Polymorphs of benzo[c]chromane compounds, processes for their preparation and uses thereof

Abstract

Disclosed are polymorphs of benzo[c]chromane compounds, and preparation methods and uses thereof, and specifically provided are polymorphs of a compound shown in formula I, and preparation methods and uses thereof. The compound shown in formula I is a cathepsin C inhibitor, and the crystal form and the pharmaceutical composition containing the crystal form can be used for treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha 1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, sinusitis, hidradenitis suppurativa or cancer.

Description

TECHNICAL FIELD

[0001] The present disclosure belongs to the technical field of medicine, and relates to a polymorph of a benzo[c]chromane compound and a preparation method and use thereof. BACKGROUND

[0002] Cathepsins are a class of proteolytic enzymes that are widely present in the lysosomes of various tissue cells. According to their structure and catalytic type, cathepsins are divided into three categories: serine proteases (cathepsins A and G), aspartic proteases (cathepsins D and E), and cysteine proteases 3. Among them, cysteine proteases are the largest cathepsin family, including 11 proteases: cathepsins B, C, F, H, K, L, O, S, W, V, and Z.

[0003] Cathepsin C (also known as dipeptidyl peptidase I or "DPP1") is constitutively expressed in many tissues, with the highest levels in lung, kidney, liver, and spleen. Some recent publications have begun to describe the role of cathepsin C in certain inflammatory processes. For example: Adkison et al., J Clin Invest. 2002 Feb; 109(3): 363-71; Tinh et al., Archives of Biochemistry and Biophysics. 2002 403: 160-170; from these studies, cathepsin C is co-expressed with certain serine proteases in granules and plays a role in processing the precursor forms of these proteases into active forms, which are then released from the granules of inflammatory cells recruited to the site of inflammation. Once activated, these proteases have many functions, including the degradation of various extracellular matrix components, which together can propagate tissue damage and chronic inflammation.

[0004] WO 2004 / 110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors.

[0005] WO 2009 / 074829 relates to peptidyl nitriles and their use as DPP1 inhibitors.

[0006] WO 2010 / 128324 relates to alpha-amino amide nitriles and their use as DPP1 inhibitors.

[0007] WO 2012 / 119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors.

[0008] WO 2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3- carboxamides and their use as DPP1 inhibitors.

[0009] WO 2001 / 096285 and WO 2003 / 048123 relate to beta-amino cyanamidines having inhibitory activity against cysteine proteases.

[0010] WO 2015 / 110826 relates to alpha-amino cyanamidines and their use as DPP1 inhibitors.

[0011] WO 2022 / 117059 provides a Cathepsin C inhibitor, which is (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepane-2-carboxamide, having the structure of Formula I,

[0012]

[0013] The crystal form as a pharmaceutical active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions can lead to changes in the crystal structure of the compound, and sometimes other forms of crystal are also produced. In general, amorphous drug products do not have a regular crystal structure, and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy caking, poor flowability, etc. The polymorphism of the drug has different requirements for product storage, production and scale-up. Therefore, it is necessary to further study the crystal form of the above-mentioned compound and improve the various properties of the above-mentioned compound. SUMMARY

[0014] The present disclosure provides a crystal form A of a compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles has characteristic peaks at 8.910, 10.273, 15.650, 18.617, 17.869 and 19.526, said 2θ angles being within error range of ±0.20,

[0015]

[0016] In some embodiments, the crystal form A of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ angles has characteristic peaks at 8.910, 10.273, 13.730, 15.650, 17.869, 18.617, 19.526 and 23.452, said 2θ angles being within error range of ±0.20.

[0017] In some embodiments, the A crystal form of the compound shown in Formula I, wherein the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ has characteristic peaks at 8.910, 10.273, 13.730, 15.650, 17.869, 18.617, 19.526, 20.785, 22.193, 23.452, 25.049, and 26.590, and the 2θ angle error range is ±0.20.

[0018] In some embodiments, the A crystal form of the compound shown in Formula I, wherein the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is as follows: Figure 1 As shown.

[0019] In some embodiments, the compound of Formula I is in crystal form A, wherein the DSC spectrum has endothermic peaks at 116 °C and 208 °C, the error range of which is ±2 °C.

[0020] This disclosure also provides a method for preparing crystal form A of the compound shown in Formula I, the method comprising:

[0021] a) The compound shown in Formula I is mixed with solvent A;

[0022] b) Stirring;

[0023] The solvent A is selected from water, C 1-4 Alcohol solvents, as well as water and C 1-4 Mixed solvents of alcohols; the C 1-4 Methanol and ethanol are preferred alcohol solvents.

[0024] In some embodiments, in the method for preparing crystal form A of the compound shown in Formula I, each milligram of the compound shown in Formula I is mixed with 0.01-0.05 ml of solvent A; more preferably, each milligram of the compound shown in Formula I is mixed with 0.01-0.03 ml of solvent A.

[0025] In some embodiments, in the method for preparing crystal form A, the stirring temperature is room temperature or 50°C.

[0026] In some embodiments, in the method for preparing crystal form A, the mixed solvent of water and alcohol is a mixed solvent of water and methanol, wherein the molar ratio of water to methanol is 0.10-0.95, preferably 0.14, 0.26, 0.37, 0.47, 0.57, 0.66, 0.74, 0.82, or 0.90.

