMSO and stirred at room temperature for one week. The solid was filtered and analyzed by XRPD. The XRPD pattern of the product is shown in Fig. 9 middle.

[0359] Reference Example 10

[0360] 0.6 g of compound 1 was dissolved in 5 ml of a 95:5:0.1 mixture of dichloromethane, methanol and ammonia. The solvent was evaporated in a Rotavapor (40°C 500 mbar) to obtain 0.6 g of off-white powder. Yield: 100%. The XRPD of the product is shown in Fig.40 middle.

[0361] Example

[0362] Example 1

[0363] To a solution of 30 mg of the free base of compound 1 in 1.2 ml of acetone was added dropwise 7.5 μl of 37% hydrochloric acid, stirred for 3 h, filtered and dried at 40° C. / vacuum. Yield: N / A. The XRPD pattern of the product was according to Fig.18 , and a moisture content of 0.6% by TGA (to 200°C).

[0364] Example 2

[0365] To a solution of 3 g of the free base of compound 1 in 36 ml of dichloromethane was added 0.6 ml of cc. hydrochloric acid in 36 ml of acetone. 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 to 22 .

[0366] Example 3

[0367] 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 adsorbent and a 95:5:0.1 mixture of dichloromethane, methanol and cc. NH3 solution as eluent. The eluent (Rotavapor) was removed and the product was resuspended in ethanol, dried, resuspended in ether and filtered to produce 1.24 g of white crystals. The XRPD pattern of the product is shown in Fig.41 It was confirmed to be a mixture of Compound 1 Type B and Compound 1 Type A.

[0368] Example 4

[0369] 100 mg of a mixture of Compound 1 free base, Form A and Form B was suspended in 2 ml of ethanol and stirred at room temperature for one week. The solid was filtered and identified as Compound 1 Form A by XRPD.

[0370] Example 5

[0371] 96.76 mg of Compound 1 was dissolved in 11 ml of ethanol under reflux, cooled and stirred for about 3 days to obtain a white precipitate identified as Compound 1 free base Form A. The XRPD pattern of the product was Fig.23 .

[0372] Example 6

[0373] 83.5 mg of Compound 1 free base was dissolved in 15 ml of acetonitrile and stirred in an open vial for two days, and the solid was filtered to obtain a white to off-white precipitate identified as Compound 1 free base Form A. The XRPD pattern of the product was according to Fig.23 .

[0374] Example 7

[0375] 1.17 g of Compound 1 free base was dissolved in 13.2 ml of dichloromethane and 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 Form A. The XRPD pattern of the product was according to Fig.23 .

[0376] Example 8

[0377] 1.17 g of Compound 1 free base was dissolved in 13.2 ml of dichloromethane and 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 Form B. The XRPD pattern of the product was according to Fig.28 .

[0378] Example 9

[0379] 51.20 mg of Compound 1 maleate was suspended in 1.5 ml of pyridine and stirred for one week. The solid was filtered and dried in vacuum at 40°C to obtain Compound 1 free base Form C. The XRPD pattern of the sample is shown in Fig.36 , TGA: 10.3%( Fig.34 ). NMR: confirmed compound 1, with 0.4 mol pyridine and 0.15 mol maleic acid. Melting of type A was detected on DSC ( Fig.33 ).

[0380] Example 10

[0381] 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 spiked with 17 μl cc. HCl. The solid was filtered and dried at 40° C. The XRPD pattern of the sample was according to Fig.35 , confirmed to be Form D of Compound 1. TGA: 4.1% (215°C).

[0382] Embodiment 11

[0383] A solution of 1 g of compound 1 free base in 50 ml of tetrahydrofuran was added to 150 ml of water under reflux, stirred for one hour, and filtered and washed with water. The XRPD pattern of the sample was according to Fig.35 .

[0384] Preparation of pharmaceutical compositions

[0385] The following formulation examples illustrate representative pharmaceutical compositions of the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0386] A) Solid oral dosage form

[0387] Tablets or capsules or filled sachets

[0388]

[0389] B) Parenteral Dosage Forms

[0390] Intravenous injection

[0391]

[0392] C) Other dosage forms: suppositories

[0393]

Claims

1. 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride.

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

3. The salt according to any one of claims 1 to 2, comprising 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Type A, characterized in that One or more of the following solid state analytical properties: a. the presence of characteristic XRPD peaks at 9.2, 12.5, 14.5, 15.1, 15.8 and 17.4° 2θ (± 0.2°) as measured at the CuKα wavelength, and / or b. In its Raman spectrum, the peaks at 1549, 1344, 1303, 1257 and 747 cm -1 ±4cm -1 There are characteristic peaks in the value range of c. In its infrared spectrum, the peaks at 2474, 2524, 1668, 1479 and 1222 cm -1 (±4cm -1 ) has characteristic absorption bands in the value range.

4. A salt according to any one of claims 1 to 3, comprising 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A having an XRPD pattern substantially similar to the XRPD pattern of Figure 18 as measured at a CuKα wavelength.

5. The salt according to any one of claims 1 to 4, wherein the salt comprises at least 5% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A.

6. The salt according to any one of claims 1 to 5, wherein the salt comprises at least 20% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A.

7. The salt according to any one of claims 1 to 6, wherein the salt comprises at least 60% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A.

8. The salt according to any one of claims 1 to 7, wherein the salt comprises at least 80% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A.

