Method of manufacturing solid form of bet bromodomain inhibitor

Abstract

To provide solid crystalline forms of a compound that modulates or inhibits the activity of BET bromodomain-containing proteins.SOLUTION: Provided is a form of Compound I which: (a) when measured on a diffractometer using a Cu-Kα radiation source, has three or more characteristic XRPD peaks at 2θ of 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 each peak is at ±0.2°θ; or (b) when measured on a diffractometer using a Cu-Kα radiation source, has six or more characteristic XRPD peaks at 2θ of 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 each peak is at ±0.2°θ.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to solid forms of Compound I (1-benzyl-6(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine) that modulate or inhibit the activity of BET bromodomain-containing proteins, including methods for their preparation, intermediates in their preparation, and pharmaceutical compositions thereof, and Compound I is useful in the treatment of diseases such as cancer. [Background technology]

[0002] Therapeutic agents 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, and cardiovascular disease. In particular, BET bromodomain modulators or inhibitors have the potential to treat B-acute lymphoblastic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, and neuroblastoma, among others. Compounds for the treatment of such diseases and conditions are disclosed in PCT Publication WO2015 / 002754, the disclosure of which is incorporated herein by reference in its entirety.

[0003] There is a significant unmet need for compounds, including solid forms of highly pure derivatives of benzimidazole, that are effective and also exhibit improved stability, solubility, and favorable pharmacokinetic and pharmacodynamic profiles for the treatment of diseases modulated by bromodomain-containing BET proteins, and importantly, compounds that can be efficiently produced on a large scale to facilitate clinical and commercial use. Summary of the Invention

[0004] Compound I is known to modulate or inhibit BET activity and is described in WO2015 / 002754. Compound I has the following formula: [ka]

[0005] The present disclosure provides solid forms of Compound I, as well as methods of making the disclosed solid forms of Compound I, intermediates used in their preparation, pharmaceutical compositions comprising crystalline forms of Compound I, and methods of using such forms and pharmaceutical compositions in the treatment of diseases mediated by BET proteins. Details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and claims. [Brief explanation of the drawings]

[0006] [Figure 1] FIG. 1 shows the X-ray powder diffraction diagram (XRPD) of Compound I-Form VII.

[0007] [Figure 2] FIG. 2 shows the differential scanning calorimetry (DSC) curve of Compound I-Form VII.

[0008] [Figure 3] FIG. 3 shows the thermogravimetric analysis (TGA) of Compound I-Form VII.

[0009] [Figure 4] FIG. 4 shows the infrared spectrum (IR) of Compound I-Form VII. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present disclosure provides a method for preparing Compound I that is suitable for scale-up and large-scale manufacturing. The method for preparing Compound I is described in WO2015 / 002754, which is incorporated herein by reference in its entirety, particularly for its description of Compound I and its synthesis. Compared to the synthesis described in WO2015 / 002754, the method provided herein has certain advantages that make it suitable for scale-up of the preferred polymorphic form of Compound I (Form VII). For example, the method described herein uses fewer hazardous reagents, lower reaction temperatures, reagents more suitable for scale-up, simplified workup procedures, and streamlined isolation of intermediates through elimination of column chromatographic purification. All of these factors result in a manufacturing process that is superior in efficiency and quality to conventional methods, leading to a reduced environmental footprint and cost savings.

[0011] In some embodiments, the method for preparing compound I includes starting materials A and G, and intermediates B, C, D, E, and F. [ka]

[0012] In some embodiments, the method for preparing compound B comprises reacting compound A (Step 1) with [ka] The method includes reacting with benzaldehyde in the presence of an acid, hi some embodiments, the acid is acetic acid.

[0013] In some embodiments, step 1 is carried out 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 provides more efficient workup and isolation by eliminating the need for column chromatography.

[0014] In some embodiments of Step 1, NaHCO3 solution is added to the reaction mixture after completion of the reaction, causing precipitation of the product and simplifying isolation and purification of Compound B.

