Salt of benzothiazole compound and crystal form and application thereof

Abstract

The invention relates to a salt of a benzothiazole compound as shown in a formula I and a crystal form and application thereof, the salt is selected from pamoate and palmitate, and the invention also relates to application of the salt of the compound as shown in the formula I and the crystal form thereof in preparation of medicines for treating Parkinson's disease and restless leg syndrome. # imgabs0 #

Description

[0001] This application claims priority to Chinese Application No. 202011304450.1, filed on November 19, 2020, entitled “Salts of benzothiazole compounds, their crystalline forms and uses”, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to a salt of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole and its crystal form and use. Background Art

[0003] Parkinson's disease (PD) is a disorder of the motor system of the nervous system. It is characterized by a progressive disease that affects movement and leads to the loss of dopamine-producing brain cells, causing tremors in the hands, arms, legs, jaws and face and / or stiffness or rigidity of the limbs and trunk. The main symptoms include muscle rigidity, slow movements, resting tremors and postural instability.

[0004] (S)-2-Amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (hereinafter referred to as "Compound I") is a non-ergot dopamine receptor agonist developed by Boehringer Ingelheim, Germany. Currently, the products listed in China and abroad are mainly hydrochloride immediate-release tablets and hydrochloride sustained-release tablets, which are used to treat Parkinson's disease and restless legs syndrome.

[0005] According to the survey, most Parkinson's patients are middle-aged and elderly people, among whom the incidence of dysphagia is as high as 70-90%, which increases the risk of aspiration pneumonia by 15-50%. Dysphagia occurs in the early stage of the disease and accompanies the entire course of the disease. It is very easy to cause choking and coughing, which increases the risk of aspiration pneumonia, and aspiration pneumonia is one of the main causes of death in Parkinson's patients. Current clinical drugs are mainly oral, and multiple doses are required per day. The single dose is large, and compliance needs to be improved urgently. In addition, the pulse-like stimulation secondary to the fluctuation of dopamine blood concentration will further aggravate the abnormality of dopamine receptor levels and function. Only continuous and stable dopamine stimulation can control or reduce the occurrence of adverse reactions of motor complications. In addition, long-term release schemes of more than 24 hours will also help patients comply, because patients with advanced PD are usually non-compliant, making it difficult to assess whether patients have received appropriate doses of drugs.

[0006] In summary, the clinical practice advocates the use of long-acting sustained-release preparations, such as oral sustained-release, long-acting patches, and long-acting injections to maintain stable blood drug concentrations and improve patient compliance; therefore, there is an urgent need to seek salt forms and their crystal forms that can be used for long-acting sustained-release preparations. Summary of the invention

[0007] The first aspect of the present invention provides a salt of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (whose structural formula is shown in Formula I), wherein the salt is selected from pamoate and palmitate,

[0008]

[0009] In some embodiments, the salt of the compound of Formula I is palmitate.

[0010] The second aspect of the present invention provides a crystal of a salt of Compound I, such as Compound I pamoate crystals AS and palmitate crystals TV. The third aspect of the present invention provides a pharmaceutical composition comprising a salt of Compound I, the salt being selected from pamoate and palmitate, in particular Compound I pamoate crystals or palmitate crystals, and one or more pharmaceutically acceptable carriers.

[0011] The fourth aspect of the present invention provides the use of a salt of Compound I or a crystal thereof, in particular Compound I pamoate crystals AS and palmitate crystals TV or a pharmaceutical composition, in the preparation of a medicament for treating Parkinson's disease and restless legs syndrome.

[0012] The salt of compound I of the present invention or its crystal has low solubility, can achieve sustained release effect, and prepare long-acting sustained release preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 This is the X-ray powder diffraction (XRPD) pattern of Compound I pamoate crystal A.

[0014] Figure 2 This is the XRPD pattern of Compound I pamoate crystal B.

[0015] Figure 3 This is the XRPD pattern of Compound I pamoate crystal C.

[0016] Figure 4 This is the XRPD pattern of Compound I pamoate crystal D.

[0017] Figure 5 This is the XRPD pattern of Compound I pamoate crystal E.

[0018] Figure 6 This is the XRPD pattern of Compound I pamoate crystal F.

[0019] Figure 7 This is the XRPD pattern of Compound I pamoate crystal G.

[0020] Figure 8 This is the XRPD pattern of Compound I pamoate crystal H.

[0021] Fig. 9 This is the XRPD spectrum of Compound I pamoate crystals I.

[0022] Fig.10 This is the XRPD pattern of Compound I pamoate crystal J.

[0023] Fig.11 This is the XRPD pattern of Compound I pamoate crystal K.

[0024] Fig.12 This is the XRPD pattern of Compound I pamoate crystal L.

[0025] Fig.13 This is the XRPD pattern of Compound I pamoate crystals M.

[0026] Fig.14 This is the XRPD pattern of Compound I pamoate crystal N.

[0027] Fig.15 This is the XRPD pattern of Compound I pamoate crystal O.

[0028] Fig.16 This is the XRPD pattern of compound I pamoate crystals P.

[0029] Fig.17 This is the XRPD pattern of Compound I pamoate crystal Q.

[0030] Fig.18 This is the XRPD pattern of Compound I pamoate crystal R.

[0031] Fig.19 This is the XRPD pattern of Compound I pamoate crystals S.

[0032] Fig. 20 This is the XRPD pattern of Compound I palmitate crystal T.

[0033] Fig.21 This is the XRPD pattern of Compound I palmitate crystal U.

[0034] Fig. 22 This is the XRPD pattern of Compound I palmitate crystal V. DETAILED DESCRIPTION OF THE INVENTION

[0036] definition

[0037] Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

[0038] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0039] As used herein, the term "about" means within an acceptable standard error considered by one of ordinary skill in the art to be within the stated value, e.g., ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3, etc.

[0040] In this document, "Compound I" and "Compound represented by Formula I" both refer to compounds having the structural formula of the following Formula I, and can be used interchangeably herein.

[0041]

[0042] The term "pharmaceutical composition" refers to an active ingredient, such as Compound I or its pamoate or palmitate, one or more of the crystalline forms of the present invention, or one or more of the crystalline compositions of the present invention, which may be optionally combined with one or more pharmaceutically acceptable chemical components (such as, but not limited to, carriers and / or excipients).

[0043] The term "administration" or "administering" etc. refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc.

[0044] With respect to a drug or pharmacologically active agent, the term "effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in the composition can be the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0045] The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition. As used herein, the term may refer to, for example, a compound of Formula I or a pamoate or palmitate thereof, one or more of the crystalline forms of the present invention, or one or more of the crystalline compositions of the present invention.

[0046] The term "amorphous" as used herein refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As described below, amorphous solids produce diffuse XRPD patterns that typically include one or two broad peaks (i.e., peaks with a base width of about 5° 2θ or greater).

[0047]

[00136] The term "crystalline form" or "crystal" as used herein refers to any solid material that exhibits a three-dimensional ordering, in contrast to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0048] As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0049] In an X-ray powder diffraction (XRPD or XRD) spectrum, the diffraction pattern obtained from a crystalline compound is often characteristic for a specific crystal form, where the relative intensity of the bands (especially at low angles) may vary due to the effect of the preferred orientation caused by differences in crystallization conditions, particle size and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic for the crystal form in question, and when judging whether it is the same as a known crystal form, more attention should be paid to the relative position of the peaks rather than their relative intensity. In addition, for any given crystal form, there may be slight errors in the position of the peaks, which is also well known in the field of crystallography. For example, due to changes in temperature, sample movement or calibration of the instrument when analyzing the sample, the position of the peak can move, and the measurement error of the 2θ value is sometimes about ±0.2°. Therefore, this error should be taken into account when determining the structure of each crystal form. If the crystal form of the present invention is described as being substantially as shown in a specified figure, the term "substantially" is also intended to cover such differences in the position of the diffraction peaks.

[0050] In XRPD spectra, the peak position is usually represented by the 2θ angle or the crystal plane distance d, and there is a simple conversion relationship between the two: d = λ / 2sinθ, where d represents the crystal plane distance, λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. For the same type of crystal form of the same compound, the peak position of its XRPD spectrum is similar overall, and the relative intensity error may be large. It should also be pointed out that in the identification of a mixture, due to factors such as a decrease in content, some diffraction lines may be missing. At this time, there is no need to rely on all the bands observed in a high-purity sample, and even one band may be characteristic for a given crystal.

[0051] The term "2θ" as used herein refers to the peak position expressed in degrees based on the experimental setup of an X-ray diffraction experiment, and is typically the unit of the abscissa in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2θ. It should be understood that the specific 2θ values ​​of a specific crystalline form mentioned herein are intended to represent the 2θ values ​​(expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0052] The term "thermogravimetric analysis (TGA) spectrum" as used herein refers to a curve recorded by a thermogravimetric analyzer.

[0053] As used herein, the term "differential scanning calorimetry (DSC) spectrum" refers to a curve recorded by a differential scanning calorimeter.

[0054] As used herein, the term "nuclear magnetic resonance ( 1 H-NMR) spectrum” refers to the signal peaks recorded by a nuclear magnetic resonance instrument.

[0055] As used herein, the term "substantially the same" for X-ray diffraction peak positions means that representative peak position and intensity variations are taken into account. For example, one skilled in the art will understand that peak position (2θ) will show some variation, typically as much as 0.1-0.2 degrees, and that the instrument used to measure diffraction will also show some variation. In addition, one skilled in the art will understand that relative peak intensities will show variation between instruments and due to variation in degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to one skilled in the art, and should be considered as only qualitative measurements.

[0056] As used herein, the term "room temperature" refers to 20°C ± 5°C.

[0057] Salt of compound I and its crystal

[0058] The present invention provides a salt of (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (Compound I), wherein the salt is selected from pamoate and palmitate.

[0059]

[0060] In other embodiments, the salt of the compound of formula (I) is the palmitate salt of the compound of formula (I).

[0061] In some embodiments, the salt of the compound of formula (I) is the pamoate salt of the compound of formula (I).

[0062] Compound I pamoate and its crystals (1:1)

[0063] In some embodiments, the stoichiometric ratio of Compound 1 to pamoic acid in the Compound 1 pamoate salt is 1:1.

