Method for manufacturing a solid form of a BET bromodomain inhibitor

Abstract

The present invention relates to a solid crystalline form of compound (I), e.g., form VII (including a pharmaceutical composition thereof), and a method for preparing crystalline compound (I) and form VII. Compound (I) regulates or inhibits the activity of BET bromodomain-containing proteins and is useful for the treatment of diseases such as cancer, inflammatory diseases, and cardiovascular diseases.

Description

Technology Field

[0001] The present disclosure relates to a solid form of compound I (1-benzyl-6-(3,5-dimethylisoxazole-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridine-2-amine) which is useful for treating diseases such as cancer and modulates or inhibits the activity of BET bromodomain-containing proteins, comprising a method for preparing the same, an intermediate during the preparation of the same, and a pharmaceutical composition thereof. Background Technology

[0002] Therapeutics that modulate or inhibit the activity of BET bromodomain-containing proteins such as BRD2, BRD3, BRD4, and BRDT have the potential to cure, treat, or improve the lives of patients suffering from diseases such as cancer, autoimmune diseases, and cardiovascular diseases. In particular, BET bromodomain modulators or inhibitors have the potential to treat B-acute lymphoblastic leukemia, Burkitt lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, and neuroblastoma. Compounds for the treatment of these diseases and conditions are disclosed in PCT publication number WO 2015 / 002754, the entire content of which is incorporated herein by reference.

[0003] Many requirements for compounds remain unmet, including solid forms of high-purity benzimidazole derivatives. A compound that, in addition to efficacy, exhibits improved stability and solubility, displays pharmacokinetic and pharmacodynamic profiles beneficial for the treatment of diseases regulated by BET proteins containing a brododomain, and, importantly, can be efficiently manufactured on a large scale to facilitate clinical and commercial use.

[0004] Compound I is known to regulate or inhibit BET activity and is described in WO 2015 / 002754. Compound I has the following chemical formula:

[0005] .

[0006] The present disclosure provides a solid form of Compound I, a method for preparing the disclosed solid form of Compound I, an intermediate used in the preparation of Compound I, a pharmaceutical composition comprising a crystalline form of Compound I, and a method for using such forms and the pharmaceutical composition for the treatment of diseases mediated by BET proteins. Details of one or more embodiments are provided in the description for carrying out the invention below. Other features, objects, and advantages will become apparent from the description for carrying out the invention and the claims. Brief explanation of the drawing

[0007] Figure 1 shows the X-ray powder diffraction (XRPD) of compound I - form VII. Figure 2 shows the differential scanning calorimetry (DSC) curve of compound I - form VII. Figure 3 shows the thermogravimetric analysis (TGA) of compound I - form VII. Figure 4 shows the infrared spectrum (IR) of compound I - form VII. Specific details for implementing the invention

[0008] The present disclosure provides a method for preparing Compound I suitable for scale-up and large-scale manufacturing. A method for preparing Compound I is described in WO 2015 / 002754, the entirety of which (in particular, details regarding Compound I and its synthesis) is incorporated herein by reference. Compared to the synthesis described in WO 2015 / 002754, the method provided herein has certain advantages in that it is suitable for scale-up of a preferred polymorphic form (Form VII) of Compound I. For example, the method described herein uses less hazardous reagents, lower reaction temperatures, reagents more suitable for scale-up, and simplified work-up procedures, and the isolation of intermediates is simplified by omitting purification by column chromatography. Due to all these factors, the method of preparation is superior to conventional methods in terms of efficiency, quality, reduction of environmental footprint, and cost reduction.

[0009] In some embodiments, a method for preparing compound I comprises starting materials A and G, and intermediates B, C, D, E, and F:

[0010]

[0011] In some embodiments, the method for preparing compound B is compound A

[0012]

[0013] It includes a step (step 1) of reacting with benzaldehyde in the presence of an acid. In some embodiments, the acid is acetic acid.

[0014] In some embodiments, Step 1 is performed in the presence of a solvent. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. Using methanol or ethanol as the solvent in Step 1 eliminates the need for column chromatography, thereby improving the efficiency of work-up and isolation.

[0015] In some embodiments of Step 1, a NaHCO3 solution is added to the reaction mixture after the reaction is complete to precipitate the product, which simplifies the isolation and purification of compound B.

[0016] In some embodiments of Step 1, compound A and benzaldehyde are used in a 1:1 molar ratio.

[0017] In some embodiments, step 1 is performed at a lowered temperature, and in some embodiments, the reaction temperature is 0 to 5°C, or less than 10℃, or less than 20℃.

[0018] In some embodiments, the method for preparing compound C is compound B

[0019]

[0020] The method includes a step (step 2) of reacting with NaCNBH3 or NaBH4 in a solvent. In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is methanol or ethanol.

[0021] In some embodiments, the solvent is ethanol, which allows the loading of NaCNBH3 or NaBH4 to be reduced to 0.6 molar equivalents compared to compound B, making the method more environmentally friendly and reducing the overall cost.

[0022] In some embodiments, the loading of NaCNBH3 or NaBH4 is 1 equivalent or less relative to compound B, e.g., less than 0.9 equivalents or less than 0.75 equivalents or less than 0.6 equivalents relative to compound B.

[0023] In some embodiments of Step 2, the work-up and isolation are performed by adding an HCl solution to quench the reaction and then adding water to precipitate the product (compound C) to a high purity (+95%), which simplifies the work-up and isolation process. In some embodiments, other agents such as water or acetic acid may be used to quench the reaction.

[0024] In some embodiments, step 2 is performed at 10 to 40°C, or 15 to 20°C, or 20 to 25°C.