[0015] In some embodiments of Step 1, Compound A and benzaldehyde are used in a 1:1 molar ratio.

[0016] In some embodiments, step 1 is carried out at low temperatures, in some embodiments the reaction temperature is 0-5°C, or less than 10°C, or less than 20°C.

[0017] In some embodiments, the method for preparing compound C comprises reacting compound B (step 2) with [ka] In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is methanol or ethanol.

[0018] In some embodiments, the solvent is ethanol, allowing the loading of NaCNBH3 or NaBH4 to be reduced to 0.6 molar equivalents relative to compound B, making the process more environmentally friendly and reducing overall costs.

[0019] In some embodiments, the loading of NaCNBH3 or NaBH4 is 1 equivalent or less relative to Compound B, for example, less than 0.9 equivalents, or less than 0.75 equivalents, or less than 0.6 equivalents relative to Compound B.

[0020] In some embodiments of step 2, workup and isolation are performed by adding HCl solution to quench the reaction, followed by adding water to precipitate the product (compound C) in high purity (+95%), thereby simplifying the workup and isolation process. In some embodiments, water or other agents such as acetic acid can be used to quench the reaction.

[0021] In some embodiments, step 2 is carried out at 10-40°C, or 15-20°C, or 20-25°C.

[0022] In some embodiments, the method for preparing compound D comprises reacting compound C (Step 3) with compound D in the presence of a transition metal catalyst and a base. [ka] Compound G and [ka] The method includes reacting a palladium catalyst with a palladium-containing amine.

[0023] In some embodiments, the palladium catalyst is [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl, dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (PD-132), or tetrakis(tri(o-tolyl)phosphine)palladium(0).

[0024] In some embodiments, the palladium catalyst is Pd(PPh 3)4 is.

[0025] 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.

[0026] The use of K3PO4 is advantageous compared to K2CO3 because K3PO4 disperses well within the reactor, thus resulting in a reaction with fewer by-products and a higher purity product (compound D).

[0027] In some embodiments, the reaction is carried out in a solvent mixture comprising 1,4-dioxane and water.

[0028] In some embodiments, the reaction is carried out at elevated temperatures, such as 80-100°C, or 90-100°C, or 90-95°C.

[0029] In some embodiments, the method for preparing compound E comprises reacting compound D (step 4) with a solvent. [ka] This involves reacting with carbonyldiimidazole (CDI).

[0030] In some embodiments, the solvent is an aprotic solvent, hi some embodiments, the solvent is 1,4-dioxane, DMSO, or DMF.

[0031] The advantage of using DMSO is that it is a safer (Class 3) and more environmentally friendly solvent. The use of DMSO also allowed for the development of a simplified isolation procedure, involving precipitation of the product (compound E) by adding water to the reaction mixture. This eliminated lengthy workup steps, including the use of chromatography, and thus efficiently provided compound E.

[0032] In some embodiments, the CDI in the solvent is added in portions to reduce heat release during addition to the reaction mixture.

[0033] In some embodiments, the reaction is carried out at elevated temperatures, such as 20-70°C, or 30-40°C, or 40-65°C, or 55-60°C.

[0034] In some embodiments, the method for preparing compound F comprises reacting compound E (step 5) with [ka] This involves reacting with a chlorinating agent in the presence of a base.

[0035] In some embodiments, the chlorinating reagent is phosphoryl chloride (POCl 3 ).

[0036] In some embodiments, POCl 3 is used in excess (2 to 30 molar equivalents relative to Compound E, or 4 to 7 equivalents, or 5 to 15 equivalents, or 7 to 10 equivalents).

[0037] In some embodiments, the base is an amine base.

[0038] In some embodiments, the amine base is N,N-diisopropylethylamine (DIPEA). In some embodiments, the amine base is trimethylamine or N,N-dimethylaniline.

[0039] In some embodiments, DIPEA is used in excess (1.01 to 10 molar equivalents relative to Compound E, or 1.01 to 3 equivalents, or 5 to 10 equivalents).