[0027] The present disclosure also provides a B crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 6.770, 11.201, 12.989, 14.931, and 20.817, said 2Q angles being within error range of ±0.20.

[0028] In some embodiments, the B crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 20.817, and 25.710, said 2Q angles being within error range of ±0.20.

[0029] In some embodiments, the B crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 20.817, 25.710, 31.066, 32.046, and 32.913, said 2Q angles being within error range of ±0.20.

[0030] In some embodiments, the B crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 15.851, 17.228, 20.817, 22.313, 22.773, 25.710, 28.192, 31.066, 32.046, and 32.913, said 2Q angles being within error range of ±0.20.

[0031] In some embodiments, the B crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 20.817, and 25.710, said 2Q angles being within error range of ±0.20. Figure 6

[0032] In some embodiments, the B crystalline form of the compound of Formula I, wherein the DSC pattern has an endothermic peak at 210 °C, said endothermic peak being within error range of ±2 °C.

[0033] The present disclosure also provides a method of preparing the B crystalline form of the compound of Formula I, the method comprising:

[0034] a) mixing the compound of Formula I above with solvent B;

[0035] b) stirring;

[0036] The solvent B is selected from nitromethane and acetonitrile.

[0037] ​In some embodiments, in the preparation method of the B crystal form of the compound of Formula I, 100 mg of the compound of Formula I is mixed with 0.5-5 ml of solvent B; more preferably, 100 mg of the compound of Formula I is mixed with 0.5-2 ml of solvent B.

[0038] In some embodiments, in the preparation method of the B crystal form of the compound of Formula I, 100 mg of the compound of Formula I is mixed with 1 ml of solvent B.

[0039] In some embodiments, in the preparation method of the B crystal form, the temperature during stirring is room temperature or 50°C.

[0040] The present disclosure also provides a C crystal form of the compound of Formula I described above, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ has characteristic peaks at 7.385, 10.171, 12.687, 15.902 and 19.645, the 2θ angles having an error range of ±0.20.

[0041] In some embodiments, the C crystal form of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 15.120, 15.902 and 19.645, the 2θ angles having an error range of ±0.20.

[0042] In some embodiments, the C crystal form of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 15.120, 15.902, 19.645, 25.539 and 26.382, the 2θ angles having an error range of ±0.20.

[0043] In some embodiments, the C crystal form of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 13.720, 15.120, 15.902, 16.842, 19.645, 20.739, 25.539, 26.382, 27.272 and 30.887, the 2θ angles having an error range of ±0.20.

[0044] In some embodiments, the C crystal form of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2θ is as shown in Figure 10

[0045] ​In some embodiments, the C crystalline form of the compound of Formula I, wherein the DSC pattern has an endothermic peak at 209 °C, with an error range of ± 2 °C.

[0046] The present disclosure also provides a method for preparing the C crystalline form of the compound of Formula I, the method comprising:

[0047] a) mixing the compound of Formula I with solvent C;

[0048] b) stirring;

[0049] The solvent C is selected from the group consisting of N,N-dimethylformamide, acetone, butanone, tetrahydrofuran and 1,2-dimethoxyethane.

[0050] In some embodiments, in the method for preparing the C crystalline form of the compound of Formula I, 100 mg of the compound of Formula I is mixed with 0.5-5 ml of solvent C; more preferably, 100 mg of the compound of Formula I is mixed with 0.5-2 ml of solvent C, and most preferably, 100 mg of the compound of Formula I is mixed with 1 ml of solvent C.

[0051] In some embodiments, in the method for preparing the C crystalline form, the temperature during the stirring is room temperature or 50 °C.

[0052] The present disclosure also provides a D crystalline form of the compound of Formula I as described above, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335 and 17.275, with an error range of ± 0.20 in the 2 theta angles.

[0053] In some embodiments, the D crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275 and 18.775, with an error range of ± 0.20 in the 2 theta angles.

[0054] In some embodiments, the D crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2 theta has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, 18.775, 20.298, 23.990, 26.006 and 28.135, with an error range of ± 0.20 in the 2 theta angles.

[0055] In some embodiments, the D crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q angles, has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, 18.775, 20.298, 23.093, 23.990, 24.921, 26.006, 27.047, 28.135, and 33.461, said 2Q angles being in error by ±0.20.

[0056] In some embodiments, the D crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q angles, has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, 18.775, 20.298, 23.093, 23.990, 24.921, 26.006, 27.047, 28.135, and 33.461, said 2Q angles being in error by ±0.20. Figure 14

[0057] In some embodiments, the D crystalline form of the compound of Formula I, wherein the DSC pattern has an endothermic peak at 211 °C, said endothermic peak being in error by ±2 °C.

[0058] The present disclosure also provides a method for preparing the D crystalline form of the compound of Formula I, said method comprising:

[0059] a) mixing the compound of Formula I with a solvent D;

[0060] b) stirring;

[0061] said solvent D is selected from the group consisting of ethyl acetate, 1,2- dimethylbenzene, toluene, 1,4-dioxane, and hexane.

