Crystalline polymorph of aminopyrimidine derivative and preparation method therefor

Abstract

The present application relates to a novel crystalline form of an aminopyrimidine derivative and a preparation method therefor.

Description

Crystal polymorphs of aminopyrimidine derivatives and methods for preparing the same

[0001] The present application relates to a crystal polymorph of an aminopyrimidine derivative and a method for producing the same.

[0002] The aryl hydrocarbon receptor (AhR) is widely known as a crucial intracellular chemical sensor that responds to various natural and artificial environmental compounds. This receptor plays a key role in various diseases, including autoimmunity, infection, and cancer, and is particularly important in cancer cell proliferation, tissue invasion, metastasis, and angiogenesis. Furthermore, AhR is closely associated with autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Therefore, the development of AhR-targeted therapies could offer a potential opportunity to overcome immune-related diseases. These findings suggest that the development of therapeutics targeting AhR could offer a new potential opportunity to overcome immune-related diseases.

[0003] The present application provides a novel polymorph of an aminopyrimidine derivative capable of modulating the AhR pathway, and a method for preparing the same. The novel polymorph according to one example of the present application exhibits improved stability compared to existing forms, and is expected to provide a more effective treatment option.

[0004] The polymorphism and method of making the same according to an example of the present application are designed to make significant advances in the fields of immune modulation and cancer treatment, and are expected to provide better treatment outcomes to patients.

[0005] An example of the present application is to provide a novel polymorph of a compound, solvate, or hydrate thereof represented by the following chemical formula 1 and a method for preparing the same:

[0006] [Chemical Formula 1]

[0007]

[0008] Another example of the present application is to provide a method for preparing a crystalline form of a compound represented by the above chemical formula 1, a solvate, or a hydrate thereof.

[0009]

[0010] Hereinafter, the present application will be described in more detail.

[0011] An example of the present application relates to a crystalline form of a compound, solvate, or hydrate thereof represented by the following chemical formula 1:

[0012] [Chemical Formula 1]

[0013]

[0014] A crystal form according to an example of the present application may have an X-ray powder diffraction pattern including a characteristic peak at a specific 2θ diffraction angle position in an X-ray powder diffraction (XRD) analysis.

[0015] The term “characteristic peak” as used herein may be a peak having a relative intensity of 0.5% or more, 0.6% or more, 0.7% or more, 0.8% or more, 0.9% or more, 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 10% or more, 11% or more, 12% or more, 15% or more, 17% or more, 18% or more, 20% or more, 25% or more, 30% or more, 34% or more, 35% or more, 40% or more, 45% or more, 50% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more of the results of X-ray powder diffraction (XRD) analysis. The relative intensity of the above peaks is expressed as a relative numerical percentage of the intensity of each peak based on 100% of the intensity of the peak with the maximum intensity.

[0016] The term “solvate” as used herein refers to a compound represented by Chemical Formula 1 according to an example of the present application, which is bound to solvent molecules by intermolecular forces, and may contain the solvent in a stoichiometric or non-stoichiometric amount. Some compounds tend to form a solvate by trapping a fixed molar ratio of solvent molecules in a crystalline solid state. The solvate may contain solvent molecules in a molar ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, for example, may contain solvent molecules in an amount of about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc. based on 1 mol of the active ingredient. In this case, when the solvent is water, the formed solvate is a hydrate. The hydrate may be, for example, a monohydrate, a 1.5-hydrate, a dihydrate, or a trihydrate, and may be, for example, a dihydrate.

[0017] An X-ray powder diffraction pattern of a crystalline form according to an example of the present application may include a characteristic peak at one or more 2θ diffraction angle positions selected from the group consisting of 7.246±0.2°, 9.389±0.2°, 13.917±0.2°, 14.470±0.2°, 18.760±0.2°, 20.210±0.2°, 21.196±0.2°, 21.788±0.2°, 22.503±0.2°, 27.872±0.2°, and 28.937±0.2° in X-ray powder diffraction (XRD) analysis.

[0018] For example, the X-ray powder diffraction pattern may include characteristic peaks at 2θ diffraction angle positions of 7.246±0.2°, 14.470±0.2°, and 20.210±0.2° in X-ray powder diffraction (XRD) analysis.

[0019] For example, the X-ray powder diffraction pattern may include characteristic peaks at 2θ diffraction angle positions of 7.246±0.2°, 9.389±0.2°, 13.917±0.2°, 14.470±0.2°, 18.760±0.2°, 20.210±0.2°, 21.196±0.2°, 21.788±0.2°, 22.503±0.2°, 27.872±0.2°, and 28.937±0.2° in X-ray powder diffraction (XRD) analysis.

[0020] Specifically, the characteristic peak at the 2θ diffraction angle position of 14.470±0.2° may be the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0021] Specifically, the characteristic peaks at the 2θ diffraction angle positions of 14.470±0.2° and 20.210±0.2° may be the two peaks with the highest relative intensities in the X-ray powder diffraction pattern.

[0022] Specifically, the characteristic peaks at the 2θ diffraction angle positions of 7.246±0.2°, 14.470±0.2°, and 20.210±0.2° may be the three peaks with the highest relative intensities in the X-ray powder diffraction pattern.

[0023] For example, the crystal form may have an X-ray powder diffraction pattern as shown in FIG. 1 or Table 1.

[0024] An X-ray powder diffraction pattern of a crystalline form according to an example of the present application may include a characteristic peak at one or more 2θ diffraction angle positions selected from the group consisting of 5.533±0.2°, 6.782±0.2°, 8.002±0.2°, 10.953±0.2°, 13.180±0.2°, 13.586±0.2°, 14.229±0.2°, 17.564±0.2°, 18.989±0.2°, and 23.738±0.2° in X-ray powder diffraction (XRD) analysis.

[0025] For example, the X-ray powder diffraction pattern may include characteristic peaks at 2θ diffraction angle positions of 5.533±0.2°, 17.564±0.2°, and 18.989±0.2° in X-ray powder diffraction (XRD) analysis.

[0026] For example, the X-ray powder diffraction pattern may include characteristic peaks at 2θ diffraction angle positions of 5.533±0.2°, 6.782±0.2°, 8.002±0.2°, 10.953±0.2°, 13.180±0.2°, 13.586±0.2°, 14.229±0.2°, 17.564±0.2°, 18.989±0.2°, and 23.738±0.2° in X-ray powder diffraction (XRD) analysis.

[0027] Specifically, the characteristic peak at the 2θ diffraction angle position of 18.989±0.2° may be the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0028] Specifically, the characteristic peaks at the 2θ diffraction angle positions of 18.989±0.2° and 17.564±0.2° may be the two peaks with the highest relative intensities in the X-ray powder diffraction pattern.

[0029] Specifically, the characteristic peaks at the 2θ diffraction angle positions of 18.989±0.2°, 17.564±0.2°, and 5.533±0.2° may be the three peaks with the highest relative intensities in the X-ray powder diffraction pattern.

[0030] For example, the crystal form may have an X-ray powder diffraction pattern as shown in FIG. 3 or Table 3.

[0031] An X-ray powder diffraction pattern of a crystal form according to an example of the present application is at least one selected from the group consisting of 5.723±0.2°, 8.893±0.2°, 11.499±0.2°, 15.501±0.2°, 16.566±0.2°, 17.777±0.2°, 18.432±0.2°, 19.305±0.2°, 21.127±0.2°, 23.136±0.2°, 24.123±0.2°, 25.091±0.2°, 26.885±0.2°, 27.707±0.2°, 28.557±0.2° and 29.363±0.2° in X-ray powder diffraction (XRD) analysis. It may contain a characteristic peak at the 2θ diffraction angle position.

[0032] For example, the X-ray powder diffraction pattern may include characteristic peaks at 2θ diffraction angle positions of 15.501±0.2°, 19.305±0.2°, and 23.136±0.2° in X-ray powder diffraction (XRD) analysis.

[0033] For example, the X-ray powder diffraction pattern includes characteristic peaks at 2θ diffraction angle positions of 5.723±0.2°, 8.893±0.2°, 11.499±0.2°, 15.501±0.2°, 16.566±0.2°, 17.777±0.2°, 18.432±0.2°, 19.305±0.2°, 21.127±0.2°, 23.136±0.2°, 24.123±0.2°, 25.091±0.2°, 26.885±0.2°, 27.707±0.2°, 28.557±0.2° and 29.363±0.2° in X-ray powder diffraction (XRD) analysis. It could be.