[0040] In some embodiments, 4-5 molar equivalents or 8-9 molar equivalents of POCl3 relative to compound E and 1.0-1.1 molar equivalents or 2.5 molar equivalents of DIPEA relative to compound E are used to reduce the formation of undesired by-products and simplify the purification process of compound E.

[0041] In some embodiments, step 5 is carried out at an elevated temperature, such as 95-100°C, or 80-100°C.

[0042] In some embodiments, step 5 further comprises co-distillation of the crude reaction mixture with ethyl acetate, which is used as an efficient method to remove excess POCl from the reaction mixture before quenching the reaction with NaHCO solution.

[0043] In some embodiments, the product (Compound F) is isolated by crystallization from a mixture of ethyl acetate and a non-polar co-solvent. In some embodiments, the non-polar co-solvent is hexane, heptane, or toluene.

[0044] In some embodiments, the product (compound F) is isolated by crystallization from an ethyl acetate / n-heptane mixture.

[0045] In some embodiments, the method for preparing compound I comprises reacting compound F (step 6) with [ka] This involves reacting with methylamine. In some embodiments, 2M methylamine in THF is used.

[0046] In some embodiments, the reaction is carried out at 20-30° C. This temperature avoids volatilization of the methylamine and pressure buildup.

[0047] In some embodiments, workup of the reaction involves dissolving the crude product in aqueous HCl solution (e.g., 7N HCl) and washing with a non-polar solvent. In some embodiments, the non-polar solvent is dichloromethane, which effectively removes remaining impurities from the previous step. The crude product is then neutralized with aqueous NaOH solution, and the product is isolated.

[0048] In some embodiments, the desired form of Compound I (Form VII) was obtained from crystallization from ethanol (EtOH) and methyl tert-butyl ether (MTBE).

[0049] In some embodiments, to remove residual HCl, dry Compound I can be dissolved in ethanol and treated with a solution of sodium hydroxide in ethanol, followed by the addition of process water to precipitate the product.

[0050] In some embodiments, crystals were seeded onto Compound I-Form VII to ensure the formation of the desired polymorph.

[0051] In some embodiments, the precipitation is carried out by (1) cooling a solution of Compound I in ethanol, (2) adding seed crystals 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 3-5 hours to precipitate Compound I-Form VII.

[0052] In some embodiments, MBTE can be added prior to adding seed crystals of Compound I-Form VII.

[0053] A method for preparing a crystalline solid form of Compound I is disclosed herein.Crystalline forms of the same compound typically have different properties, including hygroscopicity, solubility, and stability.Polymorphs with high melting points often have good thermodynamic stability, which is advantageous for extending the shelf life of formulations containing solid forms of the compound.Polymorphs with low melting points are typically not thermodynamically stable, but are preferred due to their increased aqueous solubility, often resulting in increased bioavailability of the compound.Weakly hygroscopic polymorphs are often more stable to heat and humidity and are resistant to deterioration during storage.Anhydrous polymorphs are often preferred because they can be consistently prepared with little or no change in composition due to variations in solvent and water content.

[0054] Compound I can be obtained in a solid crystalline form called Form VII. Form VII is an anhydrous form. Form VII, a polymorph of Compound I, is characterized by its XRPD and other data. Form VII of Compound I is a Cu-K α It is characterized by an X-ray powder diffraction diagram (XRPD) containing a peak at 16.5°±0.2°θ with respect to 2θ determined on a diffractometer using a radiation tube.

[0055] In some embodiments, Form VII of Compound I is characterized by an X-ray powder diffraction diagram (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 degrees in terms of two-theta, wherein each peak is a peak corresponding to a Cu—K α When determined with a diffractometer using a radiation tube, it is ±0.2°θ.

[0056] In some embodiments, Form VII of Compound I is characterized by an X-ray powder diffraction pattern (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 degrees in terms of two-theta, wherein each peak is a Cu—K α When determined with a diffractometer using a radiation tube, it is ±0.2°θ.