[0062] In some embodiments, in the method for preparing the D crystalline form of the compound of Formula I, 100 mg of the compound of Formula I is mixed with 0.5-5 ml of the solvent D; more preferably, 100 mg of the compound of Formula I is mixed with 0.5-2 ml of the solvent D, preferably, 100 mg of the compound of Formula I is mixed with 1 ml of the solvent D.

[0063] In some embodiments, in the method for preparing the D crystalline form, the temperature during the stirring is room temperature or 50 °C.

[0064] In some embodiments, the method of the present disclosure further comprises filtering, washing, and / or drying.

[0065] The present disclosure also provides an E crystalline form of the compound of Formula I as described above, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q angles, has characteristic peaks at 8.685, 15.433, 16.654, 17.526, and 18.779, said 2Q angles being in error by ±0.20.

[0066] ​In some embodiments, the E crystal form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, and 18.779, said 2Q angles being inaccurate by ±0.20.

[0067] In some embodiments, the E crystal form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, 18.779, 19.393, 20.610, 21.653, 23.319, and 24.151, said 2Q angles being inaccurate by ±0.20.

[0068] In some embodiments, the E crystal form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 7.233, 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, 18.779, 20.610, 21.653, 23.319, 24.151, 25.111, and 26.192, said 2Q angles being inaccurate by ±0.20.

[0069] In some embodiments, the E crystal form of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, is as shown in Figure 18

[0070] The present disclosure also provides a method for preparing the E crystal form of the compound of Formula I, which comprises the step of drying or heating the compound of Formula I, preferably at a temperature of 100 to 200°C.

[0071] In some embodiments, the method for preparing the E crystal form of the compound of Formula I, which comprises heating the solid compound of Formula I to a temperature of more than 100°C, preferably to a temperature of more than 120°C, more preferably to a temperature of more than 150°C.

[0072] The present disclosure also provides a pharmaceutical composition comprising the A crystal form, the B crystal form, the C crystal form, the D crystal form, or the E crystal form described above, and a pharmaceutically acceptable excipient.

[0073] The present disclosure also provides a method for preparing the pharmaceutical composition described above, which comprises the step of mixing the A crystal form, the B crystal form, the C crystal form, the D crystal form, or the E crystal form described above, with a pharmaceutically acceptable excipient.

[0074] ​The present disclosure also relates to the use of the above-mentioned Form A, Form B, Form C, Form D or Form E or the above-mentioned composition in the manufacture of a medicament for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha 1 -antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease rheumatoid arthritis, sinusitis, hidradenitis suppurativa or cancer.

[0075] The present disclosure also relates to a method for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha 1 -antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease rheumatoid arthritis, sinusitis, hidradenitis suppurativa or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the above-mentioned Form A, Form B, Form C, Form D or Form E or the above-mentioned composition.

[0076] The present disclosure also relates to the above-mentioned Form A, Form B, Form C, Form D or Form E or the above-mentioned composition for use in the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha 1 -antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, sinusitis, hidradenitis suppurativa or cancer.

[0077] The "2-theta or 2-theta angle" as described in the present disclosure refers to the diffraction angle, theta is the Bragg angle, in ° or degree; the error range of each characteristic peak 2-theta is ±0.20 (including the case that the number exceeding 1 decimal place is rounded), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0078] The "excipient" as described in the present disclosure includes but is not limited to any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifying agent which has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0079] The starting material used in the crystal form preparation method disclosed herein can be any form of compound, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.

[0080] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0081] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated data and inevitably contain a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%. Attached Figure Description

[0082] Figure 1 XRPD diagram of crystal form A;

[0083] Figure 2 The DSC diagram for crystal form A;

[0084] Figure 3 TGA image of crystal form A;

[0085] Figure 4 The DVS diagram for crystal form A;

[0086] Figure 5 The images show the XRPD spectra of crystal form A before and after DVS; (the top image shows the XRPD spectrum after DVS, and the bottom image shows the XRPD spectrum before DVS).

[0087] Figure 6 XRPD diagram of crystal form B;

[0088] Figure 7 The DSC diagram for crystal form B;

[0089] Figure 8 TGA image of crystal form B;

[0090] Figure 9 The DVS diagram for crystal form B;

[0091] Figure 10 The images show the XRPD spectra of crystal form B before and after DVS; (the top image shows the XRPD spectrum after DVS, and the bottom image shows the XRPD spectrum before DVS).

[0092] Figure 11 XRPD diagram of crystal form C;

[0093] Figure 12 DSC pattern of Form C;

[0094] Figure 13 TGA pattern of Form C;

[0095] Figure 14 DVS pattern of Form C;

[0096] Figure 15 XRPD patterns of Form C before and after DVS; (wherein the upper is the XRPD pattern after DVS, and the lower is the XRPD pattern before DVS)

[0097] Figure 16 XRPD pattern of Form D;

[0098] Figure 17 DSC pattern of Form D;

[0099] Figure 18 TGA pattern of Form D;

[0100] Figure 19 DVS pattern of Form D;

[0101] Figure 20 XRPD patterns of Form D before and after DVS; (wherein the upper is the XRPD pattern before DVS, and the lower is the XRPD pattern after DVS)

[0102] Figure 21 XRPD pattern of Form E;

[0103] Figure 22 DSC pattern of Form E;

[0104] Figure 23 TGA pattern of Form E. DETAILED DESCRIPTION

[0105] The disclosure will be explained in more detail with reference to the examples or experimental examples below, which are only used to illustrate the technical solutions in the disclosure, and do not limit the essence and scope of the disclosure.