[0064] Crystal A

[0065] In some embodiments, the present invention provides Compound I pamoate crystals A, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 4.76±0.2. o , 7.07±0.2 o , 8.32±0.2 o , 10.7±0.2 o , 11.73±0.2 o , 13.29±0.2 o , 16.25±0.2 o , 18.45±0.2 o , 21.51±0.2 o , 24.81±0.2 o and 26.17±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal A also includes a diffraction peak at about 17.87±0.2 o , 22.01±0.2 o , 25.17±0.2 o The diffraction peak at 2θ.

[0066] In some embodiments, the XRPD pattern of Compound I Pamoate Crystal A comprises a peak at about 4.76 ± 0.2 o , 7.07±0.2 o , 8.32±0.2 o , 10.7±0.2 o , 11.73±0.2 o , 13.29±0.2 o , 16.25±0.2 o , 17.87±0.2 o , 18.45±0.2 o , 21.51±0.2o , 22.01±0.2 o , 24.81±0.2 o , 25.17±0.2 o and 26.17±0.2 o The diffraction peak at 2θ.

[0067] In some embodiments, the XRPD pattern of Compound I pamoate crystal A includes the following diffraction peaks at 2θ:

[0068]

[0069]

[0070] In some embodiments, the XRPD pattern of Compound I Pamoate Crystal A is substantially as follows Figure 1 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal A is as shown in Figure 1 shown.

[0071] Crystal B

[0072] In some embodiments, the present invention provides Compound I pamoate crystal B, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 5.79±0.2. o , 6.38±0.2 o , 10.95±0.2 o , 14.72±0.2 o , 17.61±0.2 o , 18.40±0.2 o , 19.81±0.2 o and 22.18±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal B also includes a diffraction peak at about 10.61±0.2 o , 12.51±0.2 o , 17.61±0.2 o and 20.01±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal B also includes a diffraction peak at about 10.18±0.2 o , 13.15±0.2 o and 13.36±0.2 o The diffraction peak at 2θ.

[0073] In some embodiments, the XRPD pattern of Compound I Pamoate Crystal B includes a peak at about 5.79 ± 0.2o , 6.38±0.2 o , 10.61±0.2 o , 10.95±0.2 o , 12.51±0.2 o , 14.72±0.2 o , 17.61±0.2 o , 18.40±0.2 o , 19.81±0.2 o , 20.01±0.2 o and 22.18±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal B includes a diffraction peak at about 5.79±0.2 o , 6.38±0.2 o , 10.18±0.2 o , 10.61±0.2 o , 10.95±0.2 o , 12.51±0.2 o , 13.15±0.2 o , 13.36±0.2 o , 14.72±0.2 o , 17.61±0.2 o , 18.40±0.2 o , 19.81±0.2 o , 20.01±0.2 o and 22.18±0.2 o The diffraction peak at 2θ.

[0074] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal B includes the following diffraction peaks at 2θ:

[0075]

[0076]

[0077] In some embodiments, the XRPD pattern of Compound I Pamoate Crystals B is substantially as follows Figure 2 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal B is as shown in Figure 2 shown.

[0078] Crystal C

[0079] In some embodiments, the present invention provides Compound I pamoate crystals C, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 7.43±0.2. o , 11.18±0.2 o , 11.98±0.2 o , 14.78±0.2 o , 20.20±0.2 o , 20.97±0.2 o and 23.30±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal C also includes a diffraction peak at about 16.90±0.2 o , 19.73±0.2 o , 22.12±0.2 o and 25.37±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal C also includes a diffraction peak at about 19.34±0.2 o and 22.91±0.2 o The diffraction peak at 2θ.

[0080] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal C includes a peak at about 7.43 ± 0.2 o , 11.18±0.2 o , 11.98±0.2 o , 14.78±0.2 o , 16.90±0.2 o , 19.73±0.2 o , 20.20±0.2 o , 20.97±0.2 o , 22.12±0.2 o , 23.31±0.2 o and 25.37±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal C includes a diffraction peak at about 7.43±0.2 o , 11.18±0.2 o , 11.98±0.2 o , 14.78±0.2 o , 16.90±0.2 o , 19.34±0.2 o , 19.73±0.2 o , 20.20±0.2 o , 20.97±0.2 o, 22.12±0.2 o , 22.91±0.2 o , 23.31±0.2 o and 25.37±0.2 o The diffraction peak at 2θ.

[0081] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal C includes the following diffraction peaks at 2θ:

[0082] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 6.14 10.41 16.13 6.61 22.12 22.49 29.85 17.75 7.43 17.62 16.61 24.64 22.91 40.27 30.52 13.05 10.11 2.94 16.90 34.42 23.31 54.64 31.56 12.89 10.54 4.96 17.14 15.7 23.52 18.37 32.16 8.14 11.18 53.18 17.56 3.03 24.19 11.85 33.11 4.14 11.45 15.47 17.83 21.03 24.46 9.23 34.26 7.77 11.67 22.17 18.41 13.59 24.94 18.48 34.73 11.38 11.98 74.3 18.72 21.32 25.37 27.48 35.59 10.85 13.37 11.72 19.34 51.54 26.29 10.45 36.79 8.54 13.68 27.29 19.73 39.88 26.67 9.81 38.04 5.01 14.78 100 20.20 76.83 27.46 9.36 39.28 2.41 15.09 26.67 20.68 13.81 28.24 12.56 15.56 19.79 20.97 76.23 28.95 4.45

[0083] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal C is substantially as follows Figure 3 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal C is as shown in Figure 3 shown.

[0084] Crystal D

[0085] In some embodiments, the present invention provides Compound I pamoate crystal D, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 11.24±0.2 o , 11.88±0.2 o , 12.03±0.2 o , 13.57±0.2 o , 14.76±0.2 o , 15.17±0.2 o , 20.85±0.2 o , 21.15±0.2 o and 23.26±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal D also includes a diffraction peak at about 15.17±0.2 o , 16.92±0.2 o and 24.24±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal D also includes a diffraction peak at about 19.3709±0.2 o and 20.2490±0.2 o The diffraction peak at 2θ.

[0086] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal D comprises a peak at about 11.24 ± 0.2 o , 11.88±0.2 o , 12.03±0.2 o , 13.57±0.2o , 14.76±0.2 o , 15.17±0.2 o , 16.92±0.2 o , 20.85±0.2 o , 21.15±0.2 o , 23.26±0.2 o and 24.24±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal D includes a diffraction peak at about 11.24±0.2 o , 11.88±0.2 o , 12.03±0.2 o , 13.57±0.2 o , 14.76±0.2 o , 15.17±0.2 o , 16.92±0.2 o , 19.37±0.2 o , 20.85±0.2 o , 21.15±0.2 o , 23.26±0.2 o , 24.24±0.2 o and 20.25±0.2 o The diffraction peak at 2θ.

[0087] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal D includes the following diffraction peaks at 2θ:

[0088] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 7.33 17.63 17.87 27.79 23.91 17.2 31.31 9.52 7.54 15.65 18.21 14.28 24.24 32.97 32.31 7.18 11.24 61.09 18.90 14.2 24.85 20.41 33.25 5.85 11.88 44.05 19.37 34.69 25.34 10.18 34.33 20.54 12.03 70.78 19.80 28.85 25.66 18.12 35.52 8.07 13.57 43.29 20.25 73.87 26.39 7.83 36.11 4.81 14.76 100 20.85 40.65 27.16 17.11 36.81 9.4 15.17 48.71 21.15 50.06 28.19 11.55 37.34 2.71 15.69 14.69 22.25 31.28 29.07 6.96 38.51 4.7 16.51 20 22.68 18.04 29.53 18.19 16.92 38.43 22.91 24.52 29.93 7.52 17.39 14.84 23.26 47.86 30.84 7.97

[0089] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal D is substantially as follows Figure 4 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal D is as shown in Figure 4 shown.

[0090] Crystal E

[0091] In some embodiments, the present invention provides Compound I pamoate crystals E, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD spectrum includes a peak at about 7.32±0.2 o , 11.26±0.2 o , 12.04±0.2 o , 14.77±0.2 o , 15.24±0.2 o , 16.95±0.2o , 20.28±0.2 o , 21.26±0.2 o , and 23.27±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal E also includes a diffraction peak at about 19.37±0.2 o and 19.83±0.2 o The diffraction peak at 2θ.

[0092] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal E includes the following diffraction peaks at 2θ:

[0093]

[0094]

[0095] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals E is substantially as follows Figure 5 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal E is as shown in Figure 5 shown.

[0096] Crystal F

[0097] In some embodiments, the present invention provides Compound I pamoate salt crystal F, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD spectrum includes a peak at about 11.19±0.2 o , 12.10±0.2 o , 14.67±0.2 o , 15.48±0.2 o , 18.11±0.2 o , 20.25±0.2 o and 23.33±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal F also includes a diffraction peak at about 11.92±0.2 o , 14.67±0.2 o , 16.71±0.2 o and 25.84±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal F also includes a diffraction peak at about 19.19±0.2 o and 21.23±0.2 o The diffraction peak at 2θ.

[0098] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals F comprises a peak at about 11.19 ± 0.2 o , 11.92±0.2 o , 12.10±0.2 o , 14.67±0.2 o , 15.48±0.2 o , 16.71±0.2 o , 18.11±0.2 o , 20.25±0.2 o , 23.33±0.2 o and 25.84±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal F includes a diffraction peak at about 11.19±0.2 o , 11.92±0.2 o , 12.10±0.2 o , 14.67±0.2 o , 15.48±0.2 o , 16.71±0.2 o , 18.11±0.2 o , 19.19±0.2 o , 20.25±0.2 o , 21.23±0.2 o , 23.33±0.2 o and 25.84±0.2 o The diffraction peak at 2θ.

[0099] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal F includes the following diffraction peaks at 2θ:

[0100] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 6.17 30.22 17.44 26.4 23.33 69.75 31.07 30.5 7.35 23.57 18.11 64.47 24.02 32.91 31.58 9.24 11.19 72.48 18.75 6.32 24.35 23.03 32.44 4.34 11.92 85.65 19.19 57.73 24.67 10.23 33.04 8.18 12.10 79.72 19.78 42.76 25.24 21 34.24 12.08 13.78 46.64 20.25 69.24 25.84 33.43 35.29 7.02 14.67 80.22 21.23 61.03 26.95 25.88 35.67 5.37 14.84 46.68 21.39 46.85 28.29 8.74 36.59 10.53 15.48 100 22.28 18.46 29.57 8.79 38.20 5.21 16.71 79.17 22.91 24.46 29.81 16.98 38.98 2.98

[0101] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals F is substantially as follows Figure 6 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal F is as shown in Figure 6 shown.

