A polymorph of an mc4r antagonist and methods of making and using the same

Abstract

The application discloses a polymorph of an MC4R antagonist and a preparation method and application thereof. The MC4R antagonist is a compound as shown in formula (I), and the polymorph includes an amorphous form, a crystal form I, a crystal form II, a crystal form III and a crystal form IV of the compound as shown in formula (I), has good hygroscopicity, solubility, physical stability, chemical stability and / or antagonistic MC4R activity, and is suitable for drug development.

Description

Polymorphs of a MC4R antagonist, and methods of making and using the same

[0001] This application claims the priority of the prior application filed with the China National Intellectual Property Office on May 17, 2024, with the patent application number 202410619823.6, and the invention name of "Crystal Form of a MC4R Antagonist, and Methods of Making and Using the Same"; the prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of compounds, and specifically relates to a polymorph of a MC4R antagonist, and methods of making and using the same. BACKGROUND

[0003] PCT / CN2023 / 132220 (filing date November 17, 2023) describes a compound (R)-1-((S)-7-((5-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-6-methylpyridin-2-yl)amino)-5- azaspiro[2.4]heptan-5-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one, which has the structure shown in formula (I), the compound has good MC4R antagonistic activity, not only has good biological activity, good safety, and improves the transmembrane activity and drug bioavailability; in addition, the compound significantly improves the in vivo pharmacokinetic properties, while reducing the inhibition of CYP 3A4M, reducing the risk of drug-drug interactions, and improving the drugability of the compound.

[0004] The solid form of a drug is usually multiple, and it is a technical problem that researchers in the field strive to solve to study the solid form suitable for drug. SUMMARY

[0005] The present application provides polymorphs of a compound shown in formula (I), including the amorphous form, crystal form I, crystal form II, crystal form III, and crystal form IV of the compound shown in formula (I).

[0006] According to an embodiment of the present application, the amorphous form has an XRPD pattern substantially as shown in Figure 1.

[0007] According to an embodiment of the present application, the amorphous form has a weight loss of not more than 5wt% at room temperature to about 180℃, for example, a weight loss of about 3.2wt%.

[0008] According to an exemplary embodiment of the present application, the amorphous form has a TGA pattern substantially as shown in Figure 2.

[0009] According to embodiments of the application, the Form I has characteristic peaks expressed in degrees 2-theta, using Cu-Kalpharadiation, at 13.8 ± 0.20°, 18.8 ± 0.20°, 19.9 ± 0.20°, 20.4 ± 0.20°, 22.5 ± 0.20°, 24.1 ± 0.20°, and 25.5 ± 0.20°; further, it can also have characteristic peaks at 14.7 ± 0.20°, 15.7 ± 0.20°, 17.7 ± 0.20°, 18.0 ± 0.20°, 21.4 ± 0.20°, and / or 27.0 ± 0.20°; further, it can also have characteristic peaks at 6.9 ± 0.20°, 9.8 ± 0.20°, 25.0 ± 0.20°, 26.1 ± 0.20°, 27.7 ± 0.20°, 28.1 ± 0.20°, 29.5 ± 0.20°, 30.0 ± 0.20°, 30.7 ± 0.20°, and / or 32.7 ± 0.20°.

[0010] According to embodiments of the application, the Form I has characteristic peaks expressed in degrees 2-theta, using Cu-Kalpharadiation, at 6.9 ± 0.20°, 9.8 ± 0.20°, 13.8 ± 0.20°, 14.7 ± 0.20°, 15.7 ± 0.20°, 17.7 ± 0.20°, 18.0 ± 0.20°, 18.8 ± 0.20°, 19.9 ± 0.20°, 20.4 ± 0.20°, 21.4 ± 0.20°, 22.5 ± 0.20°, 24.1 ± 0.20°, 25.0 ± 0.20°, 25.5 ± 0.20°, 26.1 ± 0.20°, 27.0 ± 0.20°, 27.7 ± 0.20°, 28.1 ± 0.20°, 29.5 ± 0.20°, 30.0 ± 0.20°, 30.7 ± 0.20°, and 32.7 ± 0.20°.

[0011] According to embodiments of the application, the Form I has characteristic peaks expressed in degrees 2-theta, using Cu-Kalpharadiation, at 6.9 ± 0.20°, 9.8 ± 0.20°, 13.8 ± 0.20°, 14.7 ± 0.20°, 15.7 ± 0.20°, 17.7 ± 0.20°, 18.0 ± 0.20°, 18.8 ± 0.20°, 19.9 ± 0.20°, 20.4 ± 0.20°, 21.4 ± 0.20°, 22.5 ± 0.20°, 24.1 ± 0.20°, 25.0 ± 0.20°, 25.5 ± 0.20°, 26.1 ± 0.20°, 27.0 ± 0.20°, 27.7 ± 0.20°, 28.1 ± 0.20°, 29.5 ± 0.20°, 30.0 ± 0.20°, 30.7 ± 0.20°, and 32.7 ± 0.20°.

[0012] According to embodiments of the application, the Form I has an XRPD pattern substantially as shown in Figure 4.

[0013] According to embodiments of the application, the Form I has one endothermic peak with an onset temperature in the range of 140 to 145 °C and a peak temperature that is greater than 0 and less than 10 °C above the onset temperature; for example, the Form I has one endothermic peak with an onset temperature in the range of 141 to 144 °C and a peak temperature that is greater than 0 and less than 6 °C above the onset temperature; illustratively, the Form I has one endothermic peak with an onset temperature of 143.78 °C and a peak temperature that is 2.02 °C above the onset temperature.

[0014] According to an exemplary embodiment of the present application, the Form I has a DSC pattern substantially as shown in Figure 5.

[0015] According to an embodiment of the present application, the Form I has a weight loss of no more than 1 wt% at room temperature to about 140 °C, preferably a weight loss of no more than 0.5 wt%, 0.4 wt% or 0.35 wt%.

[0016] According to an exemplary embodiment of the present application, the Form I has a TGA pattern substantially as shown in Figure 6.

[0017] According to an embodiment of the present application, the Form I is an anhydrous crystalline form.

[0018] According to an embodiment of the present application, the Form II has X-ray powder diffraction peaks, expressed in angles of 2-theta, using Cu-Ka radiation, at 7.4 ± 0.20°, 10.1 ± 0.20°, 14.0 ± 0.20°, 14.9 ± 0.20° and 22.3 ± 0.20°; further, it can also have peaks at 8.7 ± 0.20°, 15.4 ± 0.20°, 17.3 ± 0.20°, 20.9 ± 0.20°, 21.9 ± 0.20° and / or 23.8 ± 0.20°; further, it can also have peaks at 4.2 ± 0.20°, 5.8 ± 0.20°, 10.8 ± 0.20°, 11.8 ± 0.20°, 19.5 ± 0.20°, 25.1 ± 0.20°, 26.5 ± 0.20°, 27.6 ± 0.20°, 28.1 ± 0.20°, 28.9 ± 0.20° and / or 30.0 ± 0.20°.