[0034] Specifically, the characteristic peak at the 2θ diffraction angle position of 19.305±0.2° may be the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0035] Specifically, the characteristic peaks at the 2θ diffraction angle positions of 19.305±0.2° and 23.136±0.2° may be the two peaks with the highest relative intensities in the X-ray powder diffraction pattern.

[0036] Specifically, the characteristic peaks at the 2θ diffraction angle positions of 19.305±0.2°, 23.136±0.2°, and 15.501±0.2° may be the three peaks with the highest relative intensities in the X-ray powder diffraction pattern.

[0037] For example, the crystal form may have an X-ray powder diffraction pattern as shown in FIG. 5 or Table 5.

[0038] An X-ray powder diffraction pattern of a crystalline form according to an example of the present application may include a characteristic peak at one or more 2θ diffraction angle positions selected from the group consisting of 6.832±0.2°, 11.019±0.2°, 13.621±0.2°, 16.114±0.2°, 17.526±0.2°, 18.703±0.2°, 18.95±0.2°, 19.486±0.2°, and 24.227±0.2° in X-ray powder diffraction (XRD) analysis.

[0039] For example, the X-ray powder diffraction pattern may include characteristic peaks at 2θ diffraction angle positions of 17.526±0.2°, 18.95±0.2°, and 24.227±0.2° in X-ray powder diffraction (XRD) analysis.

[0040] For example, the X-ray powder diffraction pattern may include characteristic peaks at 2θ diffraction angle positions of 6.832±0.2°, 11.019±0.2°, 13.621±0.2°, 16.114±0.2°, 17.526±0.2°, 18.703±0.2°, 18.95±0.2°, 19.486±0.2°, and 24.227±0.2° in X-ray powder diffraction (XRD) analysis.

[0041] Specifically, the characteristic peak at the 2θ diffraction angle position of 17.526±0.2° may be the peak with the highest relative intensity in the X-ray powder diffraction pattern.

[0042] Specifically, the characteristic peaks at the 2θ diffraction angle positions of 17.526±0.2° and 18.95±0.2° may be the two peaks with the highest relative intensities in the X-ray powder diffraction pattern.

[0043] Specifically, the characteristic peaks at the 2θ diffraction angle positions of 17.526±0.2°, 18.95±0.2°, and 24.227±0.2° may be the three peaks with the highest relative intensities in the X-ray powder diffraction pattern.

[0044] For example, the crystal form may have an X-ray powder diffraction pattern as shown in FIG. 7 or Table 7.

[0045] A crystal form according to an example of the present application may have a specific endothermic onset temperature and a specific endothermic peak in differential scanning calorimetry (DSC) analysis.

[0046] According to an example of the present application, the crystalline form may have an endothermic onset temperature of 55.86±2°C and an endothermic peak of 80.80±2°C in differential scanning calorimetry (DSC) analysis; and / or an endothermic onset temperature of 202.79±2°C and an endothermic peak of 215.00±2°C.

[0047] For example, the above-described crystal form may have a DSC graph as shown in FIG. 2.

[0048] According to an example of the present application, the crystalline form may have an endothermic onset temperature of 50.60±2°C and an endothermic peak of 78.26±2°C in differential scanning calorimetry (DSC) analysis; and / or an endothermic onset temperature of 187.81±2°C and an endothermic peak of 203.20±2°C.

[0049] For example, the above-described crystal form may have a DSC graph as shown in FIG. 4.

[0050] According to an example of the present application, the crystalline form may have an endothermic onset temperature of 97.91±2°C and an endothermic peak of 126.55±2°C in differential scanning calorimetry (DSC) analysis; an endothermic onset temperature of 172.52±2°C and an endothermic peak of 185.38±2°C; and / or an endothermic onset temperature of 210.73±2°C and an endothermic peak of 219.55±2°C.

[0051] For example, the above-described crystal form may have a DSC graph as shown in FIG. 6.

[0052] A crystal form according to an example of the present application may have an endothermic onset temperature of 202.48±2°C and an endothermic peak of 211.44±2°C in differential scanning calorimetry (DSC) analysis.

[0053] For example, the above-described crystal form may have a DSC graph as shown in FIG. 8.

[0054] Another example of the present application relates to a method for producing a crystal form according to an example of the present application, comprising the steps of: reacting a compound represented by the following chemical formula 2 with a phosphorylating agent; obtaining a crude crystal from the reaction solution; refluxing and stirring the crude crystal in a solvent; and obtaining a crystal.

[0055] [Chemical Formula 2]

[0056]

[0057] The above phosphorylating agent may be at least one selected from the group consisting of phosphorus oxychloride (POCl3), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), dichlorophosphoric acid (Cl2POOH), diethylchlorophosphate (ClPO(OEt)2), tetraphenylpyrophosphate (TPPP), and phosphoramidite.

[0058] The above solvent may be an aqueous acetone solution.

[0059] The above manufacturing method may further include a step of hydrating the crystal after the step of obtaining the crystal. By the step of hydrating, a crystal form of a hydrate of the compound represented by the above chemical formula 1 may be formed. The hydrate may be, for example, a dihydrate.

[0060] The above refluxing and stirring step may include a step of refluxing and stirring the crude crystal in a solvent, filtering it, and then vacuum drying it; and a step of obtaining the crystal from the vacuum dried product.

[0061] By the above refluxing and stirring step and the hydration process, a crystalline Form I of a dihydrate of the compound represented by the above chemical formula 1 can be formed.

[0062] Accordingly, the crystal form according to an example of the present application may be a crystal form of a dihydrate of a compound represented by the above chemical formula 1, and specifically, may be a crystal form of a compound represented by the following chemical formula 3:

[0063] [Chemical Formula 3]

[0064]

[0065] The above manufacturing method may further include, after the step of obtaining the crystal, a step of adding alcohol to the crystal and stirring it; and a step of obtaining the crystal by filtering and vacuum drying. By the step of adding alcohol and stirring it, the crystalline form Form II of the compound represented by the above chemical formula 1 can be formed.

[0066] The alcohol may be, for example, methanol, ethanol, propanol, butanol, and as an example, 2-propanol.

[0067] The above manufacturing method may further include, after the step of obtaining the crystal, the step of dissolving the crystal in N-methyl-2-pyrrolidone; the step of cooling the melt to obtain a solid; and the step of filtering and vacuum-drying the solid to obtain a crystal. By the step of dissolving in N-methyl-2-pyrrolidone; and the step of cooling the melt to obtain a solid, the crystalline Form III of the compound represented by the above chemical formula 1 may be formed.

[0068] The above manufacturing method may further include, after the step of obtaining the crystal, a step of dissolving the crystal in dimethyl sulfoxide; a step of filtering and adding the solution back to obtain the crystal. By the step of dissolving the crystal in dimethyl sulfoxide; and the step of filtering and adding the solution back to obtain the crystal, the crystalline Form IV of the compound represented by the above chemical formula 1 can be formed.

[0069]

[0070] Pharmaceutical compositions and uses

[0071] Another example of the present application relates to a pharmaceutical composition comprising a crystalline form according to an example of the present application.

[0072] The above pharmaceutical composition may be used for the prevention or treatment of a disease mediated by aryl hydrocarbon receptor (AhR).

[0073] The above pharmaceutical composition may be used to inhibit proliferation, tissue invasion, metastasis and / or angiogenesis of cancer cells in a subject having cancer or a malignant tumor.

[0074] Another example of the present application relates to a composition for modulating AhR activity, comprising a crystalline form according to an example of the present application. For example, the AhR activity modulation may be AhR inhibition.

[0075] Another example of the present application relates to a method for preventing or treating a disease mediated by an aryl hydrocarbon receptor (AhR), comprising administering to a subject in need thereof a crystalline form according to an example of the present application.

[0076] Another example of the present application relates to a method for modulating AhR activity, comprising administering a crystalline form according to an example of the present application to a subject in need thereof. For example, the method for modulating AhR activity may be a method for inhibiting AhR.

[0077] Diseases mediated by the above aryl hydrocarbon receptor (AhR) may be disorders associated with abnormal AhR signaling.

[0078] The disease mediated by the above aryl hydrocarbon receptor (AhR) may be a disease mediated by activation of the aryl hydrocarbon receptor (AhR).

[0079] Diseases mediated by the above aryl hydrocarbon receptor (AhR) may be cancer, malignancies, fibrotic disorders, or conditions with dysregulated immune responses.

[0080] The cancer may be selected from the group consisting of breast cancer, squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, large intestine cancer, endometrial cancer or uterine cancer, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL), hairy cell leukemia, and chronic myeloblastic leukemia.

[0081] Examples of breast cancer include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0082] Examples of lung cancers include, but are not limited to, small cell and non-small cell lung carcinomas, as well as bronchial adenomas and pleuropulmonary blastomas.