[0106] The explanations of the abbreviations used in the disclosure are as follows:

[0107] XRPD X-ray powder diffraction

[0108] DSC differential scanning calorimetry

[0109] TGA thermogravimetric analysis

[0110] DVS dynamic water adsorption

[0111] 1H-NMR liquid nuclear magnetic hydrogen spectrum

[0112] DMF N,N-dimethylformamide

[0113] MEK butanone

[0114] MTBE methyl tert-butyl ether

[0115] THF tetrahydrofuran

[0116] IPA isopropyl alcohol

[0117] ACN acetonitrile

[0118] MeOH methanol

[0119] EOH ethanol

[0120] ACT acetone

[0121] EA ethyl acetate

[0122] PA phosphoric acid

[0123] TA tartaric acid

[0124] HBr hydrobromic acid

[0125] HCl hydrochloric acid

[0126] Test conditions of the instruments used in the experiments in the present disclosure:

[0127] 1. X-ray powder diffraction spectrum (XRPD)

[0128] Instrument model: Malver Panalytical Aeris X-ray powder diffractometer

[0129] Ray: monochromatic Cu-Kα ray (λ = 1.54188)

[0130] Scanning mode: θ / 2θ, scanning range (2θ range): 3.5-50°

[0131] Voltage: 40 kV, current: 15 mA

[0132] 2. Differential scanning calorimeter (DSC)

[0133] Instrument model: TA DSC250

[0134] Purging gas: nitrogen; nitrogen purging speed: 50 mL / min

[0135] Temperature rising rate: 10℃ / min

[0136] Temperature range: 25-300 °C

[0137] 3. Thermogravimetric Analysis (TGA)

[0138] Instrument model: TA TGA550

[0139] Purge gas: nitrogen; nitrogen purge rate: 20 ml / min

[0140] Heating rate: 10 °C / min

[0141] Temperature range: 30-350 °C

[0142] 4. Dynamic Vapor Sorption (DVS)

[0143] Detection using SMS Intrinsic PLUS, at 25 °C, humidity from 50-0-90%, in steps of 10%, with a criterion of mass change dM / dT less than 0.002% per gradient, TMAX 360 min, with two cycles.

[0144] 5. The high performance liquid chromatography (HPLC) chart described in the crystalline form stability test of the present disclosure is collected on Agilent 1260 Infinity II.

[0145] The HPLC conditions in the content detection method of the high performance liquid chromatography described in the present disclosure: chromatographic column: Agilent Eclipse Plus C18 4.6mm*150mm, 3.5μm; mobile phase: A: 10mmol / L sodium dihydrogen phosphate solution (pH 8.0), B-ACN; flow rate: 1.0ml / min; wavelength: 210nm.

[0146] The HPLC conditions in the related substance detection method of the high performance liquid chromatography described in Example 8 of the present disclosure: chromatographic column: Agilent Eclipse Plus C18 4.6mm*150mm, 3.5μm; mobile phase: A: 10mmol / L ammonium acetate solution, B-ACN; flow rate: 1.0ml / min; wavelength: 210nm.

[0147] The detection method conditions of the high performance liquid chromatography of the isomer of formula I in the present disclosure: chromatographic column CHIRALPAK IG-3 4.6mm*250mm 3μm or CHIRALPAK IG-3 4.0mm*10mm 3μm, mobile phase: A: n-hexane, B: anhydrous ethanol; n-hexane: anhydrous ethanol = 25:75, flow rate: 1.0ml / min; wavelength: 254nm.

[0148] Example 1: Preparation of the compound of formula I: (S)-N-((S)-1-cyano-2-(8-cyano- 2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepane-2-carboxamide

[0149]

[0150] Synthesis of compound I-2

[0151] Methyl 2-fluoro-5-hydroxybenzoate (4.30 g, 25.29 mmol), 4-bromo-3- (bromomethyl)benzonitrile (compound I-1) (7.72 g, 25.30 mmol) and potassium carbonate (6.99 g, 50.58 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature, and the reaction mixture was heated to 40 °C and stirred for 12 hours. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound I-2. 1 H NMR (400 MHz, CDCl3) d 7.87 (d, 1H), 7.73 (d, 1H), 7.55-7.48 (m, 2H), 7.18-7.09 (m, 2H), 5.11 (s, 2H), 3.95 (s, 3H).

[0152] Synthesis of compound I-3

[0153] Compound I-2 (2.90 g, 6.37 mmol), palladium acetate (0.14 g, 0.64 mmol), potassium carbonate (1.76 g, 12.73 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.23 g, 0.64 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature under nitrogen protection, and the reaction mixture was heated to 120 °C and stirred for 1.5 hours. After the reaction was completed, the mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound I-3. 1 H NMR (400 MHz, CDCl3) d 7.80-7.72 (m, 2H), 7.60 (d, 1H), 7.52-7.49 (m, 2H), 5.18 (s, 2H), 3.98 (s, 3H).