[0019] According to an embodiment of the present application, the Form II has an XRPD pattern substantially as shown in Figure 8.

[0020] According to an embodiment of the present application, the Form II has one, two or more peaks as shown in (1)-(4) below:

[0021] (1) an endothermic peak with a starting temperature of 92-102 °C and a difference between the peak temperature and the starting temperature greater than 0 and less than 15 °C; for example, an endothermic peak with a starting temperature of 94-100 °C and a difference between the peak temperature and the starting temperature greater than 5 °C and less than 12 °C;

[0022] (2) an endothermic peak with a starting temperature of 128-138 °C and a difference between the peak temperature and the starting temperature greater than 0 and less than 8 °C; for example, an endothermic peak with a starting temperature of 130-135 °C and a difference between the peak temperature and the starting temperature greater than 0 and less than 5 °C;

[0023] (3) an endothermic peak with an onset temperature of 139-147 °C and a difference between the peak temperature and the onset temperature of more than 0 and less than 8 °C; for example, an endothermic peak with an onset temperature of 140-145 °C and a difference between the peak temperature and the onset temperature of more than 0 and less than 5 °C;

[0024] (4) an exothermic peak with an onset temperature of 107-117 °C and a difference between the peak temperature and the onset temperature of more than 0 and less than 10 °C; for example, an exothermic peak with an onset temperature of 110-115 °C and a difference between the peak temperature and the onset temperature of more than 3 °C and less than 7 °C.

[0025] According to an exemplary embodiment of the present application, the crystalline Form II has a DSC pattern substantially as shown in Figure 9.

[0026] According to an embodiment of the present application, the crystalline Form II loses 3-8 wt% from room temperature to about 110 °C, for example, about 5 wt% from room temperature to about 110 °C.

[0027] According to an exemplary embodiment of the present application, the crystalline Form II has a TGA pattern substantially as shown in Figure 10.

[0028] According to an embodiment of the present application, the crystalline Form III has X-ray powder diffraction peaks at 9.6±0.20°, 14.5±0.20° and 15.3±0.20°, expressed in terms of the 2θ angle, using Cu-Ka radiation; further, it can also have peaks at 7.4±0.20°, 17.2±0.20°, 21.0±0.20° and / or 24.0±0.20°; further, it can also have peaks at 8.9±0.20°, 10.2±0.20°, 11.1±0.20°, 13.2±0.20°, 17.8±0.20°, 19.4±0.20°, 22.1±0.20° and / or 24.7±0.20°.

[0029] According to an embodiment of the present application, the crystalline Form III has an XRPD pattern substantially as shown in Figure 12.

[0030] According to an embodiment of the present application, the crystalline Form III has one, two or three peaks as shown in (a)-(c) below:

[0031] (a) an endothermic peak with an onset temperature of 92-102 °C and a difference between the peak temperature and the onset temperature of more than 0 and less than 15 °C; for example, an endothermic peak with an onset temperature of 94-98 °C and a difference between the peak temperature and the onset temperature of more than 5 °C and less than 12 °C;

[0032] (b) an endothermic peak with an onset temperature of 128-138 °C and a peak temperature difference from the onset temperature of greater than 0 and less than 8 °C; for example, an endothermic peak with an onset temperature of 132-136 °C and a peak temperature difference from the onset temperature of greater than 0 and less than 5 °C;

[0033] (c) an exothermic peak with an onset temperature of 107-117 °C and a peak temperature difference from the onset temperature of greater than 0 and less than 10 °C; for example, an exothermic peak with an onset temperature of 110-115 °C and a peak temperature difference from the onset temperature of greater than 0 and less than 5 °C.

[0034] According to an exemplary embodiment of the present application, the Form III has a DSC pattern substantially as shown in Figure 13.

[0035] According to an embodiment of the present application, the Form III loses 3-8 wt% from room temperature to about 130 °C, for example, about 5 wt% from room temperature to about 130 °C.

[0036] According to an exemplary embodiment of the present application, the Form III has a TGA pattern substantially as shown in Figure 14.

[0037] According to an embodiment of the present application, the Form IV has X-ray powder diffraction peaks, expressed in angles of 2θ, using Cu-Kα radiation, at 8.1 ± 0.20°, 14.5 ± 0.20° and 16.9 ± 0.20°; further, it can also have peaks at 4.5 ± 0.20°, 5.8 ± 0.20°, 12.6 ± 0.20°, 20.5 ± 0.20°, 21.2 ± 0.20° and / or 22.6 ± 0.20°; further, it can also have peaks at 2.9 ± 0.20°, 3.5 ± 0.20°, 4.0 ± 0.20°, 4.8 ± 0.20°, 6.1 ± 0.20°, 7.3 ± 0.20°, 9.3 ± 0.20°, 9.9 ± 0.20°, 10.7 ± 0.20°, 11.1 ± 0.20°, 13.0 ± 0.20°, 18.5 ± 0.20°, 18.7 ± 0.20°, 23.6 ± 0.20°, 24.5 ± 0.20°, 25.1 ± 0.20°, 25.8 ± 0.20°, 27.5 ± 0.20°, 28.7 ± 0.20°, 29.6 ± 0.20° and / or 34.7 ± 0.20°.

[0038] According to embodiments of the application, the Form IV has X-ray powder diffraction peaks, expressed in angles of 2 theta, at 2.9 ± 0.20°, 3.5 ± 0.20°, 4.0 ± 0.20°, 4.5 ± 0.20°, 4.8 ± 0.20°, 5.8 ± 0.20°, 6.1 ± 0.20°, 7.3 ± 0.20°, 8.1 ± 0.20°, 9.3 ± 0.20°, 9.9 ± 0.20°, 10.7 ± 0.20°, 11.1 ± 0.20°, 12.6 ± 0.20°, 13.0 ± 0.20°, 14.5 ± 0.20°, 16.2 ± 0.20°, 16.9 ± 0.20°, 17.5 ± 0.20°, 18.5 ± 0.20°, 18.7 ± 0.20°, 20.1 ± 0.20°, 20.5 ± 0.20°, 21.2 ± 0.20°, 22.6 ± 0.20°, 23.6 ± 0.20°, 24.5 ± 0.20°, 25.1 ± 0.20°, 25.8 ± 0.20°, 26.7 ± 0.20°, 27.5 ± 0.20°, 28.1 ± 0.20°, 28.7 ± 0.20°, 29.6 ± 0.20°, 30.1 ± 0.20°, and 34.7 ± 0.20°.