[0025] In some embodiments, the method for preparing compound D is compound C

[0026]

[0027] It includes the step of reacting compound G in the presence of a transition metal catalyst and a base (step 3) (the transition catalyst is a palladium catalyst).

[0028]

[0029] In some embodiments, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (PD-132), or tetrakis(tri(o-tolyl)phosphine)palladium(0).

[0030] In some embodiments, the palladium catalyst is Pd(PPh3)4.

[0031] In some embodiments, the base is CsF. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is K2CO3. In some embodiments, the base is an alkali metal phosphate. In some embodiments, the base is K3PO4.

[0032] Using K3PO4 is advantageous compared to K2CO3 because K3PO4 disperses well within the reactor, reducing reaction byproducts and increasing the purity of the product (compound D).

[0033] In some embodiments, the reaction is carried out in a solvent mixture containing 1,4-dioxane and water.

[0034] In some embodiments, the reaction is carried out at an elevated temperature, for example, 80 to 100°C, or 90 to 100°C, or 90 to 95°C.

[0035] In some embodiments, the method for preparing compound E is compound D

[0036]

[0037] It includes a step (step 4) of reacting with carbonyldiimidazole (CDI) in a solvent.

[0038] In some embodiments, the solvent is an aprotic solvent. In some embodiments, the solvent is 1,4-dioxane, DMSO, or DMF.

[0039] The advantage of using DMSO is that it is a safer (Class 3) and more environmentally friendly solvent. Additionally, the use of DMSO has enabled the development of a simplified isolation procedure involving the addition of water to the reaction mixture to precipitate the product (compound E). This eliminates the need for lengthy work-up processes, including the use of chromatography, and thus allows compound E to be provided in an efficient manner.

[0040] In some embodiments, CDI in the solvent is added in small increments to reduce heat release during addition to the reaction mixture.

[0041] In some embodiments, the reaction is carried out at an elevated temperature, for example, 20 to 70°C, or 30 to 40°C, or 40 to 65°C, or 55 to 60°C.

[0042] In some embodiments, the method for preparing compound F is compound E

[0043]

[0044] It includes a step (step 5) of reacting with a chlorination reagent in the presence of a base.

[0045] In some embodiments, the chlorination reagent is phosphoryl chloride (POCl3).

[0046] In some embodiments, POCl3 is used in excess (2 to 30 molar equivalents, or 4 to 7 equivalents, or 5 to 15 equivalents, or 7 to 10 equivalents relative to compound E).

[0047] In some embodiments, the base is an amine base.

[0048] In some embodiments, the amine base is N,N-diisopropylethylamine (DIPEA). In some embodiments, the amine base is trimethylamine or N,N-dimethylaniline.

[0049] In some embodiments, DIPEA was used in excess (1.01 to 10 molar equivalents, or 1.01 to 3 equivalents, or 5 to 10 equivalents relative to compound E).

[0050] In some embodiments, 4 to 5 molar equivalents or 8 to 9 molar equivalents of POCl3 or 1.0 to 1.1 molar equivalents or 2.5 molar equivalents of DIPEA are used relative to compound E to reduce the formation of unwanted byproducts and simplify the purification process of compound E.

[0051] In some embodiments, step 5 is performed at a heated state, for example, 95 to 100°C or 80 to 100°C.

[0052] In some embodiments, step 5 further includes the step of co-distilling the unpurified reaction mixture using ethyl acetate. This is used as an efficient method to remove excess POCl3 from the reaction mixture before quenching the reaction with a NaHCO3 solution.

[0053] In some embodiments, the product (compound F) is isolated from a mixture of ethyl acetate and a nonpolar cosolvent by crystallization. In some embodiments, the nonpolar cosolvent is hexane, heptane, or toluene.

[0054] In some embodiments, the product (compound F) is isolated from the ethyl acetate / n-heptane mixture by crystallization.

[0055] In some embodiments, the method for preparing compound I is compound F

[0056]

[0057] It includes a step of reacting with methylamine (step 6).

[0058] In some embodiments, 2 M methylamine in THF is used.

[0059] In some embodiments, the reaction is carried out at 20 to 30°C. This temperature prevents the volatilization of methylamine and pressure accumulation.

[0060] In some embodiments, the work-up includes the step of dissolving the unpurified product in an aqueous HCl solution (e.g., 7 N HCl) and washing with a nonpolar solvent. In some embodiments, the nonpolar solvent is dichloromethane, which efficiently removes residual impurities from the previous step. Then, the unpurified product is neutralized with an aqueous NaOH solution, and the product is isolated.

[0061] In some embodiments, the desired form of compound I (form VII) was obtained from ethanol (EtOH) and methyl tert-butyl ether (MTBE) through crystallization.

[0062] In some embodiments, to remove any residual HCl, dried compound I may be dissolved in ethanol, treated with a sodium hydroxide solution in ethanol, and then process water may be added to precipitate the product.

[0063] In some embodiments, to ensure the formation of the desired polymorphism, crystals of compound I - form VII were seeded.

[0064] In some embodiments, precipitation is carried out by (1) cooling an ethanol solution of compound I, (2) adding a seed crystal of compound I-form VII, (3) stirring the mixture for about 10 hours, (4) further cooling the mixture and adding MTBE, and (5) stirring for about 3 to 5 hours to precipitate compound I-form VII.

[0065] In some embodiments, MBTE may be added before adding the seed crystal of compound I - form VII.