[0154] Synthesis of compound I-4

[0155] Compound I-3 (1.20 g, 3.81 mmol) and lithium borohydride (0.25 g, 11.47 mmol) were dissolved in tetrahydrofuran (25 mL) at room temperature, and the reaction mixture was heated to 55 °C and stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water (200 mL) was added, and extraction was performed with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. Filtration, and concentration of the filtrate under reduced pressure, the residue obtained was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound I-4. 1 H NMR (400 MHz, CDCI3) δ 7.67 (s, 2H), 7.47 (s, 1H), 7.38 (d, 1H), 7.12 (d, 1H), 5.11 (s, 2H), 4.77 (s, 2H).

[0156] Synthesis of compound I-5

[0157] Compound I-3 (450 mg, 1.59 mmol) was dissolved in dichloromethane (15 mL) at room temperature, and then phosphorus tribromide (520 mg, 1.92 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 20 minutes. After the reaction was completed, water (100 mL) was added, and extraction was performed with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filtration, and concentration of the filtrate under reduced pressure, the residue obtained was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to obtain compound I-5. 1 H NMR (300 MHz, CDCI3) δ 7.73 (s, 2H), 7.52 (s, 1H), 7.45 (d, 1H), 7.10 (d, 1H), 5.17 (s, 2H), 4.53 (s, 2H).

[0158] Synthesis of compound I-6

[0159] Diphenylmethyleneaminoacetonitrile (250 mg, 1.14 mmol), compound I-5 (470 mg, 1.26 mmol), benzyltrimethylammonium chloride (22 mg, 0.12 mmol) and sodium hydroxide (91 mg, 2.3 mmol) were dissolved in a mixed solvent of dichloromethane (6 mL) and water (6 mL) at room temperature, and the reaction mixture was heated to 35 °C and stirred for 24 hours. Water (30 mL) was added, and extraction was performed with dichloromethane (30 mL x 2). The organic phase was combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1) to obtain compound I-6. MS-ESI: m / z 458.4 [M+1] + .

[0160] Synthesis of compound I-7

[0161] Compound I-6 (520 mg, 0.90 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, followed by dropwise addition of 1M aqueous hydrochloric acid (4 mL), and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution (30 mL) was added, and extraction was performed with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated under reduced pressure. The obtained residue was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1) to obtain compound I-7. MS-ESI: m / z 293.9 [M+1] + .

[0162] Synthesis of compound I-8

[0163] Compound I-7 (220 mg, 0.68 mmol), compound a (170 mg, 0.69 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (360 mg, 0.95 mmol), and N,N-diisopropylethylamine (250 mg, 1.93 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, preparative liquid chromatography (C18, acetonitrile / water system) was performed to obtain compound I-8. MS-ESI: m / z 465.1 [M-56+1] + .

[0164] Synthesis of compound I-9

[0165] Compound I-8 (280 mg, 0.51 mmol) was subjected to chiral resolution (column: chiralpak IE, 250*25 mm, 5 μm; mobile phase: n-hexane, ethanol; gradient ratio: n-hexane phase 30%; flow rate: 15 mL / min; column temperature: 30 °C) to give compound I-9 (two diastereomeric peaks in common, compound I-9 was the first eluted peak). 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, 1H), 8.05 (d, 1H), 7.89-7.86 (m, 2H), 7.80 (s, 1H), 7.03 (d, 1H), 5.20-5.12 (m, 2H), 5.09-5.02 (m, 1H), 4.00-3.97 (m, 1H), 3.88-3.83 (m, 1H), 3.77-3.68 (m, 1H), 3.25-3.14 (m, 2H), 3.05-2.98 (m, 1H), 2.82-2.72 (m, 1H), 2.62-2.53 (m, 2H), 1.80-1.66 (m, 2H).

[0166] Synthesis of compound I

[0167] Compound I-9 (85 mg, 0.16 mmol) was dissolved in formic acid (1 mL) at room temperature, and the reaction mixture was heated to 40 °C and stirred for 1 hour. After the reaction was completed, compound I was obtained by preparative liquid chromatography (C18, ammonium bicarbonate / acetonitrile / water system). The obtained compound was detected by XRPD to be amorphous.

[0168] MS-ESI: m / z 421.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, 1H), 8.05 (d, 1H), 7.89-7.86 (m, 2H), 7.80 (s, 1H), 7.03 (d, 1H), 5.20-5.12 (m, 2H), 5.09-5.02 (m, 1H), 4.00-3.97 (m, 1H), 3.88-3.83 (m, 1H), 3.77-3.68 (m, 1H), 3.25-3.14 (m, 2H), 3.05-2.98 (m, 1H), 2.82-2.72 (m, 1H), 2.62-2.53 (m, 2H), 1.80-1.66 (m, 2H).