[0102] Crystal G

[0103] In some embodiments, the present invention provides Compound I pamoate crystals G, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes about 6.13±0.2 o , 11.24±0.2 o , 11.86±0.2o , 13.15±0.2 o , 14.79±0.2 o , 20.27±0.2 o and 23.13±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal G also includes a diffraction peak at about 11.24±0.2 o , 14.54±0.2 o , 19.90±0.2 o , 20.09±0.2 o , 22.21±0.2 o , 23.96±0.2 o and 24.76±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal G also includes a diffraction peak at about 16.88±0.2 o , 19.35±0.2 o and 20.46±0.2 o The diffraction peak at 2θ.

[0104] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals G comprises a peak at about 6.13 ± 0.2 o , 11.24±0.2 o , 11.86±0.2 o , 13.15±0.2 o , 14.54±0.2 o , 14.79±0.2 o , 19.90±0.2 o , 20.09±0.2 o , 20.27±0.2 o , 22.21±0.2 o , 23.13±0.2 o , 23.96±0.2 o and 24.76±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal G includes a diffraction peak at about 6.13±0.2 o , 11.24±0.2 o , 11.86±0.2 o , 13.15±0.2 o , 14.54±0.2 o , 14.79±0.2 o , 16.88±0.2 o , 19.35±0.2 o, 19.90±0.2 o , 20.09±0.2 o , 20.27±0.2 o , 20.46±0.2 o , 22.21±0.2 o , 23.13±0.2 o , 23.96±0.2 o and 24.76±0.2 o The diffraction peak at 2θ.

[0105] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal G includes the following diffraction peaks at 2θ:

[0106] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 6.13 12.63 16.88 44.18 23.13 65.96 29.90 16.93 7.19 16.58 17.35 28.19 23.96 53.32 31.18 4.98 11.24 55.6 18.13 14.33 24.76 42.38 31.57 6.99 11.86 97.1 19.35 40.06 25.27 20.94 32.21 6.65 12.35 7.2 19.90 33.15 26.33 14.68 32.83 6.04 13.15 39.8 20.09 33.8 26.65 7.43 33.41 5.3 14.54 57.44 20.27 100 27.15 14.2 34.22 15.41 14.79 59.37 20.46 76.23 27.74 28.07 35.20 5.44 15.57 13.54 22.21 84.09 28.28 12.12 36.87 4.51 16.20 21.8 22.88 18.86 29.04 19.09 38.46 5.16

[0107] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals G is substantially as follows Figure 7 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal G is as shown in Figure 7 shown.

[0108] Crystal H

[0109] In some embodiments, the present invention provides Compound I pamoate crystals H, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 7.08±0.2 o , 11.92±0.2 o , 13.03±0.2 o , 14.71±0.2 o , 16.90±0.2 o , 20.85±0.2 o , 21.96±0.2 o , 23.04±0.2 o and 23.56±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal H also includes a diffraction peak at about 11.76±0.2 o , 13.03±0.2 o , 20.27±0.2 o and 26.66±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal H also includes a diffraction peak at about 11.30±0.2 o , 14.71±0.2 o and 19.97±0.2 o The diffraction peak at 2θ.

[0110] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals H comprises a peak at about 7.08 ± 0.2 o , 11.76±0.2 o , 11.92±0.2 o , 13.03±0.2 o , 14.71±0.2 o , 16.90±0.2 o , 20.27±0.2 o , 20.85±0.2 o , 21.96±0.2 o , 23.04±0.2 o , 23.56±0.2 o and 26.66±0.2 o In some embodiments, the XRPD pattern of Compound I pamoate salt crystal H includes a diffraction peak at about 7.08±0.2 o , 11.76±0.2 o , 11.30±0.2 o , 11.92±0.2 o , 13.03±0.2 o , 14.71±0.2 o , 16.90±0.2 o , 19.97±0.2 o , 20.27±0.2 o , 20.85±0.2 o , 21.96±0.2 o , 23.04±0.2 o , 23.56±0.2 o and 26.66±0.2 o The diffraction peak at 2θ.

[0111] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal H includes the following diffraction peaks at 2θ:

[0112] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 6.26 8.71 17.14 17.24 22.30 22.48 28.03 6.75 7.08 25.59 17.46 15.68 23.04 40.88 28.53 28.75 7.34 2.15 17.87 10.99 23.56 41.52 28.85 6.51 11.30 28.73 18.56 9.59 23.79 20.91 29.29 8.73 11.76 24.55 19.03 11.32 24.06 30.13 29.91 9.57 11.92 78.74 19.39 16.92 24.68 11.47 30.42 5.51 12.62 8.51 19.97 30.49 25.43 39.08 30.79 13.77 13.03 33.14 20.27 60.84 25.82 15.27 31.44 7.51 14.29 16.25 20.85 66.48 26.16 5.19 32.01 3.9 14.71 100 21.27 8.57 26.66 32.98 32.26 5.09 16.11 30.48 21.96 54.69 27.25 13.71 33.50 15.44 16.90 47.33 22.17 28.39 27.69 24.91

[0113] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals H is substantially as follows Figure 8 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal H is as shown in Figure 8 shown.

[0114] Crystal I

[0115] In some embodiments, the present invention provides Compound I pamoate salt crystals I, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 5.59±0.2 o , 5.98±0.2 o , 9.39±0.2 o , 20.39±0.2 o , 25.27±0.2 o , and 26.01±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal I also includes a diffraction peak at about 7.62±0.2 o , 8.22±0.2 o , 11.59±0.2 o , 18.09±0.2 o and 22.59±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal I also includes a diffraction peak at about 7.80±0.2 o , 9.88±0.2 o and 23.40±0.2 o The diffraction peak at 2θ.

[0116] In some embodiments, the XRPD pattern of Compound I Pamoate Crystals I comprises a peak at about 5.59 ± 0.2 o , 5.98±0.2 o , 7.62±0.2 o , 8.22±0.2 o , 9.39±0.2 o , 11.59±0.2 o , 18.09±0.2 o , 20.39±0.2 o , 22.59±0.2 o , 25.27±0.2 o , and 26.01±0.2 o In another embodiment, the XRPD pattern of Compound I pamoate salt crystals I includes a diffraction peak at about 5.59 ± 0.2 o , 5.98±0.2 o , 7.62±0.2 o , 7.80±0.2 o , 8.22±0.2 o , 9.39±0.2 o , 9.88±0.2 o , 11.59±0.2 o , 18.09±0.2o , 20.39±0.2 o , 22.59±0.2 o , 23.40±0.2 o , 25.27±0.2 o , and 26.01±0.2 o The diffraction peak at 2θ.

[0117] In some embodiments, the XRPD pattern of Compound 1 Pamoate Crystals I includes the following diffraction peaks at 2θ:

[0118]

[0119]

[0120] In some embodiments, the XRPD pattern of Compound I Pamoate Crystals I is substantially as follows Fig. 9 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystals I is as shown in Fig. 9 shown.

[0121] Crystal J

[0122] In some embodiments, the present invention provides Compound I pamoate crystal J, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 5.33±0.2. o , 7.13±0.2 o , 10.90±0.2 o , 14.57±0.2 o , 16.62±0.2 o , 19.80±0.2 o and 25.29±0.2 o Preferably, the XRPD pattern of Compound I pamoate crystal J also includes a diffraction peak at about 14.99±0.2 o , 19.01±0.2 o and 20.74±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal J also includes a diffraction peak at about 19.32±0.2 o and 22.24±0.2 o The diffraction peak at 2θ.

[0123] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal J comprises a peak at about 5.33 ± 0.2 o , 7.13±0.2 o , 10.90±0.2o , 14.57±0.2 o , 14.99±0.2 o , 16.62±0.2 o , 19.01±0.2 o , 19.80±0.2 o , 20.74±0.2 o and 25.29±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal J includes a diffraction peak at about 5.33±0.2 o , 7.13±0.2 o , 10.90±0.2 o , 14.57±0.2 o , 14.99±0.2 o , 16.62±0.2 o , 19.01±0.2 o , 19.32±0.2 o , 19.80±0.2 o , 20.74±0.2 o , 22.24±0.2 o and 25.29±0.2 o The diffraction peak at 2θ.

[0124] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal J includes the following diffraction peaks at 2θ:

[0125] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 5.33 79.42 17.24 18.39 22.24 33.93 29.39 5.67 7.13 14.19 18.20 7.4 22.99 22.42 30.81 6.71 8.18 5.21 18.62 14.39 23.15 22.54 31.59 2.04 10.90 81.48 19.01 46.44 23.69 14.78 32.05 7.35 12.90 6.35 19.32 84.3 25.29 25.25 33.31 6.64 14.57 73.96 19.80 100 26.17 4.77 33.94 4 14.99 50.46 20.22 53.7 26.65 7.43 34.66 7.94 16.07 11.52 20.74 73.06 27.50 7.93 36.61 1.99 16.62 42.67 21.65 15.04 28.99 5.49 38.98 3.87

[0126] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal J is substantially as follows Fig.10 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal J is as shown in Fig.10 shown.

[0127] Crystal K

[0128] In some embodiments, the present invention provides Compound I pamoate salt crystal K, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD spectrum includes a peak at about 5.57±0.2 o , 5.97±0.2 o , 7.73±0.2 o , 11.55±0.2 o , 18.01±0.2 o and 18.90±0.2 oPreferably, the XRPD pattern of Compound I pamoate crystal K also includes a diffraction peak at about 9.34±0.2 o , 19.79±0.2 o and 25.84±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal K also includes a diffraction peak at about 23.25±0.2 o and 25.10±0.2 o The diffraction peak at 2θ.

[0129] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal K comprises a peak at about 5.57 ± 0.2 o , 5.97±0.2 o , 7.73±0.2 o , 9.34±0.2 o , 11.55±0.2 o , 18.01±0.2 o , 18.90±0.2 o , 19.79±0.2 o and 25.84±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal K includes a diffraction peak at about 5.57±0.2 o , 5.97±0.2 o , 7.73±0.2 o , 9.34±0.2 o , 11.55±0.2 o , 18.01±0.2 o , 18.90±0.2 o , 19.79±0.2 o、 23.25±0.2 o , 25.10±0.2 o and 25.84±0.2 o The diffraction peak at 2θ.