[0066] A method for preparing a crystalline solid form of Compound I is disclosed herein. Crystalline forms of the same compound generally possess different properties, including hygroscopicity, solubility, and stability. Polymorphs with high melting points often possess good thermodynamic stability, which is advantageous for extending the shelf life of formulations containing the solid form of the compound. Polymorphs with low melting points are generally less thermodynamically stable but are preferred due to improved water solubility, which is often understood to enhance the bioavailability of the compound. Polymorphs with low hygroscopicity are often more stable with respect to heat and humidity and are resistant to degradation during storage. Anhydrous polymorphs are often preferred because they can be prepared consistently with little or no change in composition due to changes in solvent and moisture content.

[0067] Compound I can be obtained in a solid crystalline form designated as Form VII. Form VII is an anhydride. Form VII, a polymorph of Compound I, is characterized by its XRPD and other data. Form VII of Compound I is Cu-K α When determined on a diffractometer using a radiation tube, the X-ray powder diffraction pattern (XRPD) is characterized by a peak at 16.5 degrees ± 0.2 degrees θ with respect to 2-θ.

[0068] In some embodiments, form VII of compound I features an X-ray powder diffraction (XRPD) comprising one or more peaks at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5° with respect to 2-θ, and Cu-K α When determined on a diffractometer using a radiation tube, each peak is ±0.2 degrees θ.

[0069] In some embodiments, form VII of compound I is characterized by an X-ray powder diffraction (XRPD) comprising three or more peaks at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5° with respect to 2-θ, and Cu-K α When determined on a diffractometer using a radiation tube, each peak is ±0.2 degrees θ.

[0070] In some embodiments, form VII of compound I is characterized by an X-ray powder diffraction (XRPD) comprising at least six peaks at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5° with respect to 2-θ, and Cu-K α When determined on a diffractometer using a radiation tube, each peak is ±0.2 degrees θ.

[0071] In some embodiments, form VII of compound I features an X-ray powder diffraction (XRPD) comprising at least 10 peaks at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5° with respect to 2-θ, and Cu-K α When determined on a diffractometer using a radiation tube, each peak is ±0.2 degrees θ.

[0072] In some embodiments, form VII of compound I features an X-ray powder diffraction (XRPD) including peaks at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5° with respect to 2-θ, and Cu-K αWhen determined on a diffractometer using a radiation tube, each peak is ±0.2 degrees θ.

[0073] In some embodiments, form VII of compound I is Cu-K α When determined on a diffractometer using a radiation tube, it features an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1.

[0074] In some embodiments, form VII of compound I features a differential scanning calorimetry (DSC) temperature change pattern having an endothermic peak at a temperature of about 205°C.

[0075] In some embodiments, form VII of compound I features a differential scanning calorimetry (DSC) temperature change pattern substantially as shown in FIG. 2.

[0076] In some embodiments, form VII of compound I features substantially the thermogravimetric analysis (TGA) temperature change diagram as shown in FIG. 3.

[0077] In some embodiments, form VII of compound I is about 3066 cm⁻¹ -1 and 1600 cm -1 It features an infrared (IR) spectrum including an IR band.

[0078] In some embodiments, form VII of compound I features an infrared (IR) spectrum substantially similar to that shown in FIG. 4.

[0079] Additionally, intermediates useful for the synthesis of BET bromodomain inhibitors, such as compounds B and C, are disclosed herein:

[0080]

[0081] .

[0082] In one embodiment, a method for preparing a therapeutic agent (Compound I) is disclosed herein, which modulates or inhibits the activity of BET bromodomain-containing proteins such as BRD2, BRD3, BRD4, and BRDT, and has the potential to heal, treat, or improve the lives of patients suffering from diseases mediated by bromodomain-containing proteins, such as certain cancers, inflammatory diseases, and cardiovascular diseases.

[0083] One embodiment relates to a method for treating a subject requiring treatment for a disease mediated at least partially by a BET bromodomain-containing protein, wherein the method comprises the step of administering a therapeutically effective amount of crystalline form VII of compound I.

[0084] In one embodiment, the disease is selected from cancer, inflammatory disease, and cardiovascular disease.

[0085] In one embodiment, the disease is a cancer including B-acute lymphoblastic leukemia, Burkitt lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, and neuroblastoma.

[0086] In one embodiment, the disease is prostate cancer.

[0087] In one embodiment, the disease is castration-resistant prostate cancer.

[0088] In one embodiment, the disease is metastatic castration-resistant prostate cancer.

[0089] In one embodiment, the disease is breast cancer.

[0090] In one embodiment, the disease is triple-negative breast cancer.

[0091] In one embodiment, the disease is estrogen-receptor positive breast cancer.

[0092] In some embodiments, the object is a human.

[0093] When treating a disease in a subject requiring treatment for a disease mediated at least partially by a BET bromodomain-containing protein, the subject may benefit from combination drug therapy. For example, the form(s) of Compound I as described herein may be combined with one or more therapeutic agents to form a single composition or to form compositions administered separately, and the separate compositions may be administered simultaneously, sequentially, or according to a specified therapeutic regimen.

[0094] In one embodiment, a form of compound I as described herein may be administered sequentially with additional therapeutic agents. “Sequentially” means that the form(s) of compound I and additional therapeutic agents are administered at intervals of seconds (e.g., 15 seconds, 30 seconds, 45 seconds, 60 seconds or less), minutes (e.g., 1 minute, 2 minutes, 5 minutes or less, 10 minutes or less, 15 minutes or less), 1 to 8 hours, 1 to 7 days, or 1 to 4 weeks. When administered sequentially, the form(s) of compound I as described herein and the additional therapeutic agents may be administered two or more times and may be contained in separate compositions or dosage forms, which may be contained in the same or different package(s).

[0095] In one embodiment, the form(s) of compound I as described herein may be combined with one or more therapeutic agents used in cancer treatment.