[0057] In some embodiments, Form VII of Compound I is characterized by an X-ray powder diffraction pattern (XRPD) comprising six 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 degrees in terms of two-theta, wherein each peak is a Cu—K α When determined with a diffractometer using a radiation tube, it is ±0.2°θ.

[0058] In some embodiments, Form VII of Compound I is characterized by an X-ray powder diffraction pattern (XRPD) comprising 10 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 degrees in terms of two-theta, wherein each peak is a Cu—K α ±0.2°θ as determined on a diffractometer using a radiation tube.

[0059] In some embodiments, Form VII of Compound I is characterized by an X-ray powder diffraction diagram (XRPD) comprising 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 degrees in terms of 2θ, each of which is a peak corresponding to a Cu—K α When determined with a diffractometer using a radiation tube, it is ±0.2°θ.

[0060] In some embodiments, Form VII of Compound I is Cu—K α It is characterized by an X-ray powder diffraction pattern (XRPD) substantially as shown in FIG. 1, as determined on a diffractometer using a radiation tube.

[0061] In some embodiments, Form VII of Compound I is characterized by a differential scanning calorimetry (DSC) thermogram pattern having an endothermic peak at a temperature of about 205°C.

[0062] In some embodiments, Form VII of Compound I is characterized by a differential scanning calorimetry (DSC) thermogram pattern substantially as shown in FIG.

[0063] In some embodiments, Form VII of Compound I is characterized by thermogravimetric analysis (TGA) substantially as shown in FIG.

[0064] In some embodiments, Form VII of Compound I has a molecular weight of about 3066 cm -1 and 1600 cm -1 It is characterized by an infrared (IR) spectrum that includes IR bands.

[0065] In some embodiments, Form VII of Compound I is characterized by an infrared (IR) spectrum substantially as shown in FIG.

[0066] In addition, in this specification, compound B [ka] and Compound C [ka] The present invention discloses intermediates useful for the synthesis of BET bromodomain inhibitors such as

[0067] In one embodiment, disclosed herein are methods for making therapeutic agents (compound I) that modulate or inhibit the activity of BET bromodomain-containing proteins, such as BRD2, BRD3, BRD4, and BRDT, which have the potential to cure, treat, or improve the lives of patients suffering from diseases mediated by bromodomain-containing proteins, such as certain cancers, inflammatory diseases, and cardiovascular diseases.

[0068] One embodiment is directed to a method of treating a disease mediated at least in part by a BET bromodomain-containing protein, comprising administering a therapeutically effective amount of crystalline Form VII of Compound I.

[0069] In one embodiment, the disease is selected from cancer, inflammatory disease, and cardiovascular disease.

[0070] In one embodiment, the disease is cancer, including B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, and neuroblastoma.

[0071] In one embodiment, the disease is prostate cancer.

[0072] In one embodiment, the disease is castration-resistant prostate cancer.

[0073] In one embodiment, the disease is metastatic castration-resistant prostate cancer.

[0074] In one embodiment, the disease is breast cancer.

[0075] In one embodiment, the disease is triple-negative breast cancer.

[0076] In one embodiment, the disease is estrogen receptor positive breast cancer.

[0077] In one embodiment, the subject is a human.

[0078] When treating a disease mediated at least in part by a BET bromodomain-containing protein in a subject in need thereof, the subject may benefit from combination drug therapy. For example, the forms of Compound I described herein may be combined with one or more therapeutic agents in a single composition or in separate compositions, which may be administered simultaneously, sequentially, or according to a particular treatment regimen.

[0079] In one embodiment, a form of Compound I described herein may be administered sequentially with an additional therapeutic agent. By sequential, it is meant that Compound I and the additional therapeutic agent or forms are administered separated in time by a few seconds (e.g., 15, 30, 45, 60 seconds or less), a few minutes (e.g., 1, 2, 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, a form of Compound I described herein and the additional therapeutic agent may be administered in two or more doses, may be contained in separate compositions or dosage forms, and may be contained in the same or different packages.

[0080] In one embodiment, a form of Compound I described herein may be combined with one or more therapeutic agents used to treat cancer.