[0130] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal K includes the following diffraction peaks at 2θ:

[0131] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 5.57 65.79 12.04 13.16 18.01 43.29 24.54 14.57 5.97 34.85 12.46 7.79 18.90 16.71 25.10 100 7.73 37.12 13.30 11.44 19.79 25.34 25.84 36.13 8.20 35.58 14.39 11.32 20.04 17.51 26.29 8.26 9.34 82.2 15.63 16.75 20.28 33.4 26.53 11.06 9.83 31.67 15.99 23.11 22.44 17.16 26.61 3.5 11.09 19.52 16.56 14.28 22.70 13.28 36.92 3.51 11.55 40.48 17.38 22.61 23.25 30.25

[0132] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal K is substantially as follows Fig.11 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal K is as shown in Fig.11 shown.

[0133] Crystal L

[0134] In some embodiments, the present invention provides Compound I pamoate crystals L, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 6.20±0.2. o , 8.13±0.2 o , 9.92±0.2 o , 10.85±0.2 o , 12.81±0.2 o and 21.82±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal L also includes a diffraction peak at about 15.29±0.2 o and 25.86±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal L also includes a diffraction peak at about 19.29±0.2 o and 25.63±0.2 o The diffraction peak at 2θ.

[0135] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal L comprises a peak at about 6.20 ± 0.2 o , 8.13±0.2 o , 9.92±0.2 o , 10.85±0.2 o , 12.81±0.2 o , 15.29±0.2 o , 21.82±0.2 o and 25.86±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal L includes a diffraction peak at about 6.20±0.2 o , 8.13±0.2 o , 9.92±0.2 o , 10.85±0.2 o , 12.81±0.2 o , 15.29±0.2 o , 19.29±0.2 o , 21.82±0.2 o , 25.63±0.2 o and 25.86±0.2 o The diffraction peak at 2θ.

[0136] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal L includes the following diffraction peaks at 2θ:

[0137]

[0138]

[0139] In some embodiments, the XRPD pattern of Compound I pamoate crystal L is substantially as follows Fig.12 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal L is as shown in Fig.12 shown.

[0140] Crystal M

[0141] In some embodiments, the present invention provides Compound I pamoate crystals M, wherein the stoichiometric ratio of Compound I to pamoic acid is 1:1, and its XRPD pattern includes a peak at about 6.31±0.2. o , 11.55±0.2 o , 14.49±0.2 o , 15.94±0.2 o , 19.58±0.2 o and 23.50±0.2 o Preferably, the XRPD pattern of Compound I pamoate crystal M also includes a diffraction peak at about 19.27±0.2 o , 20.28±0.2 o and 25.88±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal M also includes a diffraction peak at about 22.27±0.2 o and 24.88±0.2 o The diffraction peak at 2θ.

[0142] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals M comprises a peak at about 6.31 ± 0.2 o , 11.55±0.2 o , 14.49±0.2 o , 15.94±0.2 o , 19.58±0.2 o , 19.27±0.2 o , 20.28±0.2 o , 23.50±0.2 o and 25.88±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystals M includes a diffraction peak at about 6.31±0.2 o , 11.55±0.2o , 14.49±0.2 o , 15.94±0.2 o , 19.58±0.2 o , 19.27±0.2 o , 20.28±0.2 o , 22.27±0.2 o , 23.50±0.2 o , 24.88±0.2 o and 25.88±0.2 o The diffraction peak at 2θ.

[0143] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals M includes the following diffraction peaks at 2θ:

[0144] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 6.31 21.24 18.48 1.82 24.50 5.83 30.89 4.28 11.14 10.1 19.27 62.08 24.88 13.61 31.23 5.24 11.55 37.28 19.58 48.53 25.26 5.66 31.89 3.41 12.55 11.35 20.28 56.15 25.49 6.92 33.71 10.06 12.91 7.03 21.39 2.46 25.88 11.39 33.95 11.64 13.91 2.64 21.77 7.43 27.48 6.78 34.54 1.68 14.49 100 22.27 29.88 28.11 0.48 35.27 3.61 14.74 7.63 22.74 3.33 29.31 4.42 37.35 2.44 15.94 38.13 23.26 14.69 29.66 4.51 38.58 0.87 16.68 14.75 23.50 10.26 29.99 5.13 39.08 2.58 17.02 2.56 24.26 16.36 30.62 4.07 24.50 5.83

[0145] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals M is substantially as follows Fig.13 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal M is as shown in Fig.13 shown.

[0146] Compound I pamoate and its crystals (2:1)

[0147] In some embodiments, the stoichiometric ratio of Compound 1 to pamoic acid in the Compound 1 pamoate salt is 2:1.

[0148] Crystal N

[0149] In some embodiments, the present invention provides Compound I pamoate crystal N, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern includes a peak at about 5.87±0.2 o , 6.42±0.2 o , 10.11±0.2 o , 12.58±0.2 o , 13.38±0.2 o , 16.12±0.2 o and 17.86±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal N also includes a diffraction peak at about 10.55±0.2 o , 14.74±0.2 o , 24.90±0.2 o and 26.45±0.2 oMore preferably, the XRPD pattern of Compound I pamoate crystal N also includes a diffraction peak at about 10.87±0.2 o , 23.55±0.2 o and 24.29±0.2 o The diffraction peak at 2θ.

[0150] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal N comprises a peak at about 5.87 ± 0.2 o , 6.42±0.2 o , 10.11±0.2 o , 10.55±0.2 o , 12.58±0.2 o , 13.38±0.2 o , 14.74±0.2 o , 16.12±0.2 o , 17.86±0.2 o , 24.90±0.2 o and 26.45±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal N includes a diffraction peak at about 5.87±0.2 o , 6.42±0.2 o , 10.11±0.2 o , 10.55±0.2 o , 10.87±0.2 o , 12.58±0.2 o , 13.38±0.2 o , 14.74±0.2 o , 16.12±0.2 o , 17.86±0.2 o , 23.55±0.2 o , 24.29±0.2 o , 24.90±0.2 o and 26.45±0.2 o The diffraction peak at 2θ.

[0151] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal N includes the following diffraction peaks at 2θ:

[0152] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 5.87 50.69 14.74 75.86 21.47 16.32 26.11 7.31 6.42 20.09 15.62 18.67 22.22 37.25 26.45 12.56 9.01 8.73 16.12 37.95 22.62 24.95 26.94 6.63 10.11 29.52 16.89 14.69 22.84 20.56 27.35 10.52 10.55 60.03 17.16 19.02 23.01 17.03 28.04 3.34 10.87 46.88 17.86 33.61 23.55 15.02 28.80 11.74 11.23 15.05 18.43 52.59 24.00 6.47 29.54 2.18 11.84 11.28 19.04 10.16 24.29 20.66 30.01 5.7 12.58 32.03 19.59 19.52 24.90 20.21 30.50 4.29 13.00 7.95 19.87 16.22 25.13 18.31 31.68 5.48 13.38 100 20.31 19.93 25.40 15.34 32.17 2.79 14.27 11.17 20.97 8.99 25.56 11.56

[0153] In some embodiments, the XRPD pattern of Compound 1 pamoate salt crystal N is substantially as follows Fig.14In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal N is as shown in Fig.14 shown.

[0154] Crystal O

[0155] In some embodiments, the present invention provides Compound I pamoate crystal O, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern includes a peak at about 11.33±0.2 o , 11.92±0.2 o , 14.71±0.2 o , 16.11±0.2 o , 17.50±0.2 o and 20.86±0.2 o Preferably, the XRPD pattern of Compound I pamoate crystal O also includes a diffraction peak at about 20.27±0.2 o , 23.04±0.2 o , 23.57±0.2 o and 27.70±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal O also includes a diffraction peak at about 19.96±0.2 o , 24.05±0.2 o , 25.43±0.2 o and 26.66±0.2 o In some embodiments, the XRPD pattern of Compound I pamoate salt crystal O includes a diffraction peak at about 11.33±0.2 o , 11.92±0.2 o , 14.71±0.2 o , 16.11±0.2 o , 17.50±0.2 o , 20.27±0.2 o , 20.86±0.2 o , 23.04±0.2 o , 23.57±0.2 o and 27.70±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal O includes a diffraction peak at about 11.33±0.2 o , 11.92±0.2 o , 14.71±0.2 o , 16.11±0.2 o , 17.50±0.2 o, 19.96±0.2 o , 20.27±0.2 o , 20.86±0.2 o , 23.04±0.2 o , 23.57±0.2 o , 24.05±0.2 o , 25.43±0.2 o , 26.66±0.2 o and 27.70±0.2 o The diffraction peak at 2θ.

[0156] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal O includes the following diffraction peaks at 2θ:

[0157] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 11.33 29.18 17.50 21.39 23.57 31.96 31.15 3.9 11.92 100 19.96 36.09 24.05 26.35 35.14 11.82 13.06 18.27 20.27 77.96 25.43 35.48 37.09 6.37 14.71 88.59 20.86 90.51 26.66 25.49 16.11 46.85 22.11 33.19 27.70 19.6 16.89 18.47 23.04 44.04 30.27 2.71

[0158] In some embodiments, the XRPD pattern of Compound 1 Pamoate Crystal O is substantially as follows Fig.15 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal O is as shown in Fig.15 shown.

[0159] Crystal P

[0160] In some embodiments, the present invention provides Compound I pamoate crystals P, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern includes a peak at about 5.79±0.2 o , 6.36±0.2 o , 10.58±0.2 o , 10.90±0.2 o , 13.32±0.2 o , 14.69±0.2 o , 17.61±0.2 o and 25.26±0.2 o Preferably, the XRPD spectrum of the compound I pamoate salt crystal P also includes a diffraction peak at about 10.58±0.2 o , 22.20±0.2 o , 22.80±0.2 o and 23.47±0.2 o More preferably, the XRPD pattern of the compound I pamoate salt crystal P also includes a diffraction peak at about 23.76±0.2 o and 24.08±0.2 o The diffraction peak at 2θ.

[0161] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals P comprises a peak at about 5.79 ± 0.2 o , 6.36±0.2 o , 10.58±0.2 o , 10.90±0.2 o , 13.32±0.2 o , 14.69±0.2 o , 17.61±0.2 o , 22.20±0.2 o , 22.80±0.2 o , 23.47±0.2 o and 25.26±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal P includes a diffraction peak at about 5.79±0.2 o , 6.36±0.2 o , 10.58±0.2 o , 10.90±0.2 o , 13.32±0.2 o , 14.69±0.2 o , 17.61±0.2 o , 22.20±0.2 o , 22.80±0.2 o , 23.47±0.2 o , 23.76±0.2 o , 24.08±0.2 o and 25.26±0.2 o The diffraction peak at 2θ.