[0096] In one embodiment, compound I having form VII as described herein may be combined with one or more therapeutic agents used for cancer treatment.

[0097] In one embodiment, compound I having form VII as described herein may be combined with a therapeutic agent selected from androgen receptor antagonists, androgen synthesis inhibitors, aromatase inhibitors, selective estrogen receptor modulators, selective estrogen downmodulators, poly-ADP ribose polymerase (PARP) inhibitors, or immunotherapies.

[0098] In one embodiment, compound I having form VII as described herein may be combined with a therapeutic agent selected from abiraterone (Zytiga), enzalutamide (Xtandi), apalutamide (ARN-509, Erridea), darolutamide, fulvestrant, exemestane, talazoparib, olaferib, veliparib, rucaparib, talazoparib, niraparib, pembrolizumab, nivolumab, durvalumab, and rituximab.

[0099] A list of exemplary implementations includes the following:

[0100] 1. As a solid form of a compound having the following chemical formula,

[0101]

[0102] The solid form is crystalline, solid form.

[0103] 2. In Embodiment 1, the solid form is an anhydrous solid form.

[0104] 3. In Embodiment 1, the solid form is the solid form VII.

[0105] 4. In Embodiment 3, having three or more characteristic XRPD peaks with respect to 2-θ at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5°, wherein Cu-K α Solid form, each peak having a θ of ±0.2 degrees when determined using a diffractometer with a radiation tube.

[0106] 5. In Embodiment 3, having at least six characteristic XRPD peaks with respect to 2-θ at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5°, wherein Cu-K α Solid form, each peak having a θ of ±0.2 degrees when determined using a diffractometer with a radiation tube.

[0107] 6. In any one of embodiments 1 to 3, a solid form having an XRPD pattern substantially similar to that shown in FIG. 1.

[0108] 7. In any one of embodiments 1 to 6, a solid form having a DSC temperature change pattern having an endothermic peak at a temperature of about 205°C.

[0109] 8. In any one of embodiments 1 to 6, a solid form having a DSC temperature change diagram substantially similar to that shown in FIG. 2.

[0110] 9. In any one of embodiments 1 to 7, a solid form having a TGA temperature change diagram substantially similar to that shown in FIG. 3.

[0111] 10. A pharmaceutical composition comprising any one of embodiments 1 to 9 in a solid form and at least one pharmaceutically acceptable carrier.

[0112] 11. A method for treating cancer, comprising the step of administering a therapeutically effective amount of a solid form of any one of embodiments 1 to 9 or a pharmaceutical composition of embodiment 10 to a subject requiring such treatment.

[0113] 12. In Embodiment 11, the cancer is B-acute lymphoblastic leukemia, Burkitt lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, or neuroblastoma.

[0114] 13. Method in Embodiment 12, wherein the cancer is prostate cancer.

[0115] 14. Method in Embodiment 12, wherein the cancer is castration-resistant prostate cancer.

[0116] 15. Method in Embodiment 12, wherein the cancer is metastatic castration-resistant prostate cancer.

[0117] 16. Method in Embodiment 12, wherein the cancer is breast cancer.

[0118] 17. Method in Embodiment 12, wherein the cancer is triple-negative breast cancer.

[0119] 18. Method in Embodiment 12, wherein the cancer is estrogen receptor-positive breast cancer.

[0120] 19. A method for treating an inflammatory disease, comprising the step of administering a therapeutically effective amount of a solid form of any one of embodiments 1 to 9 or a pharmaceutical composition of embodiment 10 to a patient requiring such treatment.

[0121] 20. A method for treating cardiovascular disease, comprising the step of administering a therapeutically effective amount of a solid form of any one of embodiments 1 to 9 or a pharmaceutical composition of embodiment 10 to a patient requiring such treatment.

[0122] 21. In the embodiment 11, the object is a human.

[0123] 22. A method for preparing form VII of compound I

[0124]

[0125] A method comprising the step of precipitating form VII from a solution containing compound I and one or more solvents.

[0126] 23. Method of Embodiment 22, wherein the solvent is ethanol, t-butylmethyl ether (MTBE), or a mixture thereof.

[0127] 24. In Embodiment 22, the precipitate is:

[0128] (1) A step of cooling the ethanol solution of compound I;

[0129] (2) Step of adding a seed crystal of Compound I - Form VII to the solution;

[0130] (3) A step of stirring the mixture for about 10 hours;

[0131] (4) a step of further cooling the mixture and adding MTBE; and

[0132] (5) A method comprising the step of precipitating compound I - form VII by stirring for about 3 to 5 hours.

[0133] 25. In Embodiment 24, the method wherein MTBE is added prior to the step of adding a seed crystal of Compound I - Form VII to the mixture.

[0134] 26. As a method for preparing Compound I:

[0135]

[0136] A method comprising steps (a) through (d):

[0137] (a) Compound C

[0138]

[0139] React with compound G

[0140]

[0141] Step to produce compound D

[0142] ;

[0143] (b) Compound D

[0144]

[0145] Step of producing compound E by reacting with the first reagent

[0146] ;

[0147] (c) Compound E

[0148]

[0149] Step of producing compound F by reacting with a chlorinating agent

[0150] ; and

[0151] (d) Compound F

[0152]

[0153] Step of reacting with methylamine.

[0154] 27. In Embodiment 26, the method, wherein step (a) is performed in the presence of a transition metal catalyst and a base.

[0155] 28. Method of Embodiment 27, wherein the transition metal catalyst is a palladium catalyst.

[0156] 29. Method of Embodiment 28, wherein the palladium catalyst is Pd(PPh3)4.

[0157] 30. Method of Embodiment 27, wherein the base is an alkali metal carbonate.