[0039] According to embodiments of the application, the Form IV has X-ray powder diffraction peaks, expressed in angles of 2 theta, as shown in Table 6, with a ± 0.20° error.

[0040] According to embodiments of the application, the Form IV has an XRPD pattern substantially as shown in Figure 16.

[0041] According to embodiments of the application, the Form IV has one, two, or three peaks as shown in (i)-(iii) below:

[0042] (i) an endothermic peak with a starting temperature in the range of 47 to 57 °C and a peak temperature that is greater than 0 and less than 15 °C from the starting temperature; for example, an endothermic peak with a starting temperature in the range of 50 to 55 °C and a peak temperature that is greater than 4 °C and less than 10 °C from the starting temperature;

[0043] (ii) an endothermic peak with a starting temperature in the range of 127 to 137 °C and a peak temperature that is greater than 0 and less than 15 °C from the starting temperature; for example, an endothermic peak with a starting temperature in the range of 130 to 135 °C and a peak temperature that is greater than 3 °C and less than 8 °C from the starting temperature;

[0044] (iii) an endothermic peak with a starting temperature in the range of 138 to 147 °C and a peak temperature that is greater than 0 and less than 15 °C from the starting temperature; for example, an endothermic peak with a starting temperature in the range of 140 to 145 °C and a peak temperature that is greater than 2 °C and less than 6 °C from the starting temperature.

[0045] According to an exemplary embodiment of the present application, the crystal Form IV has a DSC pattern substantially as shown in Figure 17.

[0046] The present application also provides a method for preparing the crystal Form I, which is selected from any one of the following methods:

[0047] Method 1: suspending an amorphous compound of Formula (I) in a first solvent, stirring, and isolating to obtain the crystal Form I;

[0048] The first solvent is selected from one, two or more of ethanol, isopropanol, acetone, ethyl acetate, 2-methyltetrahydrofuran and acetonitrile;

[0049] Method 2: dissolving an amorphous compound of Formula (I) in a second solvent, adding a third solvent to the solution, stirring, and isolating to obtain the crystal Form I;

[0050] The second solvent is selected from one, two or more of dichloromethane, tetrahydrofuran, methanol, dimethyl sulfoxide and 1,4-dioxane;

[0051] The third solvent is selected from one, two or more of n-heptane, methyl tert-butyl ether, water and methylcyclohexane.

[0052] According to an embodiment of the present application, the stirring in the above-mentioned Method 1 and Method 2 can be carried out at room temperature.

[0053] According to an embodiment of the present application, the preparation of the amorphous compound of Formula (I) comprises: freeze-drying the compound of Formula (I) with a mixed solvent containing water to obtain the amorphous compound of Formula (I);

[0054] For example, the mixed solvent containing water is selected from a mixed solvent of acetonitrile and water;

[0055] The present application also provides a method for preparing the crystal Form IV, which comprises: heating the crystal Form II to above 100°C, preferably to 100-150°C, in an inert atmosphere, and cooling to obtain the crystal Form IV.

[0056] According to an embodiment of the present application, the preparation of the crystal Form II comprises: dissolving an amorphous compound of Formula (I) in a fourth solvent, placing a container containing the solution in a container containing a fifth solvent, and standing to precipitate to obtain the crystal Form II;

[0057] The fourth solvent is selected from acetone;

[0058] The fifth solvent is selected from n-heptane;

[0059] Preferably, the standing time is not less than 1 day, 2 days, 3 days, 4 days or 5 days.

[0060] Preferably, the temperature of the standing is room temperature.

[0061] The present application also provides a pharmaceutical composition comprising a solid form of the compound of formula (I) (i.e. the above-mentioned polymorphs), for example comprising the amorphous form, the crystalline Form I, the crystalline Form II, the crystalline Form III and / or the crystalline Form IV of the compound of formula (I).

[0062] According to an embodiment of the present application, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable excipients.

[0063] According to an embodiment of the present application, the pharmaceutical composition can further comprise an additional therapeutic agent, in combination with a solid form of the compound of formula (I).

[0064] The present application also provides the use of a polymorph of the compound of formula (I) or of the pharmaceutical composition described above for the manufacture of a medicament for the diagnosis, prevention and / or treatment of a disease or disorder mediated by MC4R receptors.

[0065] According to an embodiment of the present application, the medicament is an MC4R antagonist.

[0066] According to an embodiment of the present application, the disease or disorder comprises: cachexia (cachexia associated with cancer, cachexia associated with acquired immune deficiency syndrome (AIDS), cachexia associated with congestive heart failure (CHF), cachexia associated with chronic kidney disease (CKD), cachexia associated with treatment of other chronic diseases); anorexia or anorexia nervosa (senile anorexia, anorexia associated with chemotherapy and / or radiotherapy); nausea and vomiting; weight loss (involuntary weight loss); growth failure; sarcopenia; muscle atrophy; muscle weakness; frailty; osteoporosis; bone disease (bone loss); pain (neuropathic pain); anxiety (post-traumatic stress disorder or PTSD); depression; hypertension; malnourished obesity (such as muscle loss caused by chronic obesity); sexual dysfunction; and inflammatory disease (inflammatory disease associated with anorexia or cachexia, muscle loss or muscle atrophy).

[0067] The present application also provides a method for the diagnosis, prevention and / or treatment of a disease or disorder mediated by MC4R receptors, which comprises the administration of a therapeutically effective amount of the above-mentioned polymorph or pharmaceutical composition, alone, to a patient in need of such treatment.

[0068] According to an embodiment of the present application, the disease or disorder has the same definition as above. Advantages

[0069] The present application provides polymorphs of the compound shown in formula (I), which have good hygroscopicity, solubility, physical stability and / or chemical stability, and are suitable for drug development.

[0070] Definitions of terms and explanations

[0071] The term "solvate" refers to an association including a complex of a compound of formula (I) with one or more solvent molecules (including water and / or one or more organic solvents), in a stoichiometric or non-stoichiometric ratio, i.e. an association including a complex of a compound of formula (I) with water molecules (i.e. a hydrate), an association including a complex of a compound of formula (I) with water molecules and one, two or more organic solvent molecules, an association including a complex of a compound of formula (I) with one, two or more organic solvent molecules.

[0072] The term "anhydrous crystal form" refers to a crystal form which does not contain water molecules and organic solvent molecules, in particular a crystal form which does not contain water molecules and solvent molecules in a manner of coexistence with the compound of formula (I) by intermolecular forces, for example in a manner of adsorption.