[0083] Examples of brain cancers include, but are not limited to, neuroectodermal and pineal tumors, as well as brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, glioblastomas, medulloblastomas, and ependymomas.

[0084] Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer.

[0085] Tumors of the female reproductive organs include, but are not limited to, uterine sarcoma, as well as endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, and vulvar cancer.

[0086] Examples of ovarian cancer include, but are not limited to, serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and arrhenoblastomas.

[0087] Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, hyaline cell carcinoma, and villous adenocarcinoma.

[0088] Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0089] Examples of esophageal cancers include, but are not limited to, squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma, as well as esophageal cell carcinoma and adenocarcinoma.

[0090] Examples of gastric cancer include, but are not limited to, intestinal type and diffuse type gastric adenocarcinoma.

[0091] Examples of pancreatic cancer include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors.

[0092] Urologic tumors include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethra, and human papillary renal cell carcinoma.

[0093] Examples of kidney cancers include, but are not limited to, renal cell carcinoma, urothelial carcinoma, juxtamembrane cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear cell sarcoma of the kidney, mesoblastic nephroma, and Wilms' tumor.

[0094] Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma.

[0095] Ocular cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0096] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrous layer mutation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

[0097] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0098] Head and neck cancers include, but are not limited to, head and neck squamous cell carcinoma, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell.

[0099] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and central nervous system lymphoma.

[0100] Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0101] Leukemia includes, but is not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.

[0102] The subject may be a mammal, including a human or mammalian cell; for example, a mammal (e.g., a human) or a mammalian cell isolated therefrom suffering from a disease, disorder, or condition associated with AhR activity as described above.

[0103] The compound or pharmaceutical composition as an active ingredient may be administered orally or parenterally. For example, parenteral administration may be performed by any one of intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intradermal administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration.

[0104] The above effective amount may refer to a pharmaceutically and / or therapeutically effective amount, and may be prescribed depending on factors such as the type of preparation (formulation), route of administration, age, weight, sex and / or pathological condition of the patient.

[0105] A pharmaceutical composition according to an example of the present application may be formulated into an appropriate form with a commonly used pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" means physiologically tolerable and does not generally cause allergic reactions or similar reactions such as gastrointestinal upset and dizziness when administered to humans. In addition, the pharmaceutical composition of the present application may be formulated and used as oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, and as parenteral preparations such as topical preparations, suppositories, or sterile injectable solutions, according to conventional methods.

[0106] Examples of carriers, excipients, and diluents that may be included in the composition include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulated into a preparation, diluents or excipients such as commonly used fillers, stabilizers, binders, disintegrants, and surfactants may be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be prepared by mixing the compound of the present application with at least one excipient, such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc. In addition to simple diluents such as commonly used water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives can also be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions or suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include withepsol, macrogol, tween 61, cocoa butter, lauric butter, and glycerogelatin.For formulation as a parenteral preparation, the crystalline form may be mixed in water in a sterile state and / or may contain adjuvants such as preservatives, stabilizers, wet powders or emulsifying agents, salts for controlling osmotic pressure, and / or buffers, and other therapeutically useful substances, and then prepared as a solution or suspension and then prepared in unit dosage form in ampoules or vials.

[0107] As used herein, the terms "treat," "treating," and "treatment" refer to a method of alleviating or terminating a biological disorder and / or at least one of its accompanying symptoms. They are used in their ordinary sense, such as managing or caring for a subject for the purpose of eradicating, alleviating, reducing, alleviating, or improving the condition of a disease or disorder, such as cancer. As used herein, "alleviating" a disease, disorder, or condition means reducing the severity and / or frequency of the symptoms of the disease, disorder, or condition. Furthermore, references to "treatment" herein include references to curative, palliative, and preventative treatments. Treatment of cancer includes inhibiting cancer growth (including causing partial or complete regression of the cancer), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and / or prolonging the survival of a patient. A "therapeutically effective amount" is an amount of a drug that can achieve the desired therapeutic, palliative, or preventative effect for the condition being treated.

[0108]

[0109] Effective amount

[0110] In some embodiments, the effective dose range of a compound may be determined by measuring the patient's blood compound concentration under a specific dosing regimen to establish a concentration-time profile, consulting the established correlation between the concentration-time profile obtained during the trial and the tumor inhibition or elimination, and further considering the patient's health status or physical endurance, thereby balancing the achievable therapeutic effect with the potential for toxicity to the patient. The frequency of compound administration may be determined similarly. The administration may continue until the patient is cancer-free.

[0111] In some embodiments, the effective dose for tumor treatment may be determined by the patient's ability to stabilize disease progression and / or improve symptoms, and preferably reverse disease progression (e.g., by reducing tumor size). In some embodiments, a maintenance dose may be administered to ensure complete removal or eradication of the cancer, or prevention of residual disease, once the patient is cancer-free. The duration of maintenance administration may be determined based on clinical trial data.

[0112] In some embodiments, the compound may be administered in combination with one or more other cancer therapeutics that target AhR or molecules other than AhR. The compound may be formulated separately or together with the other cancer therapeutics. The compound may be administered on the same or a different schedule as the other cancer therapeutics. The ratio of the compound to the other cancer therapeutics may be determined through clinical trials. Combining the compound with the other cancer therapeutics may further enhance the efficacy of each other. For example, the compound of the present application may be administered with an immune checkpoint inhibitor, such as an inhibitor of PD-1, PD-L1, or PD-L2 (e.g., pembrolizumab, nivolumab, or atezolizumab), or with CAR-T therapy (e.g., axicabtagene ciloleucel), to achieve additive or synergistic anticancer effects.

[0113] Dosage regimens may be adjusted to provide the optimal desired response. The dosage unit form used herein refers to physically discrete units suited as single dosages for the patients / subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0114] It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated and may include single or multiple doses. For any particular subject, a specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. It should be further understood that the dosage ranges described herein are exemplary and are not intended to limit the scope or practice of the compositions embodied. Furthermore, dosage regimens using the compositions of the present application may be based on various variables, including the type of disease, age, weight, sex, the patient's medical condition, the severity of the condition, the route of administration, and the specific antibody used. Therefore, dosage regimens may vary widely but can be routinely determined using standard methods. For example, dosages may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxicity and / or experimental values.

[0115] Suitable dosages of the compounds of the present invention are considered to be 0.001-200 mg / kg per day, preferably about 0.01 mg / kg to about 20 mg / kg per day, such as about 0.5-50 mg / kg, for example about 1-20 mg / kg. The compounds may be administered, for example, at least 0.25 mg / kg, such as at least 0.5 mg / kg, such as at least 1 mg / kg, such as at least 1.5 mg / kg, such as at least 2 mg / kg, such as at least 3 mg / kg, such as at least 4 mg / kg, such as at least 5 mg / kg; and, for example, at most 50 mg / kg, such as at most 30 mg / kg, such as at most 20 mg / kg, such as at most 15 mg / kg. Dosages are usually repeated at appropriate intervals, for example, twice daily, three times daily, once daily, once weekly, once every two weeks, or once every three weeks, for as long as the attending physician deems appropriate, and the attending physician may optionally increase or decrease the dosage as necessary.

[0116] The compounds of the present invention can be used in particular for the treatment and prevention, i.e. prophylaxis, of tumor growth and metastasis, and in particular for solid tumors of all indications and stages, regardless of prior treatment of tumor growth.

[0117] Some embodiments of these methods may further comprise administering or treating with one or more additional anticancer therapies. In some of these embodiments, the additional anticancer therapies include surgery, radiation therapy, biotherapy, immunotherapy, chemotherapy, or any combination thereof.

[0118] Some embodiments of these methods may further comprise administration or treatment with one or more anticancer agents. In some of these embodiments, the anticancer agents are chemotherapeutic agents, growth inhibitors, antiangiogenic agents, cytotoxic agents, antihormonal agents, prodrugs, or cytokines.

[0119] In a further embodiment of the present application, the crystalline form according to an example of the present application can be used to sensitize cells to radiation, i.e., treating cells with a compound of the present application prior to radiation treatment of the cells renders them more sensitive to DNA damage and cell death than cells not treated with any of the crystalline forms according to an example of the present application. In one aspect, the cells are treated with one or more compounds of the crystalline form according to an example of the present application.

[0120] Accordingly, the present application also provides a method of killing cells, wherein one or more crystal forms of the present application are administered to the cells in combination with conventional radiation therapy.