[0081] In one embodiment, Compound I having Form VII described herein may be combined with one or more therapeutic agents used to treat cancer.

[0082] In one embodiment, Compound I having Form VII described herein may be combined with a therapeutic agent selected from an androgen receptor antagonist, an androgen synthesis inhibitor, an aromatase inhibitor, a selective estrogen receptor modulator, a selective estrogen down-regulator, a poly ADP-ribose polymerase (PARP) inhibitor, or an immunotherapeutic agent.

[0083] In one embodiment, Compound I having Form VII described herein may be combined with a therapeutic agent selected from abiraterone (Zytiga), enzalutamide (Xtandi), apalutamide (ARN-509, Erleada), darolutamide, fulvestrant, exemestane, talazoparib, olaperib, veliparib, rucaparib, talazoparib, niraparib, pembrolizumab, nivolumab, durvalumab, and rituximab.

[0084] A list of example embodiments includes: 1. A solid form of a compound having the formula: [ka] The solid form is crystalline. 2. The solid form of embodiment 1, which is anhydrous. 3. The solid form of embodiment 1, wherein the solid form is Form VII. It has three or more characteristic 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 4.2θ, and each peak corresponds to Cu-K α 4. The solid form of embodiment 3, wherein the θ is ±0.2°θ as determined by diffractometry using a radiation tube. It has six or more characteristic 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 5.2θ, and each peak corresponds to a Cu-K α4. The solid form of embodiment 3, wherein the θ is ±0.2°θ as determined by diffractometry using a radiation tube. 6. The solid form of any one of embodiments 1-3, having an XRPD pattern substantially similar to that shown in FIG. 7. The solid form of any one of embodiments 1-6, having a DSC thermogram pattern with an endothermic peak at a temperature of about 205°C. 8. The solid form of any one of embodiments 1-6, having a DSC thermogram substantially similar to that shown in FIG. 9. The solid form of any one of embodiments 1-7, having a TGA thermogram substantially similar to that shown in FIG. 10. A pharmaceutical composition comprising a solid form according to any one of embodiments 1 to 9 and at least one pharmaceutically acceptable carrier. 11. A method of treating cancer, comprising administering to a subject in need of such treatment a therapeutically effective amount of the solid form of any one of embodiments 1-9, or the pharmaceutical composition of embodiment 10. 12. The method of embodiment 11, wherein the cancer is B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, or neuroblastoma. 13. The method of embodiment 12, wherein the cancer is prostate cancer. 14. The method of embodiment 12, wherein the cancer is castration-resistant prostate cancer. 15. The method of embodiment 12, wherein the cancer is metastatic castration-resistant prostate cancer. 16. The method of embodiment 12, wherein the cancer is breast cancer. 17. The method of embodiment 12, wherein the cancer is triple-negative breast cancer. 18. The method of embodiment 12, wherein the cancer is estrogen receptor-positive breast cancer. 19. A method of treating an inflammatory disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of the solid form of any one of embodiments 1-9, or the pharmaceutical composition of embodiment 10. 20. A method for treating cardiovascular disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of the solid form of any one of embodiments 1-9, or the pharmaceutical composition of embodiment 10. 21. The method of embodiment 11, wherein the subject is a human. 22. A process for preparing Form VII of Compound I, comprising: [ka] A method comprising precipitating Form VII from a solution comprising Compound I and one or more solvents. 23. The method of embodiment 22, wherein the solvent is ethanol, t-butyl methyl ether (MTBE), or a mixture thereof. 24. Precipitation is (1) Cooling an ethanol solution of Compound I; (2) adding seed crystals of Compound I—Form VII to the solution; (3) Stir the mixture for about 10 hours, (4) The mixture is further cooled and MTBE is added; (5) The method of embodiment 22, wherein the method is carried out by stirring for about 3 to 5 hours to precipitate Compound I-Form VII. 25. The method of embodiment 24, wherein MTBE is added before adding seed crystals of Compound I—Form VII to the mixture. 