[0158] 31. Method of Embodiment 27, wherein the base is K3PO4.

[0159] 32. A method according to Embodiment 26, wherein the first reagent in step (b) is carbonyldiimidazole (CDI), and step (b) is performed in a solvent.

[0160] 33. Method according to Embodiment 32, wherein the solvent is an aprotic solvent.

[0161] 34. Method of Embodiment 32, wherein the solvent is DMSO.

[0162] 35. A method according to Embodiment 32, wherein step (b) comprises adding water to the reaction mixture and precipitating compound E.

[0163] 36. In Embodiment 26, step (c) is performed in the presence of a base.

[0164] 37. Method of Embodiment 36, wherein the chlorinating agent is phosphoryl chloride (POCl3).

[0165] 38. Method of Embodiment 36, wherein the base is N,N-diidopropylethylamine (DIPEA).

[0166] 39. A method according to Example 36, wherein 4 to 5 or 8 to 9 molar equivalents of POCl3 and 1.0 to 1.1 or 2.5 molar equivalents of DIPEA are used relative to compound E.

[0167] 40. A method according to Embodiment 36, further comprising the step of co-distilling with ethyl acetate before quenching the reaction with a NaHCO3 solution.

[0168] 41. A method according to Embodiment 36, wherein compound F is isolated from an ethyl acetate / n-heptane mixture by crystallization.

[0169] 42. In Embodiment 26, the method wherein step (d) is performed using 2 M methylamine in THF.

[0170] 43. In Embodiment 26, the method wherein step (d) is performed at 20 to 30°C.

[0171] 44. A method according to Embodiment 26, wherein step (d) further comprises a reaction work-up, wherein the reaction work-up comprises the step of dissolving the unpurified product in an aqueous HCl solution, washing with a non-polar solvent, and then neutralizing with an aqueous NaOH solution.

[0172] 45. A method according to Embodiment 26, wherein step (d) further comprises a step of removing any residual HCl, said removal step comprising dissolving the dried material in ethanol, treating it with a sodium hydroxide solution in ethanol, and then adding water to precipitate the product.

[0173] 46. ​​In Embodiment 26, compound C is

[0174] (e) Compound B

[0175]

[0176] A method prepared by the step of reacting with NaBH4 in a solvent.

[0177] 47. Method according to Embodiment 46, wherein the solvent is an alcohol.

[0178] 48. A method according to Embodiment 46, wherein the solvent is ethanol.

[0179] 49. A method according to Example 46, wherein 0.6 molar equivalents of NaBH4 are used relative to compound B.

[0180] 50. A method according to Embodiment 46, further comprising a work-up and isolation step, wherein the work-up and isolation step comprises adding an HCl solution to quench the reaction and then adding water to precipitate compound C.

[0181] 51. In Embodiment 46, compound B is

[0182] Compound A

[0183]

[0184] A method comprising the step (step 1) of reacting with benzaldehyde in the presence of acid.

[0185] 52. Method according to Example 51, wherein the acid is acetic acid.

[0186] 53. The method of Embodiment 51, wherein the solvent is additionally included, the solvent being methanol.

[0187] 54. A method according to Embodiment 51, further comprising the step of adding a NaHCO3 solution to the reaction mixture after the reaction is completed to precipitate compound B.

[0188] Examples

[0189] General methods: FT-IR of Compound I was obtained using a Nicolet 380 FT-IR spectrophotometer. TGA analysis was performed using a TA Q5000 instrument thermogravimetric analyzer. DSC analysis was performed using a TA Q2000 instrument differential scanning calorimeter at 10°C / min from 30 to 300°C. XRPD patterns of Compound I were obtained, mostly using a Bruker instrument D8 advanced diffractometer or a similar instrument, with the following settings: 40 KV, 40 mA, K a =1.5406 A (Cu-K α Radiation tube), scanning range 4–40 degrees 2θ, 15 rpm, 10 degrees / min. The NMR experiment was recorded using a Bruker AV400 MHz Spectrometer.

[0190] Example 1: 5-Bromo-N 3 Synthesis of (phenylmethylene)pyridine-2,3-diamine (compound B)

[0191]

[0192] Compound A (12.47 kg) was dissolved in methanol (100 kg) and acetic acid (2.3 kg) in a reactor. The solution was cooled to 0–5°C and stirred for 0.5–1 hour, and benzaldehyde (56.4 g) was added dropwise over 2 hours. After the reaction was complete (5–10 hours), water (53 kg) was added over 2 hours, and NaHCO3 solution (7% of water) was added dropwise over 2 hours, while maintaining the temperature low (0–5°C). The mixture was stirred for 3 hours. The solids were filtered, washed with 1:1 methanol / water, dried, and compound B with +99% purity was obtained by HPLC in a 94% yield.1 H-NMR (DMSO-d6): δ 8.75 (1H), 8.04 (2H), 7.93 (1H), 7.65 (1H), 7.50-7.60 (3H).

[0193] Example 2: N 3 Synthesis of -Benzyl-5-Bromopyridine-2,3-Diamine (Compound C)

[0194]

[0195] Compound B (17.1 kg) was dissolved in ethanol (140 kg), and NaHB4 (1.4 kg) was added in several portions while maintaining the temperature at 15–25°C. The reaction mixture was stirred for 8–15 hours until the reaction was complete, monitored by HPLC. HCl solution (2N, 12 kg) was added to adjust the pH to 6–7, and then water (350 kg) was added dropwise over 5 hours while maintaining the temperature at 15–25°C. The mixture was stirred for 1–5 hours, filtered, and washed with an ethanol / water mixture (1:1 ratio, 50 kg). The solids were dried at approximately 60°C for 15–20 hours to obtain Compound C (Yield: 14.35 kg (83%), Purity: 99%). 1 H-NMR (DMSO-d6): δ 7.2-7.4 (6 H), 6.55 (1 H), 5.70-5.83 (3 H), 4.30 (2 H).