[0121] The present application also provides a method for making a cell more susceptible to apoptosis, wherein the cell is treated with one or more crystal forms of the present application prior to treatment to cause or induce apoptosis. In one aspect, after the cell is treated with one or more crystal forms of the present application, the cell is treated with at least one compound, at least one method, or a combination thereof to induce DNA damage with the aim of inhibiting normal cell function or causing cell death.

[0122] In another embodiment of the present application, the cell is treated with at least one DNA damaging agent to cause apoptosis, i.e., the cell is treated with one or more crystal forms of the present application to sensitize the cell to apoptosis, and then the cell is treated with at least one DNA damaging agent to cause the cell to die. DNA damaging agents useful in the present application include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (e.g., X-rays, ultraviolet radiation), carcinogens, and mutagens.

[0123] In another embodiment, the cell is killed by treating the cell with at least one method that causes or induces DNA damage. Such methods include, but are not limited to, activating a cellular signaling pathway that causes DNA damage when activated, inhibiting a cellular signaling pathway that causes DNA damage when inhibited, and inducing biochemical changes in the cell that cause DNA damage. As a non-limiting example, inhibition of a cellular DNA repair pathway may inhibit the repair of DNA damage and lead to an abnormal accumulation of DNA damage in the cell.

[0124] In one aspect of the present application, the crystalline form of the present application is administered to a cell prior to radiation or other induction of DNA damage in the cell. In another aspect of the present application, the crystalline form of the present application is administered to a cell concomitantly with radiation or other induction of DNA damage in the cell. In another aspect of the present application, the crystalline form of the present application is administered to a cell immediately after radiation or other induction of DNA damage in the cell begins.

[0125] In another aspect, the cells are in vitro. In another embodiment, the cells are in vivo. The crystalline form of the present application can be administered as a single agent or in combination with one or more other pharmaceutically active ingredients, provided that the combination does not cause unacceptable side effects.

[0126] The present application also encompasses such pharmaceutical combinations. For example, the crystalline form of the present application can be combined with: 131 1-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, Anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene Bicalutamide, bisantrene, bleomycin,Blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa Dabrafenib, dasatinib, daunorubicin, decitabine, degarelix,Denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate acetate), elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, Fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine,Fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, Granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma gamma), iobitridol, iobenguane (1231),Iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, Lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metyrosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, Mitomycin, mitotane, mitoxantrone, mogamulizumab,molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy paclitaxel, palbociclib, palifermin, palladium-103 seed,Palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutane, Perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, Procodazole, propranolol, quinagolide, rabeprazole, racotumomab,Radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, Teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur,Tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin,Zinostatin stimalamer, zoledronic acid, zorubicin.

[0127] The crystalline form of the present invention may be further combined with other drugs that target the immune system, such as immune checkpoint inhibitors, for example, aPD-1 / -L1 axis antagonists.

[0128] PD-1, along with its ligands PD-L1 and PD-L2, functions as a negative regulator of T cell activation. AHR suppresses immune cell function while increasing cancer cell proliferation and motility. PD-L1 is overexpressed in many cancers, and PD-1 overexpression often occurs concurrently in tumor-infiltrating T cells. Consequently, T cell activation is weakened, immune surveillance is evaded, and anti-tumor immune responses are impaired.

[0129] Simultaneous targeting of the PD-1 / -L1 axis and AHR enhances anti-tumor immune responses beyond additive, leading to unexpected tumor growth reduction.

[0130] Therefore, a composition comprising a PD-1 / -L1 axis antagonist and an AHR antagonist is surprisingly effective in enhancing immune responses and treating cancer.

[0131] Additionally, the crystalline form of the present invention can also be used as a therapeutic agent for various other disorders involving AHR.

[0132] Examples of other disorders associated with abnormal AhR signaling inflammation may be one or more selected from the group consisting of infections and cancer vaccinations, viral infections, obesity and diet-induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids (uterine leiomyomas or uterine fibroids) in women, chronic kidney disease, acute and chronic renal failure, diabetes, inflammatory or hypertensive kidney disease, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease, thromboembolism, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, urinary retention disorders associated with benign prostatic hyperplasia, Huntington's, dementia, Alzheimer's and Creutzfeldt-Jakob.

[0133] Also, in another aspect, a pharmaceutical composition is provided, comprising an AhR modulator, such as a crystalline form according to one example of the present application, and a pharmaceutically acceptable excipient.

[0134] In some aspects, pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist in crystalline form according to one example of the present application, are provided for use in modulating constitutive AhR activity in a subject in need thereof.

[0135] In some aspects, pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist in crystalline form according to one example of the present application, are provided for use in treating cancer or a cancer condition by modulating AhR activity.

[0136] In some aspects, pharmaceutical compositions comprising an AhR modulator, such as an AhR antagonist in crystalline form according to one example of the present application, are provided for use in inhibiting cancer cell proliferation, tissue invasion, metastasis, and angiogenesis in a subject having cancer, a cancer condition, or a tumor.

[0137]

[0138] aryl hydrocarbon receptor

[0139] The aryl hydrocarbon receptor ("AhR") is a ligand-dependent member of the family of basic-helix-loop-helix transcription factors that has been shown to be activated by a variety of structurally diverse synthetic and naturally occurring compounds, such as polycyclic aromatic hydrocarbons, indoles, and flavonoids. In the absence of bound ligand, AhR resides in a latent state in the cytoplasmic compartment of cells, where it associates with two molecular chaperones, heat shock protein 90 ("hsp90"), an immunophilin-like protein, XAP2, and the hsp90-interacting protein, p23.

[0140] The term "aryl hydrocarbon receptor" or "AhR," as used herein, refers to an 848 amino acid polypeptide, as described, for example, in NP_001612, together with any naturally occurring alleles, splice variants, and engineered forms thereof. Generally, AhR refers to human AhR. The term AhR is also used to refer to truncated forms or fragments of an AhR polypeptide, for example, comprising a specific AhR domain. References to such forms of AhR may be identified herein as "AhR (122-224)".

[0141]

[0142] AhR modulators

[0143] AhR mediates a variety of functional responses, including but not limited to, de novo transcription of AhR battery genes or target genes bearing the DRE or XRE responsive element 5'-TNGCGTG-3'. Alternative pathways of AhR signaling have also been described, such as binding to the retinoblastoma protein, estrogen receptor (ER), transcription factor E2F1, and NFκB pathway subunits RelA and RelB. AhR can also act as a ubiquitin ligase. Thus, signaling through AhR encompasses multiple pathways, including constitutive and non-constitutive AhR signaling pathways or signaling activities, as such terms are defined herein.

[0144] As used herein, “constitutive AhR signaling” refers to one or more signaling pathways that are mediated or regulated by AhR, activated or driven by one or more endogenous AhR ligands, or one or more environmental ligands such as toxins or pollutants, and that result in constitutive or long-term translocation of AhR to the nucleus, and activation or regulation of one or more AhR battery genes involved in unregulated cell growth and proliferation, tumor cell invasiveness, or a combination thereof.

[0145] As used herein, "non-constitutive AhR signaling" refers to one or more signaling pathways mediated or induced by AhR that do not result in constitutive or long-term translocation of AhR to the nucleus, and do not result in activation or regulation of one or more AhR battery genes involved in unregulated cell growth, tumor cell invasiveness, or a combination thereof. In some embodiments, non-constitutive AhR signaling does not result in upregulation of CYP1A1, CYP1B1, or a combination thereof gene expression.

[0146] Accordingly, the term "AhR modulator" as used herein refers to an agent, such as a crystalline form of a compound of Formula 1, a solvate, or a hydrate thereof, that modulates, induces, or promotes a qualitative or quantitative change, alteration, or modification in one or more processes, mechanisms, effects, responses, functions, activities, or pathways mediated by the AhR receptor. Such changes mediated by AhR modulators, such as the AhR antagonists described herein, may mean a reduction, inhibition, or conversion of the constitutive activity of the AhR. The term "expression" refers to the cellular processes involved in producing RNA and proteins, including, but not limited to, secreting proteins, and, where appropriate, transcription, translation, folding, modification, and processing, as applicable. "Expression products" include RNA transcribed from a gene and polypeptides obtained by translation of mRNA transcribed from a gene.

[0147] The term "modulate" in relation to AhR modulators is used consistently with its usage in the art to mean, for example, causing or enabling a qualitative or quantitative change, alteration, or modification in one or more biological processes, mechanisms, effects, responses, functions, activities, pathways, or other phenomena of interest. Thus, as used herein, modulation refers to a qualitative or quantitative change, alteration, or modification in one or more processes, mechanisms, effects, responses, functions, activities, or pathways mediated by the AhR receptor.