[0162] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals P includes the following diffraction peaks at 2θ:

[0163]

[0164]

[0165] In some embodiments, the XRPD pattern of Compound I pamoate crystals P is substantially as follows Fig.16 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal P is as shown in Fig.16 shown.

[0166] Crystal Q

[0167] In some embodiments, the present invention provides Compound I pamoate crystals Q, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern includes a peak at about 5.75±0.2 o , 6.20±0.2 o , 10.46±0.2 o , 14.54±0.2 o , 15.26±0.2 o and 20.78±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal Q also includes a diffraction peak at about 16.16±0.2 o , 17.51±0.2 o and 24.37±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal Q also includes a diffraction peak at about 17.98±0.2 o , 21.74±0.2 o and 23.58±0.2 o The diffraction peak at 2θ.

[0168] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals Q comprises a peak at about 5.75 ± 0.2 o , 6.20±0.2 o , 10.46±0.2 o , 14.54±0.2 o , 15.26±0.2 o , 16.16±0.2 o , 17.51±0.2 o , 20.78±0.2 o and 24.37±0.2 o In other preferred embodiments, the XRPD pattern of Compound I pamoate crystal Q includes a diffraction peak at about 5.75±0.2 o , 6.20±0.2 o , 10.46±0.2 o , 14.54±0.2 o , 15.26±0.2 o , 16.16±0.2 o , 17.51±0.2 o , 17.98±0.2 o , 20.78±0.2 o , 21.74±0.2 o , 23.58±0.2 o and 24.37±0.2 oThe diffraction peak at 2θ.

[0169] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal Q includes the following diffraction peaks at 2θ:

[0170] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 5.75 52.33 13.97 8.13 20.27 12.22 27.32 5.21 6.20 11.39 14.54 100 20.78 20.93 28.16 8.34 9.01 9.55 15.26 22.97 21.36 38.07 28.86 8.63 10.10 41.7 16.16 32.13 21.74 23.23 29.39 6.63 10.46 35.54 16.92 27.26 22.23 38.68 30.25 7.26 10.70 39.6 17.51 18.44 22.69 25.38 31.62 3.25 10.89 27.15 17.98 44.48 23.58 45.14 33.15 9.86 11.62 14.35 18.51 24.34 24.37 26.69 33.97 5.37 12.57 35.96 18.99 23.67 25.01 7.82 34.62 5.62 13.17 79.31 19.61 34.85 25.41 7.63 35.65 9.97 13.55 16.8 19.77 29.48 26.21 6.45 37.28 4.73

[0171] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals Q is substantially as follows Fig.17 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal Q is as shown in Fig.17 shown.

[0172] Crystal R

[0173] In some embodiments, the present invention provides Compound I pamoate crystals R, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern includes a peak at about 5.97±0.2 o , 11.45±0.2 o , 12.06±0.2 o , 13.41±0.2 o , 17.75±0.2 o and 18.77±0.2 o Preferably, the XRPD spectrum of Compound I pamoate crystal R also includes a diffraction peak at about 19.42±0.2 o , 21.64±0.2 o , 23.89±0.2 o , 27.10±0.2 o and 28.76±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal R also includes a diffraction peak at about 21.64±0.2 o , 23.09±0.2 o and 26.18±0.2 o The diffraction peak at 2θ.

[0174] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals R comprises a peak at about 5.97 ± 0.2 o , 11.45±0.2 o , 12.06±0.2 o , 13.41±0.2 o , 17.75±0.2 o , 18.77±0.2 o , 19.42±0.2 o , 21.64±0.2o , 23.89±0.2 o , 27.10±0.2 o and 28.76±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal R includes a diffraction peak at about 5.97±0.2 o , 11.45±0.2 o , 12.06±0.2 o , 13.41±0.2 o , 17.75±0.2 o , 18.77±0.2 o , 19.42±0.2 o , 21.64±0.2 o , 23.09±0.2 o , 23.89±0.2 o , 26.18±0.2 o , 27.10±0.2 o and 28.76±0.2 o The diffraction peak at 2θ.

[0175] In some embodiments, the XRPD pattern of Compound I pamoate salt crystal R includes the following diffraction peaks at 2θ:

[0176] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 5.97 53.51 19.11 16.93 26.18 10.23 32.16 7.67 10.90 39.56 19.42 20.99 26.66 6.3 32.74 2.1 11.45 44.85 20.36 16.55 27.10 15.42 33.12 2.07 12.06 10.04 21.19 41.66 27.67 8.06 34.30 10.26 12.31 22.51 21.64 48.3 28.39 1.7 35.41 4.58 13.41 39.96 21.98 8.55 28.76 10.66 35.79 5.09 14.72 34.38 22.32 33.93 29.33 6.53 36.69 4.75 16.18 14.59 23.09 73.04 29.87 4.11 36.87 3.48 17.05 2.88 23.49 21 30.51 10.55 37.97 7.65 17.75 100 23.89 55.03 30.85 2.08 39.63 1.37 18.77 55.22 24.80 15.13 31.28 11.28

[0177] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals R is substantially as follows Fig.18 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal R is as shown in Fig.18 shown.

[0178] Crystal S

[0179] In some embodiments, the present invention provides Compound I pamoate salt crystals S, wherein the stoichiometric ratio of Compound I to pamoic acid is 2:1, and its XRPD pattern includes a peak at about 5.84±0.2 o , 6.34±0.2 o , 10.06±0.2 o , 11.14±0.2 o , 13.25±0.2 o , 14.65±0.2 o , 18.26±0.2 o and 25.25±0.2 oPreferably, the XRPD spectrum of Compound I pamoate crystal S also includes a diffraction peak at about 19.33±0.2 o , 21.53±0.2 o , 22.68±0.2 o and 24.06±0.2 o More preferably, the XRPD pattern of Compound I pamoate crystal S also includes a diffraction peak at about 20.20±0.2 o , 22.09±0.2 o and 24.06±0.2 o The diffraction peak at 2θ.

[0180] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals S comprises a peak at about 5.84 ± 0.2 o , 6.34±0.2 o , 10.06±0.2 o , 11.14±0.2 o , 13.25±0.2 o , 14.65±0.2 o , 18.26±0.2 o , 19.33±0.2 o , 21.53±0.2 o , 22.68±0.2 o , 24.06±0.2 o and 25.25±0.2 o In other embodiments, the XRPD pattern of Compound I pamoate crystal S includes a diffraction peak at about 5.84±0.2 o , 6.34±0.2 o , 10.06±0.2 o , 11.14±0.2 o , 13.25±0.2 o , 14.65±0.2 o , 18.26±0.2 o , 19.33±0.2 o , 20.20±0.2 o , 21.53±0.2 o , 22.09±0.2 o , 22.68±0.2 o , 24.06±0.2 o and 25.25±0.2 o The diffraction peak at 2θ.

[0181] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals S includes the following diffraction peaks at 2θ:

[0182] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 5.84 40.37 14.65 100 21.11 21.74 27.80 7.58 6.34 13.66 15.47 24.51 21.53 33.74 28.60 12.51 10.06 38.13 16.14 34.05 22.09 45.98 30.16 6.99 10.44 56.63 17.06 18.77 22.68 46.47 31.76 3.59 10.73 42.12 17.84 24.89 23.48 17.16 33.28 5.8 11.14 31.27 18.26 63.88 24.06 24.52 34.03 5.91 11.79 11.98 18.85 11.15 24.60 22.74 34.87 6.41 12.55 34.85 19.33 20.1 25.25 21.3 35.60 4.62 13.25 93.16 19.66 31.74 26.24 16.84 37.34 3.84 13.57 16.21 20.20 40.65 26.78 13.11 14.11 14.28 20.49 16.8 27.37 13.17

[0183] In some embodiments, the XRPD pattern of Compound I pamoate salt crystals S is substantially as follows Fig.19 In some preferred embodiments, the XRPD pattern of Compound I pamoate crystal S is as shown in Fig.19 shown.

[0184] Compound I palmitate and its crystals (1:1)

[0185] In some embodiments, the stoichiometric ratio of Compound 1 to palmitic acid in the Compound 1 palmitate salt is 1:1.

[0186] Crystal T

[0187] In some embodiments, the present invention provides Compound I palmitate salt crystals T, wherein the stoichiometric ratio of Compound I to palmitic acid is 1:1, and its XRPD pattern includes a peak at about 6.17±0.2 o , 9.73±0.2 o , 10.20±0.2 o , 11.52±0.2 o , 12.44±0.2 o , 15.16±0.2 o and 21.40±0.2 o Preferably, the XRPD spectrum of Compound I palmitate crystal T also includes a diffraction peak at about 13.82±0.2 o , 16.36±0.2 o and 16.65±0.2 o More preferably, the XRPD pattern of Compound I palmitate crystal T also includes a diffraction peak at about 16.89±0.2 o , 19.88±0.2 o and 20.18±0.2 o The diffraction peak at 2θ.

[0188] In some embodiments, the XRPD pattern of Compound I palmitate salt crystal T comprises a peak at about 6.17 ± 0.2 o , 9.73±0.2 o , 10.20±0.2 o , 11.52±0.2 o , 12.44±0.2 o , 13.82±0.2 o, 15.16±0.2 o , 16.36±0.2 o , 16.65±0.2 o and 21.40±0.2 o In other embodiments, the XRPD pattern of Compound I palmitate crystal T includes a diffraction peak at about 6.17±0.2 o , 9.73±0.2 o , 10.20±0.2 o , 11.52±0.2 o , 12.44±0.2 o , 13.82±0.2 o , 15.16±0.2 o , 16.36±0.2 o , 16.65±0.2 o , 16.89±0.2 o , 19.88±0.2 o , 20.18±0.2 o and 21.40±0.2 o The diffraction peak at 2θ.

[0189] In some embodiments, the XRPD pattern of Compound I palmitate salt crystal T includes the following diffraction peaks at 2θ:

[0190]

[0191]

[0192] In some embodiments, the XRPD pattern of Compound I palmitate salt crystal T is substantially as follows Fig. 20 In some preferred embodiments, the XRPD pattern of Compound I palmitate crystal T is as shown in Fig. 20 shown.