9. The salt according to any one of claims 1 to 8, wherein the salt comprises at least 95% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one hydrochloride Form A.

10. A crystalline 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A, characterized in that One or more of the following solid state analytical properties: a. The presence of characteristic XRPD peaks at 5.9, 17.7, 18.1, 19.8 and 22.2° 2θ (± 0.2°) as measured at the CuKα wavelength, and / or b. In its Raman spectrum, there are 1554, 1345, 1267, 1260 and 750 cm -1 ±4cm -1 There are characteristic peaks in the value range of c. In its infrared spectrum, the peaks at 1663, 1478, 1220, 860, 795 and 766 cm -1 ±4cm -1 There are characteristic absorption bands in the value range of .

11. The crystalline 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A of claim 10, having an XRPD pattern substantially similar to the XRPD pattern of Figure 23 as measured at a CuKα wavelength.

12. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 5% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A according to any one of claims 10 to 11.

13. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 20% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A according to any one of claims 10 to 12.

14. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 60% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A according to any one of claims 10 to 13.

15. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 80% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A according to any one of claims 10 to 14.

16. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 95% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form A according to any one of claims 10 to 15.

17. A crystalline 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D, characterized in that One or more of the following solid state analytical properties: a. The presence of characteristic XRPD peaks at 8.1, 18.4, 18.8, 19.0 and 20.4° 2θ (± 0.2°) as measured at the CuKα wavelength, and / or b. In its Raman spectrum, the peaks at 1644, 1552, 1539, 1301, 1257 cm -1 ±4cm -1 There are characteristic peaks in the value range of c. In its infrared spectrum, the wavelengths of 3515, 3243, 2869, 2829 and 1650 cm -1 ±4cm -1 There are characteristic absorption bands in the value range of .

18. The crystalline 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D according to claim 17, which has an XRPD pattern substantially similar to the XRPD pattern of Figure 35 as measured at a CuKα wavelength.

19. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 5% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D according to any one of claims 17 to 18.

20. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 20% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D according to any one of claims 17 to 18.

21. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 60% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D according to any one of claims 17 to 19.

22. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 80% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D according to any one of claims 17 to 20.

23. A crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one, wherein the free base comprises at least 95% of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one free base Form D according to any one of claims 17 to 21.

24. A pharmaceutical composition comprising a solid form of the hydrochloride salt or free base of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one according to claims 1 to 23 and a pharmaceutically acceptable carrier.

25. A method for preparing a salt according to any one of claims 1 to 9, comprising: a) providing a solution 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 any suitable solvent; b) mixing the solution in step a) with HCl solution; c) stirring the slurry; and d) isolating 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 hydrochloride, The solvent used in steps a) and b) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

26. A method for preparing a salt according to any one of claims 1 to 9, comprising: a) providing a solution 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 HCl salt in any suitable solvent; b) evaporating a portion of the solvent to obtain a suspension; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt Form A, The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

27. A method for preparing a salt according to any one of claims 1 to 9, comprising: a) providing a solution 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 HCl salt in any suitable solvent; b) cooling the solution to obtain a slurry; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt Form A, The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

28. A method for preparing a salt according to any one of claims 1 to 9, comprising: a) providing a solution 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 HCl salt in any suitable solvent; b) mixing the solution with an anti-solvent to obtain a slurry; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one HCl salt Form A, Wherein, the solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

29. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepipro[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base Form A polymorph according to any one of claims 10 to 16, comprising: a) providing a solution 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 any suitable solvent; b) evaporating a portion of the solvent to obtain a suspension; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form A, The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

30. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepipro[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base Form A polymorph according to any one of claims 10 to 16, comprising: a) providing a solution 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 any suitable solvent; b) cooling the solution to obtain a slurry; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form A, The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

31. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base Form A polymorph according to any one of claims 10 to 16, comprising: a) providing a suspension of a solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepipro[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in any suitable solvent; b) stirring the slurry; and c) isolating 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 Form A, The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

32. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base Form A polymorph according to any one of claims 10 to 16, comprising: a) providing a solution 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 any suitable solvent; b) mixing the solution with an anti-solvent to obtain a slurry; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form A, Wherein, the solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 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, tert-butyl acetate, isobutyl acetate, dichloromethane, dichloroethylene, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether or a mixture thereof.

33. A method for preparing a crystalline solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one comprising its free base D-type polymorph according to any one of claims 17 to 23, comprising: a) providing a solution 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 any suitable solvent; b) mixing the solution with an anti-solvent to obtain a slurry; and c) stirring the slurry; and d) isolating 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one Form D, 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 a mixture thereof.

34. A solid form of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepine[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one or its hydrochloride according to claims 1 to 23 for use in the treatment / prevention of a disease or condition associated with melanin concentrating hormone receptor 1 activity.

35. A solid form for use according to claim 34, wherein the disease or condition associated with melanin concentrating hormone receptor 1 activity is selected from the group consisting of obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, psychiatric disorders, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic disorders of the musculoskeletal system, osteoporosis, cancer and Prader-Willi syndrome.

36. The solid form for use according to claim 35, wherein the disease or disorder associated with melanin concentrating hormone receptor 1 activity is Prader-Willi syndrome.

37. The solid form for use according to claim 36, wherein the use provides improvement in one or more symptoms of Prader-Willi syndrome.

38. The solid form for use according to claim 37, wherein the one or more symptoms of Prader-Willi syndrome is binge eating disorder.

Images