[0073] The term "crystal form I" and "Form I crystal form" refer to the same crystal form, the term "crystal form II" and "Form II crystal form" refer to the same crystal form, the term "crystal form III" and "Form III crystal form" refer to the same crystal form, and the term "crystal form IV" and "Form IV crystal form" refer to the same crystal form.

[0074] The term "pharmaceutically acceptable excipient" refers to an excipient, which does not stimulate the organism significantly, and does not impair the biological activity and properties of the active compound.

[0075] The term "more" refers to three or more, for example three, four, five.

[0076] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, most preferably humans.

[0077] The term "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or does not yet exhibit the pathology or symptoms of the disease, disorder or condition. (2) inhibiting the disease: for example, inhibiting a disease, disorder or condition (i.e., arresting the further development of the pathology and / or symptoms) in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder or condition. (3) relieving the disease: for example, relieving a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder or condition.

[0078] The term "room temperature" means a temperature of 15 to 40 °C, such as 20 to 35 °C, and also such as 25 °C.

[0079] The term "about" means a temperature error of ± 3 °C, such as ± 2 °C.

[0080] The term "Form I crystal form" means crystal form I, "Form II crystal form" means crystal form II, "Form III crystal form" means crystal form III, "Form IV crystal form" means crystal form IV. BRIEF DESCRIPTION OF DRAWINGS

[0081] Figure 1 : XRPD pattern of the compound of formula (I) in amorphous form;

[0082] Figure 2: TGA pattern of the compound of formula (I) in amorphous form;

[0083] Figure 3: NMR pattern of the compound of formula (I) in amorphous form;

[0084] Figure 4: XRPD pattern of the compound of formula (I) in Form I crystal form;

[0085] Figure 5: DSC pattern of the compound of formula (I) in Form I crystal form;

[0086] Figure 6: TGA pattern of the compound of formula (I) in Form I crystal form;

[0087] Figure 7: NMR pattern of the compound of formula (I) in Form I crystal form;

[0088] Figure 8: XRPD pattern of the compound of formula (I) in Form II crystal form;

[0089] Figure 9: DSC pattern of the compound of formula (I) in Form II crystal form;

[0090] Figure 10: TGA pattern of the compound of formula (I) in Form II crystal form;

[0091] Figure 11 : NMR pattern of the compound of formula (I) in Form II crystal form;

[0092] Figure 12: XRPD pattern of the compound of formula (I) in Form III crystal form;

[0093] Figure 13: DSC pattern of the compound of formula (I) in Form III crystal form;

[0094] Figure 14: TGA pattern of the compound of formula (I) in Form III crystal form;

[0095] Figure 15: NMR spectrum of Form III of the compound of formula (I);

[0096] Figure 16: XRPD spectrum of Form IV of the compound of formula (I);

[0097] Figure 17: DSC spectrum of Form IV of the compound of formula (I);

[0098] Figure 18: NMR spectrum of Form IV of the compound of formula (I);

[0099] Figure 19: DVS spectrum of Form I of the compound of formula (I). DETAILED DESCRIPTION

[0100] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of the present application.

[0101] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0102] Patent application PCT / CN2023 / 132220 (filing date November 17, 2023, publication number WO2024104452A1) describes the compound of formula (I), all the contents involved in this patent application are added to the present application by reference.

[0103] The following are the instruments, parameters, characterization and test methods used in the examples:

[0104] (1) Nuclear magnetic analysis 1 H NMR

[0105] Several milligrams of solid sample were dissolved in dimethyl sulfoxide-d6 or deuterated methanol solvent, and nuclear magnetic analysis was performed on a Bruker AVANCE NEO 400 (Bruker, GER).

[0106] (2) X-ray powder diffraction (XRPD)

[0107] The solid sample obtained by experiment was analyzed by X-ray powder diffractometer ARL Equinox 100. The 2θ scanning angle was from 0° to 110°. The test method was Cu target Kα ray, voltage 40 kV, current 0.9 mA, and the sample disc was a zero background sample disc.

[0108] (3) Thermal gravimetric analysis (TGA)

[0109] The thermal gravimetric analyzer was a METTLER TOLEDO TGA2 (METTLER TOLEDO, US). 2-10 mg samples were placed in an open aluminum sample pan that was equilibrated and automatically weighed in the TGA furnace. The samples were heated at a rate of 10 °C / min to the final temperature, with a nitrogen purge rate of 50 mL / min at the sample and 20 mL / min at the balance.

[0110] (4) Differential scanning calorimetry analysis (DSC)

[0111] The differential scanning calorimetry analyzer was a METTLER TOLEDO DSC3 (METTLER TOLEDO, US). 1-5 mg samples were accurately weighed into pierced DSC Tzero sample pans and heated at a rate of 10 °C / min to the final temperature, with a nitrogen purge rate of 40 mL / min in the furnace.

[0112] (5) Dynamic vapor sorption analysis (DVS)

[0113] The dynamic vapor sorption analysis was performed using a DVS Intrinsic (SMS, UK). The test was performed in gradient mode with a humidity change of 0%-95%-0%, with a humidity change of 10% in the range of 0% to 90% for each gradient, and the end of the gradient was determined by dm / dt, with dm / dt less than 0.002% for 10 minutes, or a maximum of 180 minutes for each gradient. After the test was completed, the sample was analyzed by XRPD to confirm whether the solid form had changed.

[0114] (6) High performance liquid chromatography (HPLC)

[0115] The high performance liquid chromatography was performed using a Waters Arc HPLC (normal phase) and an Agilent 1260 II (reverse phase), with the test conditions shown in Tables 1 and 2.

[0116] Table 1 HPLC test conditions (reverse phase)

[0117] Table 2 HPLC test conditions (normal phase)

[0118] Preparation and characterization of the amorphous form of the compound of formula (I)

[0119] (1) Synthesis of intermediate 1c

[0120] First step (6-chloro-2-methylpyridin-3-yl)boronic acid 1j

[0121] In a 2L three-necked flask, 1c-a (50g) and tetrahydrofuran (500mL) were added under nitrogen protection. The system was cooled to -78°C. n-Butyllithium solution (2.5mol / L, tetrahydrofuran / n-hexane solution, 117mL) was added dropwise at -78°C. After the addition was completed, the reaction was stirred at -78°C for 40 minutes. Then trimethyl borate (50.33g) was added dropwise at -78°C. After the reaction was continued at -78°C for 60 minutes, saturated aqueous ammonium chloride solution (400mL) was added dropwise to quench the reaction. The system was extracted with ethyl acetate (2x300mL), and the organic phase was combined. The aqueous phase was adjusted to pH = 6 with hydrochloric acid (2M), and the aqueous phase was extracted with methanol / dichloromethane (1 / 5) (4x500mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the title compound 1j (42g, crude). The crude product was used directly in the next step without further purification.