[0193] Crystal U

[0194] In some embodiments, the present invention provides Compound I palmitate salt crystals U, wherein the stoichiometric ratio of Compound I to palmitic acid is 1:1, and its XRPD pattern includes a peak at about 5.95±0.2 o , 15.15±0.2 o , 17.90±0.2 o , 20.57±0.2 o , 21.44±0.2 o , 21.83±0.2 o and 25.82±0.2 oPreferably, the XRPD pattern of Compound I palmitate crystal U also includes a diffraction peak at about 10.81±0.2 o , 14.47±0.2 o , 18.20±0.2 o , 22.63±0.2 o and 26.63±0.2 o More preferably, the XRPD pattern of Compound I palmitate crystal U also includes a diffraction peak at about 11.27±0.2 o and 26.03±0.2 o The diffraction peak at 2θ.

[0195] In some embodiments, the XRPD pattern of Compound I palmitate salt crystal U comprises a peak at about 5.95 ± 0.2 o , 10.81±0.2 o , 14.47±0.2 o , 15.15±0.2 o , 17.90±0.2 o , 18.20±0.2 o , 20.57±0.2 o , 21.44±0.2 o , 21.83±0.2 o , 22.63±0.2 o , 25.82±0.2 o and 26.63±0.2 o In other embodiments, the XRPD pattern of Compound I palmitate crystal U includes a diffraction peak at about 5.95±0.2 o , 10.81±0.2 o , 11.27±0.2 o , 14.47±0.2 o , 15.15±0.2 o , 17.90±0.2 o , 18.20±0.2 o , 20.57±0.2 o , 21.44±0.2 o , 21.83±0.2 o , 22.63±0.2 o , 25.82±0.2 o , 26.03±0.2 o and 26.63±0.2 o The diffraction peak at 2θ.

[0196] In some embodiments, the XRPD pattern of Compound I palmitate salt crystal U includes the following diffraction peaks at 2θ:

[0197] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 4.86 0.85 16.39 5.45 20.25 6.64 24.83 0.31 5.95 14.7 17.90 21.16 20.57 24.68 25.32 0.89 7.33 1.93 18.20 9.45 21.44 100 25.82 13.02 10.81 3.42 18.34 4.48 21.83 31.75 26.03 14.48 11.27 2.28 18.59 5.16 22.24 2.74 26.46 3.12 13.31 0.54 18.98 3.2 22.63 5.71 26.63 4.05 14.02 0.67 19.26 1.54 22.78 5.69 27.01 1.43 14.47 2.86 19.51 1.96 23.24 5.44 27.53 1.17 15.15 10.28 19.89 2.45 23.68 1.78 28.85 0.66 15.43 1.02 20.02 3.29 24.00 9.24 29.09 0.94

[0198] In some embodiments, the XRPD pattern of Compound 1 palmitate salt crystal U is substantially as follows Fig.21 In some preferred embodiments, the XRPD pattern of Compound I palmitate crystal U is as shown in Fig.21 shown.

[0199] Crystal V

[0200] In some embodiments, the present invention provides Compound I palmitate salt crystal V, wherein the stoichiometric ratio of Compound I to palmitic acid is 1:1, and its XRPD pattern includes a peak at about 5.56±0.2. o , 12.99±0.2 o , 13.21±0.2 o , 13.59±0.2 o , 14.02±0.2 o , 14.71±0.2 o and 19.90±0.2 o Preferably, the XRPD pattern of Compound I palmitate crystal V also includes a diffraction peak at about 11.19±0.2 o , 19.66±0.2 o , 22.61±0.2 o , 22.80±0.2 o and 23.43±0.2 o More preferably, the XRPD pattern of Compound I palmitate crystal V also includes a diffraction peak at about 11.38±0.2 o , 19.48±0.2 o , 20.26±0.2 o and 22.96±0.2 o The diffraction peak at 2θ.

[0201] In some embodiments, the XRPD pattern of Compound I palmitate salt crystal V comprises a peak at about 5.56 ± 0.2 o , 11.19±0.2 o , 12.99±0.2 o , 13.21±0.2 o , 13.59±0.2 o , 14.02±0.2 o , 14.71±0.2 o , 19.90±0.2o , 19.66±0.2 o , 22.61±0.2 o , 22.80±0.2 o and 23.43±0.2 o In other embodiments, the XRPD pattern of Compound I palmitate crystal V includes a diffraction peak at about 5.56±0.2 o , 11.19±0.2 o , 11.38±0.2 o , 12.99±0.2 o , 13.21±0.2 o , 13.59±0.2 o , 14.02±0.2 o , 14.71±0.2 o , 19.48±0.2 o , 19.90±0.2 o , 19.66±0.2 o , 20.26±0.2 o , 22.61±0.2 o , 22.80±0.2 o , 22.96±0.2 o and 23.43±0.2 o The diffraction peak at 2θ.

[0202] In some embodiments, the XRPD pattern of Compound I palmitate salt crystal V includes the following diffraction peaks at 2θ:

[0203] <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% <![CDATA[2θ( o )±0.2 o ]]> strength% 5.56 11.79 12.59 2.55 16.26 18.36 20.71 2.76 6.40 1.29 12.99 10.58 16.86 10.39 21.04 3.23 6.98 1.04 13.21 9.65 17.14 10.55 21.30 1.97 7.64 0.7 13.31 7.82 18.11 10.37 21.82 0.86 8.40 0.93 13.59 12.39 18.61 1.34 22.61 78.44 10.32 0.64 14.02 25.5 19.13 5.89 22.80 100 11.19 14.05 14.71 17.85 19.48 53.74 22.96 49.25 11.38 13.48 14.99 10.8 19.66 40.27 23.43 54.37 11.64 9.04 15.43 14.53 19.90 71.68 23.78 27.3 12.05 3.26 15.95 12 20.26 19.18 24.06 7.03

[0204] In some embodiments, the XRPD pattern of Compound I palmitate salt crystal V is substantially as follows Fig. 22 In some preferred embodiments, the XRPD pattern of Compound I palmitate crystal V is as shown in Fig. 22 shown.

[0205] Pharmaceutical compositions and uses

[0206] Another object of the present invention is to provide a pharmaceutical composition comprising a salt of Compound I, wherein the salt is selected from pamoate and palmitate, in particular Compound I pamoate crystals or palmitate crystals, and one or more pharmaceutically acceptable carriers.

[0207] Another object of the present invention is to provide a salt of Compound I of the present invention (e.g., pamoate of Compound I and palmitate of Compound I, in particular, pamoate crystals or palmitate crystals of Compound I or any combination thereof) or a pharmaceutical composition for use in the preparation of drugs for treating Parkinson's disease and restless legs syndrome.

[0208] Another object of the present invention is to provide a salt of Compound I of the present invention (e.g., pamoate of Compound I and palmitate of Compound I, in particular, pamoate crystals or palmitate crystals of Compound I or any combination thereof) or a pharmaceutical composition for the treatment of Parkinson's disease and restless legs syndrome.

[0209] Another object of the present invention is to provide a method for treating Parkinson's disease and restless legs syndrome, which comprises administering to an individual in need thereof a therapeutically effective amount of a salt of Compound I of the present invention (e.g., pamoate of Compound I and palmitate of Compound I, in particular, pamoate crystals or palmitate crystals of Compound I or any combination thereof) or a pharmaceutical composition.

[0210] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0211] Administration of the compounds of the invention in pure form or in a suitable pharmaceutical composition can be carried out by any accepted mode of administration that provides agents with similar utilities. The pharmaceutical composition of the invention can be prepared by combining the compounds of the invention or their salts with a suitable pharmaceutically acceptable carrier.

[0212] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods and the like.

[0213] Typical routes of administration of the compounds of the present invention or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0214] In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable carriers, excipients and / or media well known in the art. These carriers, excipients and media enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0215] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules to obtain tablets or dragee cores.

[0216] Beneficial Effects

[0217] The pamoate and palmitate of compound I of the present invention have the advantages of high purity and good stability. In addition, they have lower solubility and can be used in long-acting sustained-release preparations. The pamoate and palmitate of compound I of the present invention have extended T max and T 1 / 2 Duration, it can maintain the effective blood drug concentration for a longer time, thus proving that it can achieve the effect of long-acting release.

[0218] The crystals of the present invention (such as crystal forms AS and TV) have the advantages of high purity and good stability. In addition, they have lower solubility and can be used in long-acting sustained-release preparations. The crystals of the present invention have a prolonged T max and T 1 / 2 Duration, it can maintain the effective blood drug concentration for a longer time, thus proving that it can achieve the effect of long-acting release. Example

[0219] X-ray Powder Diffraction (XRPD):

[0220] X`Pert3 Powder powder diffractometer was used to collect XRPD patterns of each crystal. The instrument used Cu palladium irradiation and Absolute scan for continuous projection scanning at room temperature. The scanning 2θ range was 3.5° to 40°, the step size was 0.013°, the dwell time was 50 s, and the scan was performed once.

[0221] All solvents used in the present invention were commercially available and used without further purification.

[0222] Example 1: Preparation of Compound I Pamoate Crystals A

[0223] 50 mg of compound I and 92 mg of pamoic acid were put into 2 mL of methanol, and suspended under 40-10°C cycle heating and cooling (40-10°C cycle heating and cooling means keeping at 40°C for 1 hour, then cooling to 10°C for 1 hour, then heating to 40°C for 1 hour, then cooling to 10°C for 1 hour, and repeating the cycle) and centrifuged after 24 hours to obtain compound I pamoate crystal A, which was subjected to XRPD detection. The obtained XRPD spectrum is shown as follows Figure 1 as shown in .

[0224] Example 2: Preparation of Compound I Pamoate Crystals B

[0225] 50 mg of compound I and 92 mg of pamoic acid were put into 2 mL of acetonitrile, placed in a 40-10°C cycle and suspended by shaking, and centrifuged after 24 hours to obtain compound I pamoate crystal B, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Figure 2 as shown in .

[0226] Example 3: Preparation of Compound I Pamoate Crystals C

[0227] 50 mg of compound I and 92 mg of pamoic acid were put into 2 mL of acetone, placed in a 40-10°C cycle and suspended by shaking, and centrifuged after 24 hours to obtain compound I pamoate crystal C, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Figure 3 as shown in .

[0228] Example 4: Preparation of Compound I Pamoate Crystal D

[0229] 50 mg of compound I and 92 mg of pamoic acid were put into 2 mL of methanol, placed in a 40-10°C cycle with shaking suspension, centrifuged after 24 hours, and then dried at 60°C to obtain compound I pamoate crystal D, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Figure 4 as shown in .