[0196] Example 3: N 3 Synthesis of -Benzyl-5-(3,5-dimethyl-1,2-oxazole-4-yl)pyridine-2,3-diamine (Compound D)

[0197]

[0198] Compound C (14.2 kg), Compound G (14.8 kg), and potassium triphosphate trihydrate (22.0 kg) were mixed, then 1,4-dioxane (145 kg) and water (28 kg) were added and stirred for 1 to 2 hours. The resulting mixture was completely purged with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (2.9 kg) was added, the solution was completely purged with nitrogen, and heated to 90 to 95°C (16 to 20 hours) until the ratio of Compound C to Compound D was 1% or less as measured by HPLC. After cooling to 20 to 30°C, the reaction mixture was filtered, the solids were washed with 1,4-dioxane (25 kg), the aqueous phase was removed, and the organic phase was concentrated. Water (96 kg) was added dropwise at 40–45°C, the mixture was cooled to 20–25°C, and the mixture was stirred for 1–2 hours until the amount of residual compound D in the mother liquor was 0.5% or less. Compound D was isolated by filtration and washed sequentially with 1,4-dioxane / water (1:2 ratio, 25 kg) and t-butylmethyl ether (27 kg). The wet cake was mixed in methyl chloride (658 kg) at 40–45°C until all solids were dissolved, and silica gel (7.0 kg) was added. After stirring for 0.5–1 hour, the mixture was cooled to 20–25°C, filtered, washed with dichloromethane (85 kg), and then concentrated. The mixture was cooled, and t-butylmethyl ether (56 kg) was added dropwise at 35–40°C. The reactor was cooled to 5–10°C and stirred for 2–3 hours. The product was isolated by filtration, washed with methyl-t-butyl ether, and dried until the levels of methylene chloride, t-butylmethyl ether, and moisture were 0.5% or less to obtain compound D (yield: 9.7 kg (65%), purity: 99%). 1H-NMR (DMSO-d6): δ 7.30-7.45 (4 H), 7.20-7.25 (2 H), 6.35 (1 H), 5.65-5.80 (3 H), 4.30-4.40 (2 H), 2.15 (3 H), 1.95 (3 H). Alternatively, the wet cake obtained after sequential washing with 1,4-dioxane / water and MTBE can be purified using an ethanol (5 volume) slurry at 30-40°C for 1-3 hours, and then dried until the moisture level is 0.5% or less and the ethanol level is 0.5% or less.

[0199] Example 4: Synthesis of 1-Benzyl-6-(3,5-Dimethyl-1,2-Oxazole-4-yl)-3H-Imidazoo[4,5-b]pyridin-2-one (Compound E)

[0200]

[0201] Carbonyldiimidazole solids (8.4 kg) were added to a stirred mixture of Compound D (10.0 kg) and Dimethyl Sulfoxide (35 kg) (CDI could be added in multiple stages). The mixture was heated at 55–60°C for 1–3 hours or at 35–40°C until the ratio of Compound D to Compound E was 0.5% NMT. ​​The mixture was cooled to 35–40°C, and water was added over 4 hours. The resulting mixture was stirred at ambient temperature for 3 hours. The product was isolated by filtration and washed with water. After confirming that the Dimethyl Sulfoxide content was 0.5% or less, it was dried using heat and vacuum treatment. Drying was completed when the moisture level was 0.5% NMT. ​​Compound E was obtained (Yield: 9.8 kg, 94%, Purity: 99.9%). 1 H-NMR (DMSO-d6): δ 11.85 (1 H), 7.90 (1 H), 7.20-7.45 (6 H), 5.05 (2 H), 3.57 (3 H), 2.35 (3 H), 2.15 (3 H).

[0202] Example 5: Synthesis of 4-[1-benzyl-2-chloro-1H-imidazo[4,5-b]pyridine-6-yl]-3,5-dimethyl-1,2-oxazole (Compound F)

[0203]

[0204] Compound E (9.6 kg) and phosphorus oxychloride (40 kg) were mixed, and then diisopropylethylamine (DIPEA) (9.8 kg) was added dropwise at 50°C. The resulting mixture was heated at 95–100°C for 60–70 hours. After the reaction was complete, the mixture was concentrated and then cooled. Ethyl acetate was added, the mixture was concentrated three times under vacuum, and co-distilled with ethyl acetate. Ethyl acetate (EtOAc) (114 kg) was added to the concentrate, the mixture was cooled to ambient temperature, and then slowly added to aqueous sodium bicarbonate (7%), maintaining the mixture at 15–25°C. The organic phase was separated, and the organic layer was washed twice with aqueous sodium bicarbonate (7%) and then washed with water. The organic phase was concentrated, ethyl acetate (288 kg) was added, and the mixture was concentrated until the moisture level was 0.2% or less. The mixture in ethyl acetate was decolorized with carbon (CUNO, containing 1.2 kg of activated carbon). The mixture was concentrated and n-heptane (23 kg) was added. The product was isolated by filtration and dried under vacuum. Drying was completed when the residual moisture, ethyl acetate, and n-heptane were 0.5% or less. Compound F was obtained (4.95 kg, 46%, purity: 95%). 1 H-NMR (MeOH-d4): δ 8.40 (1 H), 7.90 (1 H), 7.25-7.45 (5 H), 5.65 (2 H), 2.37 (3 H), 2.22 (3 H).