[0169] Example 2: Biological evaluation of the compound of formula I - in vitro CatC cell activity detection experiment

[0170] 1. Experimental materials

[0171]

[0172]

[0173] 2. Experimental procedure

[0174] Prepare complete medium RPMI1640+10%FBS, mix well. Resuscitate U937 cell line, pass for two generations or so to select cell strain with good growth condition. Take cell suspension and move into centrifuge tube, centrifuge at 800-1000 rpm for 3-5 minutes. Discard supernatant. Add appropriate volume of medium to centrifuge tube, gently blow to resuspend cells uniformly. Use Vi-Cell XR cell counter to count. Adjust cell suspension to appropriate concentration. Add cell suspension to 384-well plate, 25000 μl / well. Prepare compound in DMSO to 10 mM solution, dilute compound in DMSO to 1 mM solution, and use HPD300 to dilute 10 points in DMSO. Prepare Gly-Phe-AFC in DMSO to 35 mM solution, aliquot, and use serum-free medium to configure Gly-Phe-AFC to 1.75 mM. After adding the drug, incubate in the incubator for 1 h, then add substrate-AFC, 12.5 μl to the plate. Incubate for 30 min, then measure the plate. Place the culture plate in EnSpire plate reader, record the fluorescence reading results at Ex 400 nm, Em 505 nm, and calculate the inhibition rate according to the following formula: Inhibition rate (%) = (1-(RFU compound-RFU blank) / (RFU DMSO-RFU blank)) x 100%. Use XLFit to draw the pharmacodynamic inhibition rate curve and calculate IC 50 value. Use 4-parameter model [fit=(A+((B-A) / (1+((C / x)^D))))].

[0175] The compound of formula I of the present disclosure was measured for in vitro CatC cell activity inhibition by the above test, and the measured IC 50 value was 6.1 nM, which was significantly effective in inhibiting CatC cell activity.

[0176] Example 3: Preparation of crystalline form A of the compound of formula I

[0177] Add 10 mg of the compound of formula I to 0.2 mL of solvent, keep formula I in slurry in the solvent, stir at room temperature (about 25°C) or 50°C for one week, filter, and the obtained solid is detected by XRPD to be free crystalline form A, as shown in Table 1 below.

[0178] Table 1: Selection of solvents for slurry crystallization of A crystalline form and XRPD detection results

[0179] Solvent (molar ratio of water in mixed solvent) Crystal form (stirring at room temperature) Crystal form (stirring at 50°C) Water A A MeOH A A EOH A A 0.14 (water / MeOH) A A 0.26 (water / MeOH) A A 0.37 (water / MeOH) A A 0.47 (water / MeOH) A A 0.57 (water / MeOH) A A 0.66 (water / MeOH) A A 0.74 (water / MeOH) A A 0.82 (water / MeOH) A A 0.90 (water / MeOH) A A

[0180] The product is defined as crystalline form A by X-ray powder diffraction detection, and the XRPD spectrum is as follows:Figure 1 The positions of its characteristic peaks are shown in Table 2. The DSC spectrum is shown below. Figure 2 As shown, the endothermic peaks are at 116℃ and 208℃. The TGA spectrum is as follows. Figure 3 As shown, weight loss is 2% before 100℃, and rapid weight loss occurs above 200℃.

[0181] Table 2. XRPD characteristic diffraction peak data for crystal form A.

[0182]

[0183] DVS detection such as Figure 4 As shown, under accelerated experimental conditions (i.e., 80% RH), the moisture absorption weight gain was approximately 5.39%. During the humidity change process from 0% to 90% RH, the desorption and adsorption processes of this sample were consistent. Furthermore, the crystal form was re-determined after DVS analysis, and the XRPD spectrum is shown below. Figure 5 As shown, XRPD detection revealed that the crystal form did not change before and after DVS detection.

[0184] Example 4: Preparation of crystal form B of the compound shown in Formula I

[0185] Approximately 100 mg of compound I was added to 1 ml of solvent, and the mixture was kept in the solvent to form a slurry. The mixture was stirred at room temperature (approximately 25°C) or 50°C for 7 days. After filtration, the resulting solid was detected by XRPD to be free crystalline form B, as shown in Table 3 below.

[0186] Table 3 Solvent selection and XRPD detection results for B-type preparation by pulping and crystallization.

[0187] Solvent Crystal form (stirring at room temperature) Crystal form (stirring at 50°C) Nitromethane B B Acetonitrile B B

[0188] X-ray powder diffraction analysis determined the product to be crystal form B. The XRPD spectrum is shown below. Figure 6 The positions of its characteristic peaks are shown in Table 4. The DSC spectrum is shown below. Figure 7 As shown, the endothermic peak values ​​are 114.55℃ and 209.87℃. The TGA spectrum is as follows. Figure 8 As shown.

[0189] DVS detection such as Figure 9 As shown, under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain is approximately 0.93%; under accelerated experimental conditions (i.e., 80% RH), the moisture absorption weight gain is approximately 1.60%; and under extreme conditions (i.e., 90% RH), the moisture absorption weight gain is approximately 3.87%. Furthermore, the crystal form was re-determined after DVS analysis, and the XRPD spectrum is shown below. Figure 10 As shown, XRPD detection revealed that the crystal form did not change before and after DVS detection.

[0190] Table 4. XRPD characteristic diffraction peak data for crystal form B.