[0122] LC-MS: (ES, m / z) = 172.05 [M+H]+

[0123] Second step 6-chloro-2-methyl-3-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)pyridine 1c

[0124] 1j (17g) and 3,4-diethylhexane-3,4-diol (15.56g) were dissolved in dichloromethane (170mL) to react at room temperature for 12 hours. The reaction mixture was diluted with water (150mL) and extracted with dichloromethane (4x150mL). The combined organic phase was dried over anhydrous sodium sulfate. The obtained mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (0-15%) to obtain the title compound 1c (20g).

[0125] LC-MS: (ESI, m / z) = 310.50 [M+H]+

[0126] (2) Synthesis of intermediate 1g

[0127] First step (S)-benzyl 7-((tert-butoxycarbonyl)amino)-5-azaspiro[2.4]heptane-5-carboxylate 1l

[0128] To a 1 L three necked flask was added 1k (30 g) and triethylamine (42.90 g) dissolved in dichloromethane (300 mL) at 0 °C, benzyl chloroformate (36.16 g) was added drop wise. After the addition was complete, the system was allowed to stir at room temperature for 2 h. The reaction mixture was quenched with ice cold water (100 mL) at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 300 mL). The organic phases were combined, washed with saturated brine (1 x 100 mL), dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (3:2) to afford the title compound 1l (46.0 g).

[0129] LC-MS: (ES, m / z) = 347.10 [M+H]+

[0130] Second step (S)-7-amino-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester 1g

[0131] To a 1 L three necked flask was added 1l (46 g) dissolved in 1,4-dioxane (100 mL) at 0 °C, hydrogen chloride in 1,4-dioxane (4 M, 150 mL) was added drop wise, after the addition was complete, the system was allowed to stir at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 500 mL). The organic phases were combined, washed with saturated brine (1 x 300 mL), dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound 1g (28.0 g).

[0132] LC-MS: (ES, m / z) = 247.05 [M+H]+

[0133] (3) (R)-1-((S)-7-((5-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-6-methylpyridin-2-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-2-(5-fluoro-2-methoxypyridin-4-yl)propan-1-one Formula (I)

[0134] First step 4-bromo-2-methoxy-1-methyl-1H-imidazole 1b

[0135] Compound 1a (3 g) was dissolved in anhydrous methanol (30 mL), sodium methoxide-methanol solution (30 wt%, 45 g) was added dropwise at room temperature, after the addition was completed, the temperature was raised to 70 °C and stirred overnight. Then the reaction mixture was cooled to room temperature, diluted with water (100 mL), then the mixture was extracted with ethyl acetate (3 x 100 mL). The organic phase was combined, backwashed with saturated sodium chloride solution (2 x 100 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1b (1.1 g).

[0136] LC-MS: (ESI, m / z) = 191.25 [M+H]+

[0137] Second step 6-chloro-3-(2-methoxy-1-methyl-1H-imidazol-4-yl)-2-methylpyridine 1d

[0138] 1b (600 mg) and 1c (976 mg) were dissolved in a mixed solution of 1,4-dioxane (6 mL) and water (1.5 mL), then [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (206 mg) and potassium phosphate (1.34 g) were added, replaced with nitrogen three times and raised to 80 °C and stirred for 3 hours. After the reaction mixture was cooled to room temperature, it was filtered, the filtrate was diluted with water (30 mL), then the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was combined, backwashed with saturated sodium chloride solution (2 x 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluent ethyl acetate / petroleum ether (0-18%), to give the title compound 1d (350 mg).

[0139] LC-MS: (ESI, m / z) = 238.00 [M+H]+

[0140] Third step 4-(6-chloro-2-methylpyridin-3-yl)-1-methyl-1H-imidazol-2-ol 1e

[0141] 1d (350 mg) was dissolved in tetrahydrofuran (4 mL), then dilute hydrochloric acid solution (1 M, 4 mL) was added and the temperature was raised to 60 °C and stirred for 1 hour. After the reaction system was cooled to room temperature, the pH was adjusted to weakly acidic with saturated sodium bicarbonate solution, then the mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was combined, backwashed with saturated sodium chloride solution (2 x 30 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1e (300 mg).

[0142] LC-MS: (ESI, m / z) = 224.00 [M+H]+

[0143] Fourth step 6-chloro-3-(2-(difluoromethoxy)-l-methyl-lH-imidazol-4-yl)-2- methylpyridine If

[0144] Dissolve le (300 mg) in 1,4-dioxane (10 mL), add sodium hydroxide solution (20 wt%, 10 mL) and warm to 65 °C, then pass in chlorodifluoromethane gas and continue stirring at 65 °C for 1 hour. Cool the reaction to room temperature, dilute with water (30 mL), then extract the mixture with ethyl acetate (3 x 50 mL). Combine the organic phases, backwash with saturated sodium chloride solution (2 x 30 mL) and dry over anhydrous sodium sulfate. Filter the resulting mixture, then concentrate the filtrate under reduced pressure. Purify the residue by column chromatography on silica gel using ethyl acetate / petroleum ether (0-18%) as eluent to give the title compound If (230 mg).

[0145] LC-MS: (ESI, m / z) = 273.95 [M+H]+

[0146] Fifth step (S)-7-((5-(2-(difluoromethoxy)-l-methyl-lH-imidazol-4-yl)-6- methylpyridin-2-yl)amino)-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester Ih

[0147] Dissolve If (200 mg) and Ig (198 mg) in toluene (2 mL), then add tris(dibenzylideneacetone)dipalladium (67 mg), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (60 mg) and sodium tert-butoxide (140 mg), replace with nitrogen three times and warm to 90 °C, then continue stirring at 90 °C for 1 hour. Cool the reaction mixture to room temperature, then filter, dilute the filtrate with water (30 mL), then extract the mixture with ethyl acetate (3 x 50 mL). Combine the organic phases, backwash with saturated sodium chloride solution (2 x 30 mL) and dry over anhydrous sodium sulfate. Filter the resulting mixture, then concentrate the filtrate under reduced pressure. Purify the residue by column chromatography on silica gel using ethyl acetate / petroleum ether (0-38%) as eluent to give the title compound Ih (240 mg).