[0205] Example 6: Synthesis of 1-Benzyl-6-(3,5-Dimethyl-1,2-Oxazole-4-yl)-N-Methyl-1H-Imidazō[4,5-b]pyridine-2-amine (Compound I)

[0206]

[0207] Compound F (4.54 kg) in tetrahydrofuran (THF) methylamine (31.9 kg, 2 MIt was mixed with ) and stirred at room temperature until the ratio of compound F to compound I was 0.1% NMT by HPLC. After the reaction was complete, the mixture was concentrated under vacuum, water (34 kg) was added dropwise, maintained at ambient temperature, stirred for 1 to 1.5 hours, and the product was isolated by filtration. The filter cake was washed with water. The wet cake was placed in a reactor, water (17 kg) was added, hydrochloric acid (36 kg, 35%) was added, and the mixture was stirred for 2 hours to dissolve the solids. The resulting solution was washed twice with methylene chloride to remove impurities. Sodium hydroxide solution (14.5 kg, 15%) was added dropwise over 1.5 hours to neutralize the aqueous solution, and the mixture was stirred for 5 hours. Compound I was isolated by filtration, washed with water, and dried under vacuum. If it is necessary to remove any residual hydrochloric acid, the dried material was dissolved in ethanol (13.4 kg), treated with a sodium hydroxide solution in ethanol (0.2 kg NaOH in 4 kg ethanol), stirred for 1 hour, and then 70 kg of water was added to precipitate the product. Compound I was isolated by filtration, washed with water, and dried. If necessary, Compound I can be further purified by slurrying in hot water.

[0208] Dry compound I was dissolved in ethanol (16.2 kg), and the resulting solution was filtered into a clean room. The ethanol solution was azeotropically dried with anhydrous ethanol. The resulting mixture was heated to dissolve and concentrate the product. The mixture was heated to reflux dissolve any solid and seeded (compound I - form VII) while slowly cooling. The mixture was stirred at 50–60°C for 10 hours. XRPD indicated form VII. The mixture was further cooled to 45–50°C and stirred at 45–50°C for 3 hours, and the XRPD of the solid indicated that the mixture was form VII. T-butylmethyl ether (MTBE) (26 kg) was added dropwise at 45–50°C for at least 4 hours and stirred at 45–50°C for 1 hour. The mixture was cooled to 20–30°C for 3 hours and stirred at 20–30°C for 2 hours. The solids were filtered, rinsed with MTBE, and dried to obtain Compound I - Form VII (2.82 kg, 63%, purity >99%). 1 H-NMR (DMSO-d6): δ 7.96 (d, 1H, J=2.0 Hz), 7.42 (d, 1H, J=2.0 Hz), 7.37 (q, 1H, J=4.2 Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.24 (m, 2H), 5.30 (s, 2H), 3.00 (d, 3H, 4.5 Hz), 2.34 (s, 3H), 2.16 (s, 3H). 13C-NMR (DMSO- d6): d 164.8, 158.4, 157.7, 156.0, 141.1, 136.4, 128.6 (2C), 127.5, 127.4, 127.2 (2C), 115.8, 114.2 (2C), 44.5, 29.3, 11.2, 10.3). Alternatively, MTBE can be added before adding the seed crystal of compound I - form VII to the mixture.