[0191]

[0192] Example 5: Preparation of crystalline Form C of the compound of Formula I

[0193] About 100 mg of Compound I was added to 1 ml of solvent to keep Formula I in slurry in the solvent, stirred at room temperature (about 25 °C) or 50 °C for 7 days, filtered, and the obtained solid was detected as Form C by XRPD, as shown in Table 5 below.

[0194] Table 5. Selected solvents for slurry crystallization to prepare Form C and XRPD detection results

[0195] Solvent Crystal form (stirring at room temperature) Crystal form (stirring at 50°C) DMF C C Acetone C C MEK C C THF C / 1,2-Dimethylethane C C

[0196] The product was defined as Form C by X-ray powder diffraction, and the XRPD spectrum is shown in Figure 11 , and the characteristic peak positions are shown in Table 6. The DSC spectrum is shown in Figure 12 , showing endothermic peaks with peak values of 75.84 °C and 208.87 °C. The TGA spectrum is shown in Figure 13 .

[0197] The DVS detection is shown in Figure 14 , showing that under normal storage conditions (i.e. 25 °C, 60% RH), the sample absorbs moisture and increases in weight by about 0.65%; under accelerated experimental conditions (i.e. 80% RH), the moisture absorption and weight increase is about 0.89%; and under extreme conditions (i.e. 90% RH), the moisture absorption and weight increase is about 1.16%. After DVS detection, the Form C was retested by XRPD, and the XRPD spectrum is shown in Figure 15 , and the XRPD detection shows that the Form C does not change before and after DVS detection.

[0198] Table 6. XRPD characteristic diffraction peak data of Form C

[0199]

[0200] Example 6: Preparation of crystalline Form D of the compound of Formula I

[0201] About 100 mg of Compound I was added to 1 ml of solvent to keep Formula I in slurry in the solvent, stirred at room temperature (about 25 °C) or 50 °C for 7 days, filtered, and the obtained solid was detected as Form D by XRPD, as shown in Table 7 below.

[0202] Table 7. Selected solvents for slurry crystallization to prepare Form D and XRPD detection results

[0203]

[0204]

[0205] The product was defined as Form D by X-ray powder diffraction, and the XRPD spectrum is shown in Figure 1. Figure 16 The characteristic peak positions are shown in Table 8. The DSC spectrum is shown in Figure 2, which shows an endothermic peak with a peak value of 211.29 °C. The TGA spectrum is shown in Figure 3. Figure 17 Figure 18

[0206] The DVS test is shown in Figure 4, which shows that under normal storage conditions (i.e. 25 °C, 60% RH), the sample absorbs moisture and increases in weight by about 0.64%; under accelerated test conditions (i.e. 80% RH), the moisture absorption is about 0.76%; and under extreme conditions (i.e. 90% RH), the moisture absorption is about 0.84%. After the DVS test, the crystal form was retested by XRPD, and the XRPD spectrum is shown in Figure 5, which shows that the crystal form does not change before and after the DVS test. Figure 19 Figure 20

[0207] Table 8 XRPD characteristic diffraction peak data of Form D

[0208]

[0209] Example 7: Preparation of Form E of the compound of Formula I

[0210] The compound of Formula I, Form B, Form C, Form D obtained in Example 1 were dried at 120 °C under vacuum for 30 min, and the obtained solid was detected by XRPD as free Form E.

[0211] The compound of Formula I, Form B, C, D obtained in Example 1 were heated at 150 °C, and the obtained solid was detected by XRPD as free Form E. The XRPD spectrum is shown in Figure 6. Figure 21 The characteristic peak positions are shown in Table 9. The DSC spectrum is shown in Figure 7, which shows an endothermic peak with a peak value of 207.44 °C. The TGA spectrum is shown in Figure 8. Figure 22 Figure 23

[0212] Table 9 XRPD characteristic diffraction peak data of Form E

[0213]

[0214] Example 8: Stability test of free base Form E of the compound of Formula I

[0215] To determine whether temperature and humidity have an effect on the stability of free base Form E of the compound of Formula I:

[0216] ​​​​​​The free base Form E was placed in a light-stable box, and a series of temperature and humidity combination conditions were used for the influence factor experiment. The samples were taken out after being placed under light and each temperature and humidity condition for different days, and the related substances (impurities) were checked by high performance liquid chromatography. The obtained solid was compared with the initial free base Form E, and there was no obvious increase or only slight increase in impurities; the samples were taken out after being placed under light for different days, and the impurities increased, and the results are shown in Table 10.

[0217] The samples taken out on the last day of being placed under light and each temperature and humidity condition were detected by XRPD, and it was shown that the free base Form E had no change and had good stability.

[0218] Table 10 Influence factor results after drying treatment of free base Form E

[0219]

[0220]

Claims

1. A crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 8.910, 10.273, 15.650, 18.617, 17.869 and 19.526, said 2Q angles being within error range of ±0.20, 2. The crystalline form of claim 1, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 8.910, 10.273, 13.730, 15.650, 17.869, 18.617, 19.526 and 23.452, said 2Q angles being within error range of ±0.

20.

3. The crystalline form of claim 1, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 8.910, 10.273, 13.730, 15.650, 17.869, 18.617, 19.526, 20.785, 22.193, 23.452, 25.049 and 26.590, said 2Q angles being within error range of ±0.