[0148] LC-MS: (ESI, m / z) = 484.10 [M+H]+

[0149] Sixth step (S)-N-(5-(2-(difluoromethoxy)-l-methyl-lH-imidazol-4-yl)-6- methylpyridin-2-yl)-5-azaspiro[2.4]heptan-7-amine Ii

[0150] Put 1h (240 mg) into a reaction flask, add trifluoroacetic acid (5 mL) at room temperature and continue stirring at 60 °C for 1 hour. Concentrate the reaction mixture under reduced pressure to give the trifluoroacetate salt of the title compound 1i (180 mg, crude). The crude product was used directly in the next step without further purification.

[0151] LC-MS: (ESI, m / z) = 350.05 [M+H]+.

[0152] Step 7 (R)-1-((S)-7-((5-(2-(difluoromethoxy)-1-methyl-1H-imidazol-4-yl)-6- methylpyridin-2-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-2-(5-fluoro-2-methoxypyridin-4- yl)propan-1-one Formula (I)

[0153] Dissolve the trifluoroacetate salt of 1i (90 mg, crude) and compound 1f (50 mg) in N,N-dimethylacetamide (2 mL), add N,N-diisopropylethylamine (322 mg) to make the system alkaline, then add 1-propylphosphonic anhydride (50 wt% in ethyl acetate, 800 mg) and continue stirring at room temperature for 1 hour. Filter the resulting mixture, and wash the filter cake with N,N-dimethylacetamide (2 x 1 mL). Purify the crude product by high performance liquid chromatography (column specifications: Kinetex 5 μm EVO C18, 30*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 39% B to 54% B in 10 minutes) to give the title compound, Formula (I) (46.67 mg).

[0154] Freeze-dry the title compound, Formula (I), with a mixture of acetonitrile / water, 1v / 4v, to give an amorphous material, which was characterized by XRPD. The XRPD, TGA, and NMR spectra of the title compound, Formula (I), are shown in Figures 1-3. The amorphous material loses about 3.2 wt% from room temperature to about 180 °C.

[0155] LC-MS: (ESI, m / z) = 530.90 [M+H]+.

[0156] Preparation and characterization of the title compound, Formula (I), Form I

[0157] Take 50 mg of the amorphous material of the title compound, Formula (I), and add 0.6 mL of ethanol to form a suspension. Stir the suspension at room temperature for 2 weeks, then centrifuge the suspension to obtain a solid. The XRPD spectrum of the solid is shown in Figure 4, and the resolved data are shown in Table 3. The solid is designated as Form I of the title compound, Formula (I).

[0158] Table 3

[0159] The Form I crystal form of the compound of formula (I) was detected by DSC, TGA and NMR, and the graphs are shown in Figures 5-7. The Form I crystal form has an endothermic peak with an onset temperature of 143.78°C and a peak temperature of 145.80°C, and the crystal form I loses about -14.0305e-03wt% at room temperature to about 140°C. It is shown that the Form I crystal form is an anhydrous crystal form.

[0160] Example 3

[0161] The amorphous raw material of the compound of formula (I) 50 mg was weighed, 0.3 mL of acetone was added, and a suspension was formed by stirring at room temperature. The solid was collected after centrifugal separation. The solid was characterized by XRPD, and the XRPD spectrum was basically consistent with the Form I crystal form of Figure 4 in Example 2, indicating that the obtained crystal was Form I crystal form.

[0162] Example 4 Preparation and characterization of Form II crystal form of the compound of formula (I)

[0163] The amorphous raw material of the compound of formula (I) 20 mg was dissolved in 0.2 mL of acetone at room temperature, and then filtered into a 2 mL glass bottle 1. 1.6 mL of n-heptane was added to a 40 mL glass bottle 2. The opening of the glass bottle 1 was placed in the glass bottle 2, and the bottle opening of the glass bottle 2 was covered. After standing at room temperature for about 5 days, a solid was precipitated. The XRPD spectrum of the solid is shown in Figure 8, and the analysis data is shown in Table 4. It is recorded as Form II crystal form of the compound of formula (I).

[0164] Table 4

[0165] The Form II crystal form of the compound of formula (I) was detected by DSC, TGA and NMR, and the graphs are shown in Figures 9-11. The Form II crystal form has four peaks: an endothermic peak with an onset temperature of 97.14°C and a peak temperature of 107.15°C; an endothermic peak with an onset temperature of 133.99°C and a peak temperature of 137.42°C; an endothermic peak with an onset temperature of 142.79°C and a peak temperature of 146.66°C; and an exothermic peak with an onset temperature of 112.35°C and a peak temperature of 117.50°C. The Form II crystal form loses about 5.15wt% at room temperature to about 110°C. It is shown that the Form II crystal form is a solvate.

[0166] Example 5 Preparation and characterization of Form III crystal form of the compound of formula (I)

[0167] The compound of formula (I) amorphous material 20 mg was weighed, dissolved in 0.3 mL of ethyl acetate at room temperature, filtered and placed in a 2 mL glass bottle 1; 2.4 mL of n-heptane was taken and placed in a 40 mL glass bottle 2; the opening of the glass bottle 1 was placed in the glass bottle 2, the bottle opening of the glass bottle 2 was covered, and it was left to stand at room temperature, and solid precipitated after about 5 days. The XRPD pattern of the solid is shown in Figure 12, and the analysis data is shown in Table 5. It is recorded as Form III crystal form of the compound of formula (I).

[0168] Table 5

[0169] The Form III crystal form of the compound of formula (I) was subjected to DSC, TGA, NMR detection, and the patterns are shown in Figures 13-15. The Form III crystal form has three peaks: an endothermic peak with an onset temperature of 96.48°C and a peak temperature of 107.96°C; an exothermic peak with an onset temperature of 112.50°C and a peak temperature of 115.50°C; an endothermic peak with an onset temperature of 134.47°C and a peak temperature of 137.43°C. The Form III crystal form loses about 5.31 wt% at room temperature to about 130°C. It is shown that the Form III crystal form is a solvate.

[0170] Example 6 Preparation and characterization of Form IV of the compound of formula (I)

[0171] An appropriate amount of Form II crystal form of the compound of formula (I) obtained in Example 4 was weighed, heated to 130°C in a nitrogen atmosphere, and sampled after cooling and subjected to XRPD test. The XRPD pattern of the solid is shown in Figure 16, and the analysis data is shown in Table 6. It is recorded as Form IV crystal form of the compound of formula (I).

[0172] Table 6

[0173] The Form IV crystal form of the compound of formula (I) obtained was subjected to DSC, NMR detection, and the patterns are shown in Figures 17-18. The Form IV crystal form has three peaks: an endothermic peak with an onset temperature of 53.19°C and a peak temperature of 59.66°C; an endothermic peak with an onset temperature of 132.01°C and a peak temperature of 137.23°C; an endothermic peak with an onset temperature of 142.92°C and a peak temperature of 146.82°C. It is shown that the Form IV crystal form is an anhydrous crystal form.