[0148] The term "agent" as used herein in connection with an AhR modulator means any compound or substance, such as, but not limited to, a small molecule compound, a nucleic acid, a polypeptide, a peptide, a drug, an ion, and the like. An "agent" can be any chemical, entity, or moiety, and includes, without limitation, synthetic and naturally occurring proteinaceous and non-proteinaceous materials. In some embodiments, the agent is a nucleic acid, a nucleic acid analog, a protein, an antibody, a peptide, an aptamer, an oligomer of a nucleic acid, an amino acid, or a carbohydrate, and includes, without limitation, proteins, oligonucleotides, ribozymes, DNAzymes, glycoproteins, siRNAs, lipoproteins, aptamers, and modifications and combinations thereof. In certain embodiments, as described herein, the agent is a small molecule having a chemical moiety. For example, the chemical moiety comprises an unsubstituted or substituted alkyl, aromatic, or heterocyclyl moiety. Compounds may be known to have the desired activity and / or property (e.g., modulating AhR activity) or may be selected from a library of diverse compounds, for example, using the screening methods described herein.

[0149] In some embodiments, an AhR modulator selectively binds to AhR. As used herein, "selectively binds" or "specifically binds" refers to the ability of an AhR antagonist to bind to a target, such as AhR. D　 10 -5　 M (10000 nM) or less, for example, 10 -6　 M and below, 10 -7　 M and below, 10 -8　 M and below, 10 -9　 M and below, 10 -10　 M and below, 10 -11　 M or less, or 10 -12　 It binds to less than M. For example, the antagonist described herein is 10 -5K below M D An agent binds specifically to AhR if it binds to AhR but not to other molecules or related homologues. Specific binding can be influenced by, for example, the affinity and avidity of the antagonist, and the concentration of the antagonist used. One skilled in the art can determine appropriate conditions under which an antagonist described herein selectively binds using any suitable method, such as those described herein (e.g., titration of an AhR antagonist in an appropriate cell binding assay).

[0150] In some aspects of the compositions and methods described herein, the AhR modulator is an AhR antagonist having a crystalline form described herein.

[0151] As used herein, an AhR modulator is an "AhR antagonist." An AhR antagonist refers to an AhR inhibitor that, when specifically bound to the AhR, does not induce a biological response itself, but blocks or attenuates an agonist- or ligand-mediated response. That is, an AhR antagonist can bind to the AhR but does not activate the AhR; the binding interferes with the interaction, displaces the AhR agonist, and / or inhibits the function of the AhR agonist. Therefore, as used herein, an AhR antagonist does not function as an inducer of AhR activity when bound to the AhR; that is, they function as pure AhR inhibitors. In some embodiments, an AhR antagonist selectively binds to the AhR.

[0152] In some embodiments of these aspects, the AhR antagonists described herein, such as the crystalline forms according to one embodiment of the present application, block constitutive AhR effector function that mediates the growth and progression of established tumors. In other embodiments, the small molecule AhR antagonists described herein, in crystalline form, act as chemopreventive agents by blocking AhR-mediated CYP1A1 induction and mutagenesis upon exposure to environmental ligands.

[0153] In some embodiments of these aspects, the crystalline form of the AhR antagonist described herein inhibits the initial contribution of constitutively active AhR in inducing malignant transformation. In some embodiments, the crystalline form of the compound described herein inhibits constitutive AhR signaling-mediated cancer or tumor cell growth. In some embodiments, the crystalline form of the compound described herein inhibits constitutive AhR signaling-mediated tumor invasion in inducing malignant transformation.

[0154] The novel crystalline form according to an example of the present application has excellent storage stability and can be usefully used as an AhR modulator compound.

[0155] FIG. 1 is a drawing showing the X-ray powder diffraction (XRPD) results of a crystalline Form Ⅰ according to an example of the present application.

[0156] FIG. 2 is a diagram showing the differential scanning calorimetry (DSC) results of a crystal form Form Ⅰ according to an example of the present application.

[0157] FIG. 3 is a drawing showing the X-ray powder diffraction (XRPD) results of a crystalline Form II according to an example of the present application.

[0158] FIG. 4 is a diagram showing differential scanning calorimetry (DSC) results of a crystal form Form II according to an example of the present application.

[0159] FIG. 5 is a drawing showing the X-ray powder diffraction (XRPD) results of a crystalline Form III according to an example of the present application.

[0160] FIG. 6 is a diagram showing differential scanning calorimetry (DSC) results of a crystal form Form III according to an example of the present application.

[0161] FIG. 7 is a diagram showing the X-ray powder diffraction (XRPD) results of a crystalline Form IV according to an example of the present application.

[0162] FIG. 8 is a diagram showing differential scanning calorimetry (DSC) results of a crystal form Form IV according to an example of the present application.

[0163] Hereinafter, to facilitate understanding of this application, examples will be provided in detail. However, the following examples merely illustrate the contents of this application and are not intended to limit the scope of this application. The examples in this application are provided to provide a more complete explanation of this application to those with average knowledge in the art.

[0164]

[0165] <Experimental Example>

[0166] The following experimental examples are intended to provide experimental examples commonly applied to each embodiment according to the present application.

[0167]

[0168] Experimental Example 1. Powder X-ray diffraction

[0169] Powder X-ray diffraction patterns were obtained using a BRUKER D8 FOCUS model with CuKα irradiation at 1.54178Å (30kV, 10mA) with a solid-state detector. Analysis was performed at 2θ angles of 3 o 40 inland o 0.01 across the range o It was measured with step size.

[0170]

[0171] Experimental Example 2. Thermal Analysis

[0172] Differential scanning calorimetry (DSC) was performed using a METTLER TOLEDO DSC1. Approximately 1 to 10 mg of sample was weighed and placed in a lidded aluminum pan. The sample was placed at 25 o C to 350 o 10 in C range o It was evaluated using a linear heating lamp of C / min.

[0173]

[0174] Manufacturing Example 1. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol

[0175]

[0176] Intermediate 1. Nicotinimidamide hydrochloride

[0177] To a suspension of 3-cyanopyridine (5 g, 48.03 mmol) in 50 mL of methanol was added 30 wt% sodium methoxide in methanol (4 mL), and the mixture was stirred at room temperature for 24 hours. After adding ammonium chloride (16.5 g, 0.31 mol), the mixture was heated under reflux for 6 hours and then cooled. The solvent was removed in vacuo, ethanol (60 mL) was added, and the mixture was heated under reflux for 30 minutes. After the reaction mixture was cooled to room temperature, the solid was filtered, and the filtrate was concentrated in vacuo. A suspension of the reaction mixture in 3 mL of ethanol was filtered, and the solid product was dried to obtain 4.9 g of the title compound.

[0178] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 9.43 (bs, 4H), 8.98 (d,J= 1.6 Hz, 1H), 8.74 (dd,J= 4.8 Hz,J= 1.2 Hz, 1H), 8.20-8.23 (m, 1H), 7.64-7.67 (m, 1H); MS (ESI, m / z): 122.1 [M+H] +

[0179]

[0180] Intermediate 2. 2-Pyridin-3-yl-pyrimidine-4,6-diol

[0181] To a solution of 3-pyridyl amidine hydrochloride (4.8 g, 30.46 mmol) in methanol (120 mL) was added diethyl malonate (4.63 mL, 30.46 mmol), followed by the addition of a 30 wt% solution of sodium methoxide in methanol (20 mL) at 0°C. The resulting mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo. The resulting residue was used without further purification.

[0182] MS (ESI, m / z): 190.0 [M+H] +

[0183]

[0184] Intermediate 3. 4,6-Dichloro-2-pyridin-3-yl-pyrimidine

[0185] phosphoryl chloride Dimethylaminoaniline (4.77 g, 35.03 mmol) was added to a solution of 2-pyridin-3-yl-pyrimidine-4,6-diol (5.0 g of the crude compound from the previous step) in (10 mL), and the reaction mixture was heated at 120°C for 4 hours. The residue was cooled to room temperature, extracted with 500 mL of ethyl acetate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to obtain 4.45 g of the title compound.

[0186] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.36 (s, 1H), 7.49 (dd, J= 4.8 Hz, J= 1.6 Hz, 1H), 8.80-8.72 (m, 2H), 9.64 (br, 1H); MS (ESI, m / z): 226.0 [M+H] +

[0187]

[0188] Intermediate 4. 4-chloro-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine

[0189] To a mixture of 4,6-dichloro-2-pyridin-3-yl-pyrimidine (1.03 g, 4.6 mmol), (4-chlorophenyl)boronic acid (0.66 g, 4.2 mmol), and sodium carbonate (1.01 g, 9.5 mmol) in 50 mL of tetrahydrofuran / H2O (4 / 1) was added Pd(PPh3)4 (203 mg, 0.18 mmol). The mixture was heated in a microwave at 80 °C for 20 min, cooled to room temperature, and extracted three times with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1.02 g of the title compound.