Claims

Claim 1 As a solid crystalline form of a compound having the following chemical formula, The above-mentioned solid crystalline form is Compound I, Form VII; additionally, the above-mentioned solid crystalline form has at least five characteristic X-ray powder diffraction (XRPD) peaks with respect to 2-θ at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5°, wherein Cu-K α A crystalline form of solid matter, with each peak having ±0.2 degrees 2θ when determined using a diffractometer with a radiation tube. Claim 2 In claim 1, a solid crystalline form having an XRPD pattern as illustrated in FIG. 1 below. [Fig. 1] Claim 3 A crystalline form of solid content having a differential scanning calorimetry (DSC) temperature change pattern having an endothermic peak at a temperature of 205°C, according to claim 1. Claim 4 In claim 1, a crystalline solid form having a differential scanning calorimetry (DSC) temperature change diagram as shown in FIG. 2 below. [Fig. 2] Claim 5 In claim 1, a crystalline solid form having a thermogravimetric analysis (TGA) temperature change diagram as shown in FIG. 3 below. [Fig. 3] Claim 6 A pharmaceutical composition for treating cancer, wherein the pharmaceutical composition comprises a solid crystalline form according to any one of claims 1 to 5 and at least one pharmaceutically acceptable carrier. Claim 7 A pharmaceutical composition for treating cancer in a subject requiring cancer treatment, comprising a therapeutically effective amount of a solid crystalline form according to any one of claims 1 to 5 and at least one pharmaceutically acceptable carrier. Claim 8 A pharmaceutical composition according to claim 7, wherein the cancer is B-acute lymphoblastic leukemia, Burkitt lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, or neuroblastoma. Claim 9 A pharmaceutical composition in which, in paragraph 8, the cancer is prostate cancer. Claim 10 A pharmaceutical composition in which, in paragraph 8, the cancer is castration-resistant prostate cancer. Claim 11 A pharmaceutical composition in which, in paragraph 8, the cancer is metastatic castration-resistant prostate cancer. Claim 12 A pharmaceutical composition in which, in paragraph 8, the cancer is breast cancer. Claim 13 A pharmaceutical composition in which, in paragraph 8, the cancer is triple-negative breast cancer. Claim 14 A pharmaceutical composition in which, in paragraph 8, the cancer is estrogen receptor-positive breast cancer. Claim 15 A pharmaceutical composition for treating inflammatory diseases comprising a therapeutically effective amount of a solid crystalline form according to any one of claims 1 to 5 and at least one pharmaceutically acceptable carrier. Claim 16 A pharmaceutical composition for treating cardiovascular disease comprising a therapeutically effective amount of a solid crystalline form according to any one of claims 1 to 5 and at least one pharmaceutically acceptable carrier. Claim 17 In paragraph 7, the subject is a human being, a pharmaceutical composition. Claim 18 A method for preparing solid crystalline compound I, form VII The method comprises the step of precipitating Compound I, Form VII from a solution comprising Compound I and ethanol, t-butylmethyl ether (MTBE), or a mixture thereof; additionally, said solid crystalline Compound I, Form VII has at least five characteristic X-ray powder diffraction (XRPD) peaks at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5° with respect to 2-θ, wherein Cu-K α A method in which, when determined using a diffractometer with a radiation tube, each peak is ±0.2 degrees 2θ. Claim 19 A method according to claim 18, wherein the precipitation step is performed by (1) cooling an ethanol solution of compound I; (2) adding a seed crystal of compound I, form VII to the solution; (3) stirring the mixture for 10 hours; (4) further cooling the mixture and adding MTBE; and (5) stirring for 3 to 5 hours to precipitate compound I, form VII. Claim 20 As a method for preparing solid crystalline compound I, form VII: Steps (a) to (d) comprising: (a) compound C React with compound G Step to produce compound D ;(b) Compound D Step of producing compound E by reacting with carbonyldiimidazole (CDI). ;(c) Compound E Step of producing compound F by reacting with a chlorinating agent ; and (d) compound F A step of reacting with methylamine to produce compound I; the method further comprises a step of precipitating compound I, form VII from a solution comprising compound I and ethanol, t-butylmethyl ether (MTBE), or a mixture thereof; additionally, the solid crystalline compound I, form VII has at least five characteristic X-ray powder diffraction (XRPD) peaks with respect to 2-θ at 7.2°, 10.3°, 11.2°, 12.0°, 13.8°, 13.9°, 15.2°, 15.6°, 16.5°, 17.3°, 20.7°, 20.9°, 21.6°, and 22.5°, wherein Cu-K α A method in which, when determined using a diffractometer with a radiation tube, each peak is ±0.2 degrees 2θ. Claim 21 A method according to claim 20, wherein the step of precipitating compound I, form VII comprises: (1) cooling a solution containing ethanol and compound I; (2) adding a seed crystal of compound I, form VII to the solution; (3) stirring the mixture for 10 hours; (4) adding MTBE after cooling the mixture; and (5) stirring for 3 to 5 hours to precipitate compound I, form VII. Claim 22 In paragraph 20, step (a) is performed in the presence of a transition metal catalyst and a base; optionally, the transition metal catalyst is a palladium catalyst; optionally, the palladium catalyst is Pd(PPh3)4, method. Claim 23 In paragraph 22, the base is an alkali metal carbonate; optionally the base is K3PO4, method. Claim 24 In paragraph 20, step (b) is performed in a solvent; optionally the solvent is an aprotic solvent; optionally the solvent is DMSO, method. Claim 25 In paragraph 24, the method comprises step (b) adding water to the reaction mixture and precipitating compound E. Claim 26 In paragraph 20, step (c) is performed in the presence of a base; optionally, the base is N,N-diisopropylethylamine (DIPEA), method. Claim 27 In paragraph 26, the chlorinating agent is phosphoryl chloride (POCl3); optionally, 8 to 9 molar equivalents of POCl3 and 2.5 molar equivalents of N,N-diisopropylethylamine (DIPEA) are used relative to compound E. Claim 28 A method according to claim 26, further comprising the step of co-distilling with ethyl acetate before quenching the reaction with a NaHCO3 solution. Claim 29 In paragraph 26, the method wherein compound F is isolated from a mixture of ethyl acetate / n-heptane by crystallization. Claim 30 In paragraph 20, step (d) is performed using 2 M methylamine in tetrahydrofuran (THF), a method. Claim 31 In paragraph 20, step (d) is a method performed at 20 to 30°C. Claim 32 A method according to claim 20, wherein step (d) further comprises a reaction workup, wherein the reaction workup comprises the step of dissolving the unpurified product in an aqueous HCl solution, washing with a non-polar solvent, and then neutralizing with an aqueous sodium hydroxide (NaOH) solution. Claim 33 In claim 20, step (d) further comprises a step of removing any residual HCl, said removal step comprising dissolving the dried material in ethanol, treating it with a sodium hydroxide (NaOH) solution in ethanol, and then adding water to precipitate the product. Claim 34 In paragraph 20, compound C is (e) compound B A method prepared by the step of reacting with NaBH4 in a solvent; optionally the solvent is an alcohol; optionally the solvent is ethanol. Claim 35 A method according to paragraph 34, wherein 0.6 molar equivalents of NaBH4 relative to compound B are used. Claim 36 A method according to claim 34, further comprising a work-up and isolation step, wherein the work-up and isolation step comprises adding an HCl solution to quench the reaction and then adding water to precipitate compound C. Claim 37 In paragraph 34, compound B is (f) compound A A method comprising the step of reacting with benzaldehyde in the presence of an acid; optionally, the acid is acetic acid. Claim 38 A method in paragraph 37, further comprising a solvent, wherein the solvent is methanol. Claim 39 A method according to claim 37, further comprising the step of adding a NaHCO3 solution to the reaction mixture after the reaction is completed to precipitate compound B. Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete Claim 48 delete Claim 49 delete Claim 50 delete Claim 51 delete Claim 52 delete Claim 53 delete Claim 54 delete

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