[0174] Example 7 Evaluation of hygroscopicity

[0175] Dynamic water sorption-desorption analysis was performed on Form I crystal form of compound of formula (I), and the results are shown in Figure 19. The results show that Form I crystal form has a weight gain of about 0.4% at 80% RH, and a weight loss of 0.08% when the humidity is returned to 0%, indicating that Form I crystal form has little hygroscopicity.

[0176] XRPD analysis of the solid before and after the test showed that Form I crystal form did not change after DVS test.

[0177] Example 8 Dynamic solubility test in biological media and water

[0178] The preparation process of the biological media is shown in Table 7. The crystal form sample was added to the biological media and water and stirred at 37°C for 24 h. Samples were taken at 0.5 h, 2 h and 24 h, respectively. The sampled solution was filtered with a 0.22 μm water filter membrane, and some samples with high concentration were appropriately diluted with diluent. The signal peak area of the solution was measured by HPLC, and finally the concentration of the compound in the solution was calculated according to the peak area, the HPLC standard curve of the raw material and the dilution factor. In addition, the 24 h supernatant was tested for pH value.

[0179] Table 7 Preparation process of biological media

[0180] The corresponding results are shown in Table 8. The results show that Form I crystal form has a higher solubility in FaSSGF, greater than 2 mg / ml, and a smaller solubility in the other three systems.

[0181] Table 8

[0182] Example 9 Stability test

[0183] Stability studies of Form I crystal form were performed under high temperature (60°C), high humidity (25°C / 92.5% RH) and light (25°C / 4500 Lux) conditions. Samples were taken at day 5 for XRPD characterization and HPLC test, and the results are shown in Table 9. The XRPD results show that Form I crystal form did not change under high temperature, high humidity and light conditions for 5 days. The HPLC test results show that the chemical purity decreased slightly after 5 days of stability test compared with the results at T0, and the main peak area value of normal phase HPLC test did not decrease significantly.

[0184] Table 9

[0185] Form IV crystal form has the same or similar hygroscopicity and stability as Form I crystal form.

[0186] Example 10 In vitro cell activity test of compound of formula (I)

[0187] a. Experimental Consumables (as shown in Table 10):

[0188] Table 10

[0189] b. Experimental Procedure

[0190] Cell Line: flipin-293-MC4

[0191] Cell Culture Medium: DMEM, 10% fetal bovine serum 1*PS, 200 μg / ml hygromycin

[0192] Experimental Buffer: HBSS, 20 mM HEPES, 0.1% BSA, 500 μM IBMX

[0193] Positive Compound: ML00253764

[0194] c. Antagonist Detection

[0195] 1. Cells were suspended in experimental buffer after cell digestion, then seeded into 384-well cell assay plates.

[0196] 2. Formula (I) compounds were added to the cell plates, and incubated at 37°C for 10 minutes.

[0197] 3. Melanotan I was added to the cell plates, and incubated at 37°C for 30 minutes.

[0198] 4. EU cAMP tracer and ulight anti-camp detection reagents were thawed and diluted with the lysis solution in the kit.

[0199] 5. The diluted detection reagents were added to the cell plates. Incubated at room temperature for 1 hour.

[0200] 6. Envision reading (excitation light: 340 nm, emission light: 615 nm and 665 nm).

[0201] d. Data Analysis

[0202] 1. % Inhibition Calculation:

[0203] % Inhibition = (Signal cmpd - Signal Ave VC) / (Signal Ave PC - Signal Ave VC) x 100.

[0204] Signal cmpd: Compound signal value;

[0205] Signal Ave VC: Signal value of negative control;

[0206] Signal Ave PC: signal value of positive control

[0207] % inhibition: percentage of inhibition

[0208] 2. Compound IC50 was calculated using GraphPad nonlinear fit equation 50 :

[0209] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0210] X: compound concentration log value; Y: percentage of inhibition

[0211] The activity of the test compounds antagonizing MC4R is shown in Table 11.

[0212] Table 11

[0213] The above describes embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the scope of the present application.

Claims

1. A polymorph of a compound of formula (I) characterized by, The polymorphs include amorphous, Form I, Form II, Form III, Form IV of the compound of Formula (I); 2. The polymorph of claim 1, characterized by, said amorphous form has an XRPD pattern substantially as shown in Figure 1 ; and / or, said amorphous form has a weight loss of no more than 5wt% from room temperature to about 180°C; and / or, said amorphous form has a TGA pattern substantially as shown in Figure 2.

3. The polymorph of claim 1, characterized by, said crystalline Form I has an X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 13.8±0.20°, 18.8±0.20°, 19.9±0.20°, 20.4±0.20°, 22.5±0.20°, 24.1±0.20° and 25.5±0.20°; preferably, further at 14.7±0.20°, 15.7±0.20°, 17.7±0.20°, 18.0±0.20°, 21.4±0.20°, and / or 27.0±0.20°; preferably, further at 6.9±0.20°, 9.8±0.20°, 25.0±0.20°, 26.1±0.20°, 27.7±0.20°, 28.1±0.20°, 29.5±0.20°, 30.0±0.20°, 30.7±0.20° and / or 32.7±0.20°; preferably, said crystalline Form I has an XRPD pattern substantially as shown in Figure 4; and / or, said crystalline Form I has an endothermic peak with an onset temperature of 140-145°C, and a peak temperature which is more than 0 and less than 10°C from the onset temperature; and / or, said crystalline Form I has a DSC pattern substantially as shown in Figure 5; and / or, said crystalline Form I has a weight loss of no more than 1wt% from room temperature to about 140°C; and / or, said crystalline Form I has a TGA pattern substantially as shown in Figure 6.