[0190] 1 H NMR (600 MHz, CDCl3) δ [ppm] = 7.52 (d, 2H), 7.74 (s, 1H), 7.79 (dd, 1H), 8.06 (d, 2H), 9.02 (d, 1H), 9.12 (d, 1H), 10.16 (s, 1H); MS (ESI, m / z): 302.0 [M+H] +

[0191]

[0192] Manufacturing Example 1. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol

[0193] To a solution of 4-chloro-6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidine (45 mg, 0.15 mmol) in tetrahydrofuran (6 mL) was added triethylamine (0.3 mL, 2.15 mmol), followed by 2-(piperazin-1-ylsulfonyl)ethan-1-ol (32 mg, 0.16 mmol) at room temperature. The reaction mixture was heated in a sealed tube at 120 °C for 4 h and cooled to room temperature. The residue was filtered, evaporated in vacuo, and separated by preparative HPLC to give 50 mg of the title compound.

[0194] 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.59 (s, 1H), 8.75 (dd,J= 8.0, 2.0 Hz, 1H), 8.70 (d,J= 4.7 Hz, 1H), 8.37 (d,J= 8.3 Hz, 2H), 7.61 (d,J= 8.3 Hz, 2H), 7.55 (dd,J= 8.0, 4.8 Hz, 1H), 7.45 (s, 1H), 5.04 (s, 1H), 3.97 (s, 4H), 3.75 (t,J= 6.1 Hz, 2H), 3.31 (d,J= 5.1 Hz, 4H), 3.23 (t,J= 6.1 Hz, 2H); MS (ESI, m / z): 460.1 [M+H] +

[0195]

[0196] Example 1. Crystalline Form Ⅰ of 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate dihydrate

[0197]

[0198] Triethylphosphate (1000 mL, 5885 mmol) was added to the reactor under a nitrogen atmosphere and stirred for more than 10 minutes. 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)ethan-1-ol (25 g, 54.35 mmol) was added to the reactor while maintaining the internal temperature and stirred. After cooling the internal temperature to -6 to 0°C, phosphoryl chloride (15.7 mL, 168.44 mmol) was added dropwise while maintaining the internal temperature. The internal temperature was increased to 0 to 6°C. Stirring was performed for more than 2 hours while maintaining the internal temperature at 0 to 6°C, and then a process inspection was performed. When the reaction was complete, the internal temperature was cooled to -10 to -4°C. While maintaining the internal temperature at -10 to -4℃, 425mL of 9% sodium bicarbonate was slowly added dropwise and adjusted to pH 5.0 to 5.5. After increasing the internal temperature to 0 to 10℃, 1125mL of purified water was added dropwise while maintaining the internal temperature. After cooling the internal temperature to -1 to 5℃, stirring was performed for 2 hours while maintaining the internal temperature. The solid product was filtered, washed with 250mL of methanol and 250mL of acetone, dried under reduced pressure at 45 to 55℃ for 24 hours, and then left in a silica gel desiccator for 24 hours to synthesize 28.7g (yield 97.8%) of crude 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate. 1H NMR (600 MHz, DMSO-d6) δ [ppm] = 9.58 (s, 1H), 8.75 (d,J= 7.9 Hz, 1H), 8.71 (d,J= 4.7 Hz, 1H), 8.38 - 8.33 (m, 2H), 7.62 - 7.58 (m, 2H), 7.58 - 7.53 (m, 1H), 7.42 (s, 1H), 4.15 (q,J= 6.1 Hz, 2H), 3.96 (s, 4H), 3.49 (t,J= 6.1 Hz, 2H), 3.38 - 3.31 (m, 4H); MS (ESI, m / z): 540.1 [M+H] +

[0199] The obtained crude crystals were refluxed and stirred for more than 12 hours in a mixed solvent of tertiary distilled water (430 mL) and acetone (430 mL), cooled to room temperature, suspended and stirred for more than 3 hours, filtered, washed with acetone (144 mL), and vacuum-dried at 50°C for more than 12 hours. The crystals were stored in a constant temperature and humidity chamber at a temperature of 20 to 30°C and a relative humidity of 75±5% for more than 12 hours, and moisture content tests were conducted at 12-hour intervals. After 24 hours of storage in the constant temperature and humidity chamber, the polymorph Form Ⅰ of 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate dihydrate with a moisture content of 5.94% was obtained. The XRD pattern of this is shown in Fig. 1 and Table 1, and the DSC results are shown in Fig. 2 and Table 2.

[0200] Position [ o2θ]Height [cts]d-spacing [Å]Relative Intensity [%]14.4734786.116100.00%20.2127604.3978.30%7.246224712.1963.90%21.78811984.07632.50%21.19699 84.18826.50%13.9178286.35822.00%18.766784.72617.80%27.8725563.19814.50%9.3895239.41213.70%22 .5035083.94812.50%28.9374793.08312.20%21.0114734.22511.00%8.17241510.81110.10%16.8353705.2629.40%4.1942721.0698.40%15.2113195.827.40%30.6183092.9177.30%23.4942963.7837.00%8.32625310.61 15.40%24.1842303.6775.10%34.8022152.5764.90%28.3712173.1434.50%24.6362053.614.40%34.0391992.6324.40%18.2251994.8644.20%13.0871986.763.60%29.7971862.9963.60%16.2791535.4413.00%35.472129 2.5292.50%32.5631292.7472.40%10.8881368.1192.30%12.6131477.0132.30%26.9721183.3032.00%6.63510713.3111.10%25.98380.83.4261.10%36.59472.52.4541.00%38.90773.62.3130.80%31.28279.22.8570.70%

[0201] ItemOnset ( o C) / Peak ( o C) Peak shape Peak 155.86 / 80.80 Endothermic peak Peak 2202.79 / 215.00 Endothermic peak

[0202] Example 2. Preparation and analysis of crystalline Form II of 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate

[0203] 2-Propanol (30 v / w) was added to the crystalline Form Ⅰ compound of Example 1 above and 85 o The mixture was stirred under reflux for more than 12 hours at C. Cooled to room temperature, filtered the solid, and 90 o The polymorph Form Ⅱ of 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate was obtained by vacuum drying at C for more than 24 hours. Its XRD pattern is shown in Fig. 3 and Table 3, and the DSC results are shown in Fig. 4 and Table 4.

[0204] Position [ o 2θ]Height [cts]d-spacing [Å]Relative Intensity [%]18.98911204.67100.00%17.56410805.04596.50%5.53375416.55767.80%6.78272013.02364.80%10.9537198.07164.60 %23.7386593.74559.10%14.2296356.21956.70%19.5535404.53647.90%21.1114294.20538.10%16.1183515.49531.50%13.1 83366.71230.00%8.00232311.0429.00%13.5862796.51224.60%26.8522233.31719.30%21.5252104.12518.40%17.981884.9315.90%17.0791665.18814.50%24.241583.66914.00%8.18610310.7939.10%25.44296.73.4988.20%25.75665.73.4565.20%

[0205] ItemOnset ( o C) / Peak ( oC) Peak shape Peak 150.60 / 78.26 Endothermic peak Peak 2187.81 / 203.20 Endothermic peak

[0206] Example 3. Preparation and analysis of crystalline Form III of 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate hydrate

[0207] The crystalline Form I compound of Example 1 was dissolved by adding it to N-methyl-2-pyrrolidone and heating at 95 degrees for 3 hours. After cooling to room temperature, it was added dropwise to constant volume to produce crystals. The produced crystals were suspended and stirred at room temperature for 3 hours, and then the solid was filtered and vacuum-dried at 50 degrees Celsius for more than 12 hours to obtain the crystalline polymorph Form III of 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate hydrate. The XRD pattern thereof is shown in Fig. 5 and Table 5, and the DSC results are shown in Fig. 6 and Table 6.