[0230] Example 5: Preparation of Compound I Pamoate Crystals E

[0231] 50 mg of compound I and 92 mg of pamoic acid were put into a mixed solvent of 1 mL of acetonitrile and 1 mL of water, and suspended under a 40-10°C cycle of temperature rise and fall, and centrifuged after 24 hours to obtain compound I pamoate crystal E, which was subjected to XRPD detection. The obtained XRPD spectrum is shown as follows: Figure 5 as shown in .

[0232] Example 6: Preparation of Compound I Pamoate Crystals F

[0233] 50 mg of compound I and 92 mg of pamoic acid were put into 3 mL of acetonitrile, placed in a 40-10°C cycle with shaking suspension, centrifuged after 24 hours, and then dried at 60°C to obtain compound I pamoate crystal F, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Figure 6 as shown in .

[0234] Example 7: Preparation of Compound I Pamoate Crystals G

[0235] 50 mg of compound I and 92 mg of pamoic acid were put into 4 mL of acetonitrile, placed in a 50°C shaking suspension, and centrifuged after 4 hours to obtain compound I pamoate crystal G, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Figure 7 as shown in .

[0236] Example 8: Preparation of Compound I Pamoate Crystals H

[0237] 50 mg of compound I and 92 mg of pamoic acid were put into 4 mL of methanol, placed in a 50°C shaking suspension, and centrifuged after 4 hours to obtain compound I pamoate crystal H, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Figure 8 as shown in .

[0238] Example 9: Preparation of Compound I Pamoate Crystals I

[0239] 50 mg of compound I and 92 mg of pamoic acid were put into a mixed solvent of 1 mL of methanol and 1 mL of water, and suspended at 25°C by shaking. After 24 hours, centrifugation was performed to obtain compound I pamoate crystals I, which were subjected to XRPD detection. The obtained XRPD spectrum is shown as follows: Fig. 9 as shown in .

[0240] Example 10: Preparation of Compound I Pamoate Crystal J

[0241] 50 mg of compound I and 92 mg of pamoic acid were put into 2 mL of THF, placed in a 40-10°C cycle and suspended by shaking, and centrifuged after 24 hours to obtain compound I pamoate crystal J, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Fig.10 as shown in .

[0242] Example 11: Preparation of Compound I Pamoate Crystal K

[0243] 50 mg of compound I and 92 mg of pamoic acid were put into a mixed solution of 1 mL of methanol and 3 mL of water, and placed in a 40-10°C cycle with shaking suspension. After 24 hours, centrifugation was performed to obtain compound I pamoate crystals K, which were subjected to XRPD detection. The obtained XRPD spectrum is shown as follows: Fig.11 as shown in .

[0244] Example 12: Preparation of Compound I Pamoate Crystal L

[0245] 50 mg of compound I and 92 mg of pamoic acid were put into a mixed solution of 0.4 mL of methanol and 1.6 mL of MTBE, and the mixture was suspended under a 40-10°C cycle of temperature rise and fall, and centrifuged after 24 hours to obtain compound I pamoate crystal L, which was subjected to XRPD detection. The obtained XRPD spectrum is shown as follows: Fig.12as shown in .

[0246] Example 13: Preparation of Compound I Pamoate Crystals M

[0247] 50 mg of compound I and 92 mg of pamoic acid were put into a mixed solution of 1 mL of THF and 1 mL of water, and placed in a 40-10°C cycle with shaking suspension. After 24 hours, centrifugation was performed to obtain compound I pamoate crystals M, which were subjected to XRPD detection. The obtained XRPD spectrum is shown as follows: Fig.13 as shown in .

[0248] Example 14: Preparation of Compound I Pamoate Crystals N

[0249] 50 mg of compound I and 46 mg of pamoic acid were put into 2 mL of acetone, placed in a 40-10°C cycle and suspended by shaking, and centrifuged after 24 hours to obtain compound I pamoate crystal N, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Fig.14 as shown in .

[0250] Example 15: Preparation of Compound I Pamoate Crystal O

[0251] 50 mg of compound I and 46 mg of pamoic acid were put into 2 mL of methanol, placed in a 40-10°C cycle and suspended by shaking, and centrifuged after 24 hours to obtain compound I pamoate crystal O, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Fig.15 as shown in .

[0252] Example 16: Preparation of Compound I Pamoate Crystals P

[0253] 50 mg of compound I and 46 mg of pamoic acid were put into 2 mL of acetonitrile, placed in a 40-10°C cycle and suspended by shaking, and centrifuged after 24 hours to obtain compound I pamoate crystals P, which were subjected to XRPD detection. The obtained XRPD spectrum is as follows: Fig.16 as shown in .

[0254] Example 17: Preparation of Compound I Pamoate Crystals Q

[0255] 50 mg of compound I and 46 mg of pamoic acid were put into 2 mL of isopropanol, placed in a 40-10°C cycle and suspended by shaking, and centrifuged after 24 hours to obtain compound I pamoate crystal Q, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Fig.17 as shown in .

[0256] Example 18: Preparation of Compound I Pamoate Crystals R

[0257] 50 mg of compound I and 46 mg of pamoic acid were put into 2 mL of THF, placed in a 40-10°C cycle and suspended by shaking, and centrifuged after 24 hours to obtain compound I pamoate crystal R, which was subjected to XRPD detection. The obtained XRPD spectrum is as follows: Fig.18 as shown in .

[0258] Example 19: Preparation of Compound I Pamoate Crystals S

[0259] 50 mg of compound I and 46 mg of pamoic acid were put into a mixed solvent of 0.4 mL of ethanol and 1.6 mL of n-heptane, and suspended under a 40-10°C cycle of temperature rise and fall, and centrifuged after 24 hours to obtain compound I pamoate crystals S, which were subjected to XRPD detection. The obtained XRPD spectrum is shown as follows: Fig.19 as shown in .

[0260] Example 20: Preparation of Compound I Palmitate Crystals T

[0261] 2.0 g of compound I and 2.4 g of palmitic acid were put into 30 mL of ethyl acetate, stirred at 25° C., and filtered after 2 h to obtain compound I palmitate crystal T. XRPD was performed on it, and the obtained XRPD spectrum was as follows: Fig. 20 as shown in .

[0262] Example 21: Preparation of Compound I Palmitate Crystals U

[0263] 20 mg of Compound I palmitate crystals T (prepared in Example 20) were placed in 1 mL of ethanol, placed in a 40-10°C cycle with shaking and suspension, and centrifuged after 24 hours to obtain Compound I palmitate crystals U, which were subjected to XRPD detection. The obtained XRPD spectrum is shown as follows: Fig.21 as shown in .

[0264] Example 22: Preparation of Compound I Palmitate Crystals V

[0265] 20 mg of Compound I palmitate crystals T (prepared in Example 20) were placed in 1 mL of acetone, placed in a 40-10°C cycle with shaking and suspension, and centrifuged after 24 hours to obtain Compound I palmitate crystals V, which were subjected to XRPD detection. The obtained XRPD spectrum is shown as follows: Fig. 22 as shown in .

[0266] Test Example 1: Solubility Test

[0267] 1-1 Solubility of Crystal T, Crystal U, Crystal V and Compound I

[0268] The sample was put into pure water, and then an excess sample was added. The sample was shaken at room temperature for 15 hours, filtered, and tested by HPLC. HPLC test conditions: mobile phase: sodium octane sulfonate-potassium dihydrogen phosphate buffer (5.0 g of sodium octane sulfonate and 9.1 g of potassium dihydrogen phosphate were dissolved in 1000 ml of water, and the pH value was adjusted to 3.0 with phosphoric acid)-acetonitrile (72:28); detection wavelength was 264 nm; flow rate was 1.5 ml per minute; column temperature was 40 ° C; injection volume: 10 μl; chromatographic column: octadecylsilane bonded silica gel as filler (CAPCELL PAKMG II C18, 4.6 mm × 250 mm, 5 μm).

[0269] Crystal Crystal T Crystal U Crystal V Compound I Solubility (mg / ml) 0.010 0.017 0.016 0.14

[0270] It can be seen from the data in the above table that the crystals of the present invention have lower solubility than the free base of Compound I and can be used in long-acting sustained-release preparations.

[0271] 1-2 Solubility of Crystal D and Crystal N

[0272] Pamoate crystals D and N were tested by the test method 1-1, and their solubility test results are shown in the following table.

[0273] name Solubility (mg / ml) Crystal D 0.018 Crystal N 0.046 Compound I 0.14

[0274] It can be seen from the data in the above table that the crystals of the present invention have lower solubility than the free base of Compound I and can be used in long-acting sustained-release preparations.

[0275] Test Example 2 Pharmacokinetics test in rats

[0276] Pharmacokinetics of 2-1 pamoate in rats

[0277] Take 4 female rats, and administer 5 mg / kg of pamoate crystals D of compound I to the rats by intramuscular injection, and only administer once. Take 0.3 ml of venous blood samples (EDTA-K2 anticoagulation) before and after administration at 5min, 15min, 30min, 1h, 2h, 4h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, and 168h, respectively. Then measure the blood drug concentration after administration, and fit the drug-time curve to calculate the pharmacokinetic parameters. See the table below for relevant data.

[0278] Pamoate Crystalline Pharmacokinetic Data

[0279] PK parameters Numeric <![CDATA[T 1 / 2 (h)]]> 4.88 <![CDATA[T max (h)]]> 0.625 <![CDATA[C max (ng / ml)]]> 389 <![CDATA[AUC last (h*ng / ml)]]> 1624 <![CDATA[AUC INF (h*ng / ml)]]> 1639 Vz_F(ml) 55549 Cl_F(ml / h) 7519 <![CDATA[MRT last (h)]]> 4.11

[0280] According to FDA information (FDA. ER TM(pramipexole dihydrochloride), NDA 22-421, Serial 000 received 10 / 24 / 08) showed that when compound I (pramipexole) was orally administered to rats, the T max 0.5h, T 1 / 2 It can be seen that compared with Compound I itself, the pamoate crystals of Compound I of the present invention can maintain effective blood drug concentration for a longer time and have a longer T max and T 1 / 2 Duration, achieving a long-lasting sustained-release effect.