4. The polymorph of claim 1, characterized by, said crystalline Form II has an X-ray powder diffraction expressed in angles of 2-theta using Cu-Kalpha radiation at 7.4±0.20°, 10.1±0.20°, 14.0±0.20°, 14.9±0.20° and 22.3±0.20°; further at 8.7±0.20°, 15.4±0.20°, 17.3±0.20°, 20.9±0.20°, 21.9±0.20° and / or 23.8±0.20°; further at 4.2±0.20°, 5.8±0.20°, 10.8±0.20°, 11.8±0.20°, 19.5±0.20°, 25.1±0.20°, 26.5±0.20°, 27.6±0.20°, 28.1±0.20°, 28.9±0.20° and / or 30.0±0.20°; preferably, said crystalline Form II has an XRPD pattern substantially as shown in Figure 8; and / or, said crystalline Form II has one, two or more peaks as shown in (1)-(4) below: (1) an endothermic peak with an onset temperature of 92-102°C, and a peak temperature which is more than 0 and less than 15°C from the onset temperature; (2) an endothermic peak with an onset temperature of 128-138°C, and a peak temperature which is more than 0 and less than 8°C from the onset temperature; (3) an endothermic peak with an onset temperature of 139-147 °C and a difference between the peak temperature and the onset temperature greater than 0 and less than 8 °C; (4) an exothermic peak with an onset temperature of 107-117 °C and a difference between the peak temperature and the onset temperature greater than 0 and less than 10 °C; and / or, the Form II has a DSC pattern substantially as shown in Figure 9; and / or, the Form II loses 3-8 wt% from room temperature to about 110 °C; and / or, the Form II has a TGA pattern substantially as shown in Figure 10.

5. The polymorph of claim 1, characterized by, the Form III has X-ray powder diffraction peaks, expressed in angles of 2-theta (°) using Cu-Kalpha radiation, at 9.6 ± 0.20°, 14.5 ± 0.20° and 15.3 ± 0.20°; further, at 7.4 ± 0.20°, 17.2 ± 0.20°, 21.0 ± 0.20° and / or 24.0 ± 0.20°; further, at 8.9 ± 0.20°, 10.2 ± 0.20°, 11.1 ± 0.20°, 13.2 ± 0.20°, 17.8 ± 0.20°, 19.4 ± 0.20°, 22.1 ± 0.20° and / or 24.7 ± 0.20°; Preferably, the Form III has an XRPD pattern substantially as shown in Figure 12; and / or, the Form III has one, two or three peaks as shown in (a)-(c) below: (a) an endothermic peak with an onset temperature of 92-102 °C and a difference between the peak temperature and the onset temperature greater than 0 and less than 15 °C; (b) an endothermic peak with an onset temperature of 128-138 °C and a difference between the peak temperature and the onset temperature greater than 0 and less than 8 °C; (c) an exothermic peak with an onset temperature of 107-117 °C and a difference between the peak temperature and the onset temperature greater than 0 and less than 10 °C; and / or, the Form III has a DSC pattern substantially as shown in Figure 13; and / or, the Form III loses 3-8 wt% from room temperature to about 130 °C; and / or, the Form III has a TGA pattern substantially as shown in Figure 14.

6. The polymorph of claim 1, characterized by, The crystal Form IV has X-ray powder diffraction peaks at 8.1±0.20°, 14.5±0.20° and 16.9±0.20° in terms of 2θ angle using Cu-Kα radiation; further, it also has peaks at 4.5±0.20°, 5.8±0.20°, 12.6±0.20°, 20.5±0.20°, 21.2±0.20° and / or 22.6±0.20°; further, it also has peaks at 2.9±0.20°, 3.5±0.20°, 4.0±0.20°, 4.8±0.20°, 6.1±0.20°, 7.3±0.20°, 9.3±0.20°, 9.9±0.20°, 10.7±0.20°, 11.1±0.20°, 13.0±0.20°, 18.5±0.20°, 18.7±0.20°, 23.6±0.20°, 24.5±0.20°, 25.1±0.20°, 25.8±0.20°, 27.5±0.20°, 28.7±0.20°, 29.6±0.20° and / or 34.7±0.20°; Preferably, the crystal Form IV has an XRPD pattern substantially as shown in FIG. 16; and / or, the crystal Form IV has one, two or three peaks as shown in (i)-(iii) below: (i) an endothermic peak with an onset temperature of 47-57°C and a peak temperature difference from the onset temperature of more than 0 and less than 15°C; (ii) an endothermic peak with an onset temperature of 127-137°C and a peak temperature difference from the onset temperature of more than 0 and less than 15°C; (iii) an endothermic peak with an onset temperature of 138-147°C and a peak temperature difference from the onset temperature of more than 0 and less than 15°C; and / or, the crystal Form IV has a DSC pattern substantially as shown in FIG. 17; 7. A process for preparing the crystalline Form I of claim 3, characterized in that, The preparation method is selected from any one of the following methods: Method 1: forming a suspension of an amorphous compound of formula (I) with a first solvent, stirring, separating to obtain the crystal Form I; The first solvent is selected from one, two or more of ethanol, isopropanol, acetone, ethyl acetate, 2-methyltetrahydrofuran and acetonitrile; Method 2: dissolving an amorphous compound of formula (I) in a second solvent, adding a third solvent to the solution, stirring, separating to obtain the crystal Form I; The second solvent is selected from one, two or more of dichloromethane, tetrahydrofuran, methanol, dimethyl sulfoxide and 1,4-dioxane; The third solvent is selected from one, two or more of n-heptane, methyl tert-butyl ether, water and methylcyclohexane.

8. A process for preparing the crystalline Form IV of claim 6, characterized in that, The preparation method comprises: heating the crystal Form II to above 100°C in an inert atmosphere, cooling to obtain the crystal Form IV; The preparation of the crystal Form II comprises: dissolving an amorphous compound of formula (I) in a fourth solvent, placing the container containing the solution in a container containing a fifth solvent, standing to precipitate to obtain the crystal Form II; The fourth solvent is selected from acetone; The fifth solvent is selected from n-heptane.

9. A pharmaceutical composition, characterized by, A solid form comprising the compound of formula (I) according to any one of claims 1 to 6.

10. Use of a polymorph of the compound of formula (I) according to any one of claims 1 to 6 or of a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the diagnosis, prevention and / or treatment of a disease or condition mediated by MC4R receptors. Preferably, the disease or condition is cachexia (cachexia associated with cancer, cachexia associated with acquired immune deficiency syndrome (AIDS), cachexia associated with congestive heart failure (CHF), cachexia associated with chronic kidney disease (CKD), cachexia associated with treatment of other chronic illnesses); anorexia or anorexia nervosa (geriatric anorexia, anorexia associated with chemotherapy and / or radiotherapy); nausea and vomiting; weight loss (involuntary weight loss); growth failure; sarcopenia; muscle atrophy; muscle weakness; frailty; osteoporosis; bone disease (bone loss); pain (neuropathic pain); anxiety (post-traumatic stress disorder or PTSD); depression; hypertension; malnourished obesity (such as muscle loss caused by chronic obesity); sexual dysfunction; and inflammatory disease (inflammatory disease associated with anorexia or cachexia, muscle loss or muscle atrophy).

11. A method for the diagnosis, prevention and / or treatment of a disease or condition mediated by MC4R receptors, the method comprising administering to a patient in need thereof a therapeutically effective amount of a polymorph according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 9, alone.

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