[0208] Position [ o 2θ]Height [cts]d-spacing [Å]Relative Intensity [%]19.3057484.594100.00%23.1365283.84168.70%15.5015025.71264.60%17.7774604.98554.00%27.7074073.217 49.00%16.5663995.34745.80%24.1232263.68620.60%28.5572263.12319.90%26.8852203.31319.80%18.4322394.81 18.20%29.3631983.09316.00%21.1271864.20212.60%25.0911613.54611.30%11.4991237.68910.40%5.72397.415.4296.50%33.4121022.686.40%8.89387.69.9366.20%35.89680.22.54.80%38.961832.314.10%34.37577.12.6073.70%

[0209] ItemOnset ( o C) / Peak ( o C) Peak shape Peak 197.91 / 126.55 Endothermic peak Peak 2172.52 / 185.38 Endothermic peak Peak 3210.73 / 219.55 Endothermic peak

[0210] Example 4. Preparation and analysis of crystalline Form IV of 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate hydrate

[0211] The crystalline Form Ⅰ compound of Example 1 was dissolved in dimethyl sulfoxide by suspension and stirring at room temperature for more than 3 hours, and only the filtered solution was added dropwise to a 1 / 1 IPA / H2O mixture to form crystals. The formed crystals were suspended and stirred at room temperature for more than 3 hours, and the obtained solid was filtered to obtain 2-((4-(6-(4-chlorophenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)sulfonyl)-ethyl dihydrogen phosphate hydrate crystalline polymorph Form Ⅳ. Its XRD pattern is shown in Fig. 7 and Table 7, and the DSC results are shown in Fig. 8 and Table 8.

[0212] Position [ o2θ]Height [cts]d-spacing [Å]Relative Intensity [%]17.52622535.056100.00%18.9514054.69760.60%24.2277473.66831.40%18.7033964.7414.00%11.01927 88.02310.50%6.83226812.9289.50%13.6211876.4966.40%19.4861964.5524.90%16.1141715.4964.80%34.36 91412.6073.90%21.5081554.1283.80%31.9791202.7963.10%21.1531374.1972.80%7.95811911.1012.70%25.3091113.5162.20%36.63886.22.4512.00%20.4321144.3431.50%14.23774.76.2161.20%31.146722.8691.00%

[0213] ItemOnset ( o C) / Peak ( o C) Peak shape Peak 1202.48 / 211.44 Endothermic peak

[0214] Test Example 1. Evaluation of AhR inhibition efficacy

[0215] AhR activation induces target gene expression, such as CYP1A1 and CYP1B1, by binding to AhR-responsive DNA elements, also known as XREs (xenobiotics responsive elements). The assay used to measure AhR activity here is a luciferase assay using cell lines transfected with a luciferase reporter plasmid containing an XRE upstream of a reporter gene. Cells transfected with the XRE-luciferase reporter (XRE-Luc) plasmid drive luciferase activity, which reflects activation and inhibition of AhR in the cells. In addition to transfection with the XRE-reporter vector, cells were co-transfected with a nano-luciferase reporter gene construct (Nano-Luc) containing a constitutively active promoter as an internal control. Kynurenine and kynurenic acid (endogenous AhR agonists) were used to stimulate cells to test the antagonistic properties of the compounds. The half-maximal inhibitory concentration (IC50) and half-maximal effective concentration (EC50) values ​​were calculated using nonlinear regression (four parameters) with Prism8.0 software (GraphPad).

[0216]

[0217] (1) In vitro assay 1: Antagonism in human cell lines

[0218] HepG2 (human hepatoma cell line) cells (Invivogen) stably harboring XRE-luciferase reporter were plated in complete medium and cultured at 37°C in a CO2 incubator. After 24 h, cells were treated with kynurenine (200 μM) alone (negative control) or together with test compounds for 6 h. Luciferase activity was measured using commercial kits such as Promega Luciferase kit or Invivogen Luciferase kit. IC50 values ​​were calculated using luciferase activities. Luciferase activities were further normalized to the kynurenine alone group as the maximum control group and the vehicle group as the minimum control group. The AhR antagonistic potency of compounds in Preparation Example 1 is shown in Table 9. (IC 50 The values ​​are grouped into A, B, C and D, where A: IC 50 < 0.01 μM; B: 0.01 < IC 50 < 0.1 μM; C: 0.1 < IC 50 < 1.0 μM; D: IC 50 >1.0μM)

[0219]

[0220] (2) In vitro assay 2: Antagonism in mouse cell lines

[0221] Hepa1c1c7 (murine hepatoma cell line) cells co-transfected with XRE-Luc and Nano-Luc plasmids were plated in complete medium and cultured overnight at 37°C in a CO2 incubator. After incubation, cells were treated with AhR-activating ligands such as kynurenic acid and kynurenine (#) with or without test compounds for 6 h. Firefly luciferase and Nano-luciferase activities were measured using Nano-glo Luciferase kit (Promega) and relative luciferase activities (Firefly / Nano-Luc) were expressed as IC 50The values ​​were calculated. The relative luciferase activities were further normalized to the agent-only group as the maximum control and the vehicle group as the minimum control. The AhR antagonistic potency of compounds of Preparation Example 1 is shown in Table 9. (IC50 values ​​are grouped into A, B, C and D, where A: IC 50 < 0.01 μM; B: 0.01 < IC 50 < 0.1 μM; C: 0.1 < IC 50 < 1.0 μM; D: IC 50 > 1.0μM)

[0222] Example 1 Analysis 1: AhR-Luc human antagonism (IC 50 , nM)A Assay 2: AhR-Luc mouse antagonism (IC 50 , nM)A

[0223] Test Example 2. Conversion Rate Evaluation

[0224] Human liver microsomes were added to 0.5 mg / mL of 0.1 M KPO4 buffer (pH 7.4) and preincubated at 37°C for 5 minutes. Then, 1% of 0.1 mM DMSO stock of compound of Example 1 was added and incubated at a concentration of 1 uM. After 60 minutes of addition of the compound, the reaction was terminated by adding an organic solvent, and the mixture was centrifuged and quantitatively analyzed using LC-MS / MS. At this time, the conversion rate was calculated using the ratio of the concentration of the compound of Preparation Example 1 and the concentration of each compound before the reaction. The results of the conversion rate evaluation are shown in Table 10.

[0225] Compound conversion rate (%) Example 199.6

[0226] As shown in Table 10, it was confirmed that all compounds of Example 1 were converted to compounds of Preparation Example 1 under experimental conditions. Therefore, the compound according to one example of the present application that was converted to compounds of Preparation Example 1 in vivo had an AhR inhibitory effect.

[0227] Test Example 3. Stability Evaluation

[0228] The crystal forms I to IV of Examples 1 to 5 were stored under harsh conditions to evaluate their stability. Specifically, the initial purity of the crystals manufactured in Examples 1 to 5 was analyzed, and the crystals were stored for 6 weeks at 60°C. o C, after storage under 97% relative humidity conditions, the crystal purity and crystal form were analyzed and shown in Table 11.

[0229] Example Initial relative purity (%) Relative purity after 6 weeks (%) Initial crystal polymorphism Crystal polymorphism after 6 weeks Example 199.6 299.71 Form Ⅰ Form Ⅰ Example 299.4 699.49 Form Ⅱ Form Ⅰ+ Form Ⅱ Example 398.1 697.10 Form Ⅲ Form Ⅲ Example 499.6 499.32 Form Ⅳ Form Ⅲ

[0230] As shown in Table 11, the crystal form according to an example of the present application maintained the same initial purity even after storage under harsh conditions, demonstrating excellent physical stability. In addition, after storage under harsh conditions, the crystal form of Form II was partially converted to Form I, and the crystal form of Form IV was converted to Form III, indicating that among the crystal forms according to an example of the present application, Form I and Form III had particularly excellent stability.

[0231] While specific portions of this application have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and do not limit the scope of this application. Therefore, the substantial scope of this application is defined by the appended claims and their equivalents.

Claims

1. A crystalline form of a compound, solvate, or hydrate thereof represented by the following chemical formula 1: [Chemical Formula 1] 2. In paragraph 1, A crystalline form having an X-ray powder diffraction pattern, wherein the crystalline form comprises a characteristic peak at one or more 2θ diffraction angle positions selected from the group consisting of 7.246±0.2°, 9.389±0.2°, 13.917±0.2°, 14.470±0.2°, 18.760±0.2°, 20.210±0.2°, 21.196±0.2°, 21.788±0.2°, 22.503±0.2°, 27.872±0.2°, and 28.937±0.2° in X-ray powder diffraction (XRD) analysis.

3. In paragraph 2, The above X-ray powder diffraction pattern is a crystalline form, which includes characteristic peaks at 2θ diffraction angle positions of 7.246±0.2°, 9.389±0.2°, 13.917±0.2°, 14.470±0.2°, 18.760±0.2°, 20.210±0.2°, 21.196±0.2°, 21.788±0.2°, 22.503±0.2°, 27.872±0.2°, and 28.937±0.2° in X-ray powder diffraction (XRD) analysis.

4. In paragraph 1, The above crystal form is a crystal form having an X-ray powder diffraction pattern shown in Fig.

1.