20.

4. The crystalline form of any one of claims 1-3, wherein the DSC pattern has endothermic peaks at 116 °C and 208 °C, said endothermic peaks being within error range of ±2 °C.

5. A method of preparing the crystalline form of any one of claims 1-3, the method comprising: a) mixing the compound of Formula I with solvent A; b) stirring; The solvent A is selected from water, C 1-4 alcoholic solvents, and water and C 1-4 a mixture of alcoholic solvents.

6. The method of manufacture according to claim 5, wherein the C 1-4 The alcoholic solvent is selected from methanol and ethanol.

7. A crystalline form of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 6.770, 11.201, 12.989, 14.931 and 20.817, said 2Q angles being within error range of ±0.20, 8. The crystalline form of claim 7, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 20.817 and 25.710, said 2Q angles being within error range of ±0.

20.

9. The crystalline form of claim 7, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 20.817, 25.710, 31.066, 32.046 and 32.913, said 2Q angles being within error range of ±0.

20.

10. The crystalline form of claim 7, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 15.851, 17.228, 20.817, 22.313, 22.773, 25.710, 28.192, 31.066, 32.046 and 32.913, said 2Q angles being within error range of ±0.

20.

11. The crystalline Form B of claim 7, wherein the DSC pattern has endothermic peaks at 114 °C and 210 °C, with an error range of ± 2 °C.

12. A process for preparing the crystalline Form B of claim 7, the process comprising: a) mixing the compound of Formula I with solvent B; b) stirring; wherein the solvent B is selected from nitromethane and acetonitrile.

13. A crystalline Form C of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 7.385, 10.171, 12.687, 15.902, and 19.645, with an error range of ± 0.20, 14. The crystalline Form C of claim 13, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 15.120, 15.902, and 19.645, with an error range of ± 0.

20.

15. The crystalline Form C of claim 13, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 15.120, 15.902, 19.645, 25.539, and 26.382, with an error range of ± 0.

20.

16. The crystalline Form C of claim 13, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 13.720, 15.120, 15.902, 16.842, 19.645, 20.739, 25.539, 26.382, 27.272, and 30.887, with an error range of ± 0.

20.

17. The crystalline Form C of claim 13, wherein the DSC pattern has endothermic peaks at 76 °C and 209 °C, with an error range of ± 2 °C.

18. A process for preparing the crystalline Form C of claim 13, the process comprising: a) mixing the compound of Formula I with solvent C; b) stirring; wherein the solvent C is selected from N,N-dimethylformamide, acetone, butanone, tetrahydrofuran, and 1,2-dimethylethane.

19. A crystalline Form D of the compound of Formula I, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, and 17.275, with an error range of ± 0.20, 20. The crystalline Form D of claim 19, wherein the X-ray powder diffraction pattern expressed in terms of diffraction angles 2Q has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, and 18.775, with an error range of ± 0.

20. ​ ​ ​ ​ ​ ​ 21. The crystalline Form D of claim 19, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, 18.775, 20.298, 23.990, 26.006, and 28.135, said 2Q angles being inaccurate by ±0.

20.

22. The crystalline Form D of claim 19, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, 18.775, 20.298, 23.093, 23.990, 24.921, 26.006, 27.047, 28.135, and 33.461, said 2Q angles being inaccurate by ±0.

20.

23. The crystalline Form D of claim 19, wherein the DSC pattern has an endothermic peak at 211 °C, said endothermic peak being inaccurate by ±2 °C.

24. A process for preparing the crystalline Form D of claim 19, said process comprising: a) mixing the compound of Formula I with a solvent D; b) stirring; said solvent D being selected from the group consisting of ethyl acetate, 1,2- dimethylbenzene, toluene, 1,4-dioxane, and hexane.

25. A crystalline Form E of the compound of Formula I, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 8.685, 15.433, 16.654, 17.526, and 18.779, said 2Q angles being inaccurate by ±0.

20.

26. The crystalline Form E of claim 25, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, and 18.779, said 2Q angles being inaccurate by ±0.

20.

27. The crystalline Form E of claim 25, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, 18.779, 19.393, 20.610, 21.653, 23.319, and 24.151, said 2Q angles being inaccurate by ±0.

20.

28. The crystalline Form E of claim 25, wherein the X-ray powder diffraction pattern, expressed in terms of diffraction angles 2Q, has characteristic peaks at 7.233, 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, 18.779, 20.610, 21.653, 23.319, 24.151, 25.111, and 26.192, said 2Q angles being inaccurate by ±0.

20.

29. The E crystalline form of claim 25, wherein the DSC profile has an endothermic peak at 207 °C with an error range of ± 2 °C.

30. A pharmaceutical composition comprising the crystalline form of any one of claims 1-3, 7-10, 13-16, 19-22, and 25-28 and a pharmaceutically acceptable excipient.

31. Use of the crystalline form of any one of claims 1-3, 7-10, 13-16, 19-22, and 25-28 or the pharmaceutical composition of claim 30 in the manufacture of a medicament for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, alpha 1 -antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, sinusitis, hidradenitis suppurativa, or cancer.

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