[0281] Pharmacokinetics of 2-2 Palmitate in Rats

[0282] Take 4 female rats, administer 5mg / kg of palmitate crystals T of compound I to the rats by intramuscular injection, and only administer once. Before administration and 5min, 15min, 30min, 1h, 2h, 4h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 168h after administration, take 0.3ml of venous blood samples (EDTA-K2 anticoagulation) respectively. Then measure the blood drug concentration after administration, and fit the drug-time curve to calculate the pharmacokinetic parameters. See the table below for relevant data.

[0283] Palmitate Pharmacokinetic Data

[0284] PK parameters Numeric <![CDATA[T 1 / 2 (h)]]> 21.0 <![CDATA[T max (h)]]> 1.33 <![CDATA[C max (ng / ml)]]> 949 <![CDATA[AUC last (h*ng / ml)]]> 10116 <![CDATA[AUC INF (h*ng / ml)]]> 10205 Vz_F(ml) 15091 Cl_F(ml / h) 521 <![CDATA[MRT last (h)]]> 22.3

[0285] According to FDA information (FDA. ER TM (pramipexole dihydrochloride), NDA 22-421, Serial 000 received 10 / 24 / 08) showed that when compound I (pramipexole) was orally administered to rats, the T max 0.5h, T 1 / 2 It can be seen that compared with Compound I itself, the palmitate crystals of Compound I of the present invention can maintain effective blood drug concentration for a longer time and have a longer T max and T 1 / 2 Duration, achieving a long-lasting sustained-release effect.

[0286] The above specific implementations further describe the present invention in detail, but it should not be understood that the scope of the above subject matter of the present invention is limited to the listed embodiments, and all technical solutions implemented based on the content of the present invention fall within the scope of the present invention.

Claims

1. A pamoate salt crystal D of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 11.24±0.2°, 11.88±0.2°, 12.03±0.2°, 13.57±0.2°, 14.76±0.2°, 15.17±0.2°, 20.85±0.2°, 21.15±0.2° and 23.26±0.2°.

2. The pamoate salt crystal D of the compound of formula I as shown in claim 1, wherein its XRPD pattern further comprises diffraction peaks at 2θ of about 15.17±0.2°, 16.92±0.2° and 24.24±0.2°.

3. The pamoate salt crystal D of the compound of formula I as shown in claim 2, wherein its XRPD pattern further comprises diffraction peaks at 2θ of about 19.37±0.2° and 20.25±0.2°.

4. The pamoate salt crystal D of the compound of formula I as shown in any one of claims 1 to 3, whose XRPD pattern is substantially as shown in FIG. 4 .

5. The pamoate salt crystal D of the compound of formula I as shown in any one of claims 1 to 4, whose XRPD pattern is shown in FIG. 4 .

6. A pamoate salt crystal N of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 5.87±0.2°, 6.42±0.2°, 10.11±0.2°, 12.58±0.2°, 13.38±0.2°, 16.12±0.2° and 17.86±0.2°.

7. The pamoate salt crystal N of the compound of formula I as shown in claim 6, wherein its XRPD pattern further comprises diffraction peaks at 2θ of about 10.55±0.2°, 14.74±0.2°, 24.90±0.2° and 26.45±0.2°.

8. A crystalline pamoate salt of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern comprises diffraction peaks at 2θ of about 4.76±0.2°, 7.07±0.2°, 8.32±0.2°, 10.7±0.2°, 11.73±0.2°, 13.29±0.2°, 16.25±0.2°, 18.45±0.2°, 21.51±0.2°, 24.81±0.2°, and 26.17±0.2°; Or, pamoate crystal B of the compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 5.79±0.2°, 6.38±0.2°, 10.95±0.2°, 14.72±0.2°, 17.61±0.2°, 18.40±0.2°, 19.81±0.2° and 22.18±0.2°; Or, crystalline pamoate of the compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of about 7.43±0.2°, 11.18±0.2°, 11.98±0.2°, 14.78±0.2°, 20.20±0.2°, 20.97±0.2°, and 23.30±0.2°; Or, crystalline pamoate of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of about 7.32±0.2°, 11.26±0.2°, 12.04±0.2°, 14.77±0.2°, 15.24±0.2°, 16.95±0.2°, 20.28±0.2°, 21.26±0.2°, and 23.27±0.2°; Or, crystalline pamoate of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of about 11.19±0.2°, 12.10±0.2°, 14.67±0.2°, 15.48±0.2°, 18.11±0.2°, 20.25±0.2°, and 23.33±0.2°; Or, crystalline pamoate of a compound of formula I G, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of about 6.13±0.2°, 11.24±0.2°, 11.86±0.2°, 13.15±0.2°, 14.79±0.2°, 20.27±0.2°, and 23.13±0.2°; Or, crystalline H of a pamoate salt of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of about 7.08±0.2°, 11.92±0.2°, 13.03±0.2°, 14.71±0.2°, 16.90±0.2°, 20.85±0.2°, 21.96±0.2°, 23.04±0.2°, and 23.56±0.2°; Or, pamoate salt crystals I of the compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 5.59±0.2°, 5.98±0.2°, 9.39±0.2°, 20.39±0.2°, 25.27±0.2°, and 26.01±0.2°; Or, crystalline J of a pamoate salt of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD pattern includes diffraction peaks at 2θ of about 5.33±0.2°, 7.13±0.2°, 10.90±0.2°, 14.57±0.2°, 16.62±0.2°, 19.80±0.2°, and 25.29±0.2°; Or, a pamoate salt crystal K of the compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 5.57±0.2°, 5.97±0.2°, 7.73±0.2°, 11.55±0.2°, 18.01±0.2°, and 18.90±0.2°; Or, a pamoate salt crystal L of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 6.20±0.2°, 8.13±0.2°, 9.92±0.2°, 10.85±0.2°, 12.81±0.2°, and 21.82±0.2°; Or, pamoate salt crystals M of the compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 1:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 6.31±0.2°, 11.55±0.2°, 14.49±0.2°, 15.94±0.2°, 19.58±0.2°, and 23.50±0.2°; Or, crystalline pamoate of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of about 11.33±0.2°, 11.92±0.2°, 14.71±0.2°, 16.11±0.2°, 17.50±0.2°, and 20.86±0.2°; Or, a pamoate salt crystal P of a compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of about 5.79±0.2°, 6.36±0.2°, 10.58±0.2°, 10.90±0.2°, 13.32±0.2°, 14.69±0.2°, 17.61±0.2°, and 25.261±0.2°; Or, a pamoate salt crystal Q of the compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 5.75±0.2°, 6.20±0.2°, 10.46±0.2°, 14.54±0.2°, 15.26±0.2°, and 20.78±0.2°; Or, a pamoate salt crystal R of the compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD pattern includes diffraction peaks at 2θ of about 5.97±0.2°, 11.45±0.2°, 12.06±0.2°, 13.41±0.2°, 17.75±0.2°, and 18.77±0.2°; Or, pamoate salt crystals S of the compound of formula I, wherein the stoichiometric ratio of compound I to pamoic acid is 2:1, and its XRPD spectrum includes diffraction peaks at 2θ of about 5.84±0.2°, 6.34±0.2°, 10.06±0.2°, 11.14±0.2°, 13.25±0.2°, 14.65±0.2°, 18.26±0.2° and 25.25±0.2°.

9. The pamoate salt crystal A of the compound of formula I as shown in claim 8, wherein its XRPD spectrum further comprises diffraction peaks at 2θ of about 17.87±0.2°, 22.01±0.2°, and 25.17±0.2°; Or, the pamoate crystal B of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 10.61±0.2°, 12.51±0.2°, 17.61±0.2° and 20.01±0.2°; Or, the pamoate crystal C of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 16.90±0.2°, 19.73±0.2°, 22.12±0.2° and 25.37±0.2°; Or, the pamoate crystal E of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 19.37±0.2° and 19.83±0.2°; Or, the pamoate salt crystal F of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 11.92±0.2°, 14.67±0.2°, 16.71±0.2° and 25.84±0.2°; Or, the pamoate salt crystal G of the compound of formula I as shown in claim 8, whose XRPD spectrum also includes diffraction peaks at 2θ of about 11.24±0.2°, 14.54±0.2°, 19.90±0.2°, 20.09±0.2°, 22.21±0.2°, 23.96±0.2° and 24.76±0.2°; Or, the pamoate salt crystal H of the compound of formula I as shown in claim 8, whose XRPD spectrum also includes diffraction peaks at 2θ of about 11.76±0.2°, 13.03±0.2°, 20.27±0.2° and 26.66±0.2°; Or, the pamoate salt crystal I of the compound of formula I as shown in claim 8, whose XRPD spectrum also includes diffraction peaks at 2θ of about 7.62±0.2°, 8.22±0.2°, 11.59±0.2°, 18.09±0.2° and 22.59±0.2°; Or, the pamoate salt crystal J of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 14.99±0.2°, 19.01±0.2° and 20.74±0.2°; Or, the pamoate salt crystal K of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 9.34±0.2°, 19.79±0.2° and 25.84±0.2°; Or, the pamoate crystal L of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 15.29±0.2° and 25.86±0.2°; Or, the pamoate salt crystal M of the compound of formula I as shown in claim 8, whose XRPD spectrum also includes diffraction peaks at 2θ of about 19.27±0.2°, 20.28±0.2° and 25.88±0.2°; Or, the pamoate salt crystal O of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 20.27±0.2°, 23.04±0.2°, 23.57±0.2° and 27.70±0.2°; Or, the pamoate crystal P of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 10.58±0.2°, 22.20±0.2°, 22.80±0.2° and 23.47±0.2°; Or, the pamoate salt crystal Q of the compound of formula I as shown in claim 8, whose XRPD spectrum further includes diffraction peaks at 2θ of about 16.16±0.2°, 17.51±0.2° and 24.37±0.2°; Or, the pamoate crystal R of the compound of formula I as shown in claim 8, whose XRPD pattern also includes diffraction peaks at 2θ of about 19.42±0.2°, 21.64±0.2°, 23.89±0.2°, 27.10±0.2° and 28.76±0.2°; Or, as claimed in claim 8, the pamoate salt crystal S of the compound of formula I, its XRPD spectrum also includes diffraction peaks at 2θ of about 19.33±0.2°, 21.53±0.2°, 22.68±0.2° and 24.06±0.2°.

10. A pharmaceutical composition comprising: a pamoate salt crystal of the compound of formula I according to any one of claims 1 to 9, and one or more pharmaceutically acceptable carriers.

11. Use of the pamoate salt crystal of the compound of formula I according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating Parkinson's disease and restless legs syndrome.

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