5. In paragraph 2, The above crystalline form has an endothermic onset temperature of 55.86±2°C and an endothermic peak of 80.80±2°C in differential scanning calorimetry (DSC) analysis; and / or an endothermic onset temperature of 202.79±2°C and an endothermic peak of 215.00±2°C.

6. In paragraph 1, A crystalline form having an X-ray powder diffraction pattern, wherein the crystalline form comprises a characteristic peak at one or more 2θ diffraction angle positions selected from the group consisting of 5.533±0.2°, 6.782±0.2°, 8.002±0.2°, 10.953±0.2°, 13.180±0.2°, 13.586±0.2°, 14.229±0.2°, 17.564±0.2°, 18.989±0.2°, and 23.738±0.2° in X-ray powder diffraction (XRD) analysis.

7. In paragraph 6, The above X-ray powder diffraction pattern is a crystalline form, which includes characteristic peaks at 2θ diffraction angle positions of 5.533±0.2°, 6.782±0.2°, 8.002±0.2°, 10.953±0.2°, 13.180±0.2°, 13.586±0.2°, 14.229±0.2°, 17.564±0.2°, 18.989±0.2°, and 23.738±0.2° in X-ray powder diffraction (XRD) analysis.

8. In paragraph 6, The above crystal form is a crystal form having an X-ray powder diffraction pattern shown in FIG.

3.

9. In paragraph 6, The above crystalline form has an endothermic onset temperature of 50.60±2°C and an endothermic peak of 78.26±2°C in differential scanning calorimetry (DSC) analysis; and / or an endothermic onset temperature of 187.81±2°C and an endothermic peak of 203.20±2°C.

10. In paragraph 1, The X-ray powder diffraction pattern of the above crystal form is, in X-ray powder diffraction (XRD) analysis, at least one 2θ diffraction angle selected from the group consisting of 5.723±0.2°, 8.893±0.2°, 11.499±0.2°, 15.501±0.2°, 16.566±0.2°, 17.777±0.2°, 18.432±0.2°, 19.305±0.2°, 21.127±0.2°, 23.136±0.2°, 24.123±0.2°, 25.091±0.2°, 26.885±0.2°, 27.707±0.2°, 28.557±0.2° and 29.363±0.2°. A crystalline form containing a characteristic peak at the location.

11. In paragraph 10, The above X-ray powder diffraction pattern includes characteristic peaks at 2θ diffraction angle positions of 5.723±0.2°, 8.893±0.2°, 11.499±0.2°, 15.501±0.2°, 16.566±0.2°, 17.777±0.2°, 18.432±0.2°, 19.305±0.2°, 21.127±0.2°, 23.136±0.2°, 24.123±0.2°, 25.091±0.2°, 26.885±0.2°, 27.707±0.2°, 28.557±0.2° and 29.363±0.2° in X-ray powder diffraction (XRD) analysis. Determinant.

12. In paragraph 10, The above crystal form is a crystal form having an X-ray powder diffraction pattern shown in FIG.

5.

13. In paragraph 10, The above crystalline form is a crystalline form having an endothermic onset temperature of 97.91±2°C and an endothermic peak of 126.55±2°C in differential scanning calorimetry (DSC) analysis; an endothermic onset temperature of 172.52±2°C and an endothermic peak of 185.38±2°C; and / or an endothermic onset temperature of 210.73±2°C and an endothermic peak of 219.55±2°C.

14. In paragraph 1, A crystalline form having an X-ray powder diffraction pattern, wherein the crystalline form comprises a characteristic peak at one or more 2θ diffraction angle positions selected from the group consisting of 6.832±0.2°, 11.019±0.2°, 13.621±0.2°, 16.114±0.2°, 17.526±0.2°, 18.703±0.2°, 18.95±0.2°, 19.486±0.2°, and 24.227±0.2° in X-ray powder diffraction (XRD) analysis.

15. In paragraph 14, The above X-ray powder diffraction pattern is a crystalline form, which includes characteristic peaks at 2θ diffraction angle positions of 6.832±0.2°, 11.019±0.2°, 13.621±0.2°, 16.114±0.2°, 17.526±0.2°, 18.703±0.2°, 18.95±0.2°, 19.486±0.2°, and 24.227±0.2° in X-ray powder diffraction (XRD) analysis.

16. In paragraph 14, The above crystal form is a crystal form having an X-ray powder diffraction pattern shown in Fig.

7.

17. In paragraph 14, The above crystal form is a crystal form having an endothermic onset temperature of 202.48±2℃ and an endothermic peak of 211.44±2℃ in differential scanning calorimetry (DSC) analysis.

18. A step of reacting a compound represented by the following chemical formula 2 with a phosphorylating agent; A step of obtaining a crude crystal from a reaction solution; A step of refluxing and stirring the above-mentioned crude product in a solvent; and comprising a step of obtaining a decision, Method for producing a crystal form according to any one of claims 1 to 17: [Chemical Formula 2] 19. A manufacturing method according to claim 18, wherein the phosphorylating agent is at least one selected from the group consisting of phosphorus oxychloride (POCl3), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), dichlorophosphoric acid (Cl2POOH), diethylchlorophosphate (ClPO(OEt)2), tetraphenylpyrophosphate (TPPP), and phosphoramidite.

20. A manufacturing method according to claim 18, wherein the solvent is an aqueous acetone solution.

21. In paragraph 18, The above reflux stirring step is: A step of vacuum drying the above crude crystal after reflux stirring and filtering in a solvent; and A manufacturing method comprising a step of obtaining a crystal from a vacuum-dried product.

22. In paragraph 18, A manufacturing method further comprising a step of hydrating the above decision.

23. In paragraph 18, A step of adding alcohol to the above decision and stirring; and A manufacturing method further comprising the step of obtaining crystals by filtration and vacuum drying.

24. In paragraph 18, A step of dissolving the above decision in N-methyl-2-pyrrolidone; A step of cooling the above melt to obtain a solid; and A manufacturing method further comprising a step of filtering and vacuum drying the solid to obtain a crystal.

25. In paragraph 18, A step of dissolving the above decision in dimethyl sulfoxide; A manufacturing method further comprising a step of filtering and reverse-fluxing the dissolved substance to obtain a crystal.

26. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 17.

27. A pharmaceutical composition according to claim 26, wherein the pharmaceutical composition is used for the prevention or treatment of a disease mediated by an aryl hydrocarbon receptor (AhR).

28. In paragraph 27, The above aryl hydrocarbon receptor (AhR) mediated disease is a disorder associated with abnormal AhR signaling, pharmaceutical composition.

29. In paragraph 27, A pharmaceutical composition, wherein the disease mediated by the above aryl hydrocarbon receptor (AhR) is a disease mediated by activation of the aryl hydrocarbon receptor (AhR).

30. In paragraph 27, A pharmaceutical composition, wherein the disease mediated by the above aryl hydrocarbon receptor (AhR) is cancer, a malignant tumor, a fibrotic disorder, or a condition having dysregulated immune responses.

31. In paragraph 30, A pharmaceutical composition, wherein the cancer is selected from the group consisting of breast cancer, squamous cell carcinoma, respiratory tract cancer, lung cancer, peritoneal cancer, hepatocellular carcinoma, stomach cancer, pancreatic cancer, brain cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, large intestine cancer, uterine cancer, endometrial cancer, salivary gland carcinoma, kidney or renal cancer, prostate cancer, testicular cancer, vulvar cancer, thyroid cancer, head and neck cancer, B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, and chronic myeloblastic leukemia.

32. In paragraph 30, A pharmaceutical composition, wherein the fibrotic disorder is selected from the group consisting of hepatic fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, diabetic fibrotic damage, myelofibrosis, scleroderma, localized scleroderma, keloid, hypertrophic scar, nevus, diabetic retinopathy, proliferative vitreoretinopathy, and sarcoidosis.

33. In paragraph 30, A pharmaceutical composition, wherein the condition having the above dysregulated immune response is selected from the group consisting of sepsis, multiple organ failure, inflammatory disorders of the kidney, chronic intestinal inflammation, pancreatitis, peritonitis, inflammatory skin disorders, inflammatory eye disorders, rheumatic diseases, systemic lupus erythematosus and multiple sclerosis.

34. In paragraph 26, The pharmaceutical composition is used to inhibit proliferation, tissue invasion, metastasis and / or angiogenesis of cancer cells in a subject having cancer or a malignant tumor.

35. A composition for modulating AhR activity, comprising a crystalline form according to any one of claims 1 to 17.

36. A composition according to claim 35, wherein the AhR activity regulation is AhR inhibition.

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