26. A method for preparing compound I, comprising: [ka] Steps (a)~(d), (a) Compound C [ka] React with compound G [ka] Compound D is produced, [ka] (b) Compound D [ka] reacting with a first reagent to form compound E; [ka] (c) Compound E [ka] reacting with a chlorinating agent to form compound F; [ka] (d) Compound F [ka] reacting with methylamine. 27. The method of embodiment 26, wherein step (a) is carried out in the presence of a transition metal catalyst and a base. 28. The method of embodiment 27, wherein the transition metal catalyst is a palladium catalyst. 29. Palladium catalyst is Pd(PPh 3)4 29. The method of embodiment 28, wherein 30. The method of embodiment 27, wherein the base is an alkali metal carbonate. 31. The method of embodiment 27, wherein the base is K3PO4. 32. The method of embodiment 26, wherein the first reagent in step (b) is carbonyldiimidazole (CDI), and step (b) is carried out in a solvent. 33. The method of embodiment 32, wherein the solvent is an aprotic solvent. 34. The method of embodiment 32, wherein the solvent is DMSO. 35. The method of embodiment 32, wherein step (b) comprises adding water to the reaction mixture and precipitating compound E. 36. The method of embodiment 26, wherein step (c) is carried out in the presence of a base. 37. The chlorinating agent is phosphoryl chloride (POCl 3)37. The method of embodiment 36, wherein 38. The method of embodiment 36, wherein the base is N,N-diidopropylethylamine (DIPEA). 39. The method of embodiment 36, wherein 4-5 or 8-9 molar equivalents of POCl3 and 1.0-1.1 or 2.5 molar equivalents of DIPEA relative to compound E are used. 40. The method of embodiment 36, further comprising co-distilling with ethyl acetate before quenching the reaction with the NaHCO3 solution. 41. The method of embodiment 36, wherein compound F is isolated by crystallization from an ethyl acetate / n-heptane mixture. 42. The method of embodiment 26, wherein step (d) is carried out using 2M methylamine in THF. 43. The method of embodiment 26, wherein step (d) is carried out at 20-30°C. 44. The method of embodiment 26, wherein step (d) further comprises a reaction work-up comprising dissolving the crude product in aqueous HCl solution and washing with a non-polar solvent, followed by neutralization with aqueous NaOH solution. 45. The method of embodiment 26, wherein step (d) further comprises removing any remaining HCl and comprises dissolving the dried material in ethanol and treating with a solution of sodium hydroxide in ethanol, followed by adding water to precipitate the product. 46. ​​Compound C is (e) Compound B [ka] 27. The method of embodiment 26, wherein the compound is prepared by reacting with NaBH4 in a solvent. 47. The method of embodiment 46, wherein the solvent is an alcohol. 48. The method of embodiment 46, wherein the solvent is ethanol. 49. The method of embodiment 46, wherein 0.6 molar equivalents of NaBH4 relative to compound B are used. 50. The method of embodiment 46, further comprising work-up and isolation, comprising adding an HCl solution to quench the reaction, followed by adding water to precipitate compound C. 51. Compound B is Compound A is reacted with the compound A in the presence of an acid. [ka] 47. The method of embodiment 46, wherein the compound is prepared by reacting with benzaldehyde. 52. The method of embodiment 51, wherein the acid is acetic acid. 53. The method of embodiment 51, further comprising a solvent, wherein the solvent is methanol. 54. The method of embodiment 51, further comprising adding a NaHCO3 solution to the reaction mixture to precipitate compound B after the reaction is complete. [Example]

[0085] General Methods: FT-IR of Compound I was obtained on a Nicolet 380 FT-IR spectrophotometer. TGA analysis was performed on a TA Q5000 instrument thermogravimetric analyzer. DSC analysis was performed on a TA Q2000 instrument differential scanning calorimeter from 30 to 300 °C at 10 °C / min. XRPD patterns of Compound I were primarily obtained using the following settings: 40 KV, 40 mA, K a =1.5406A(Cu-K a NMR experiments were recorded on a Bruker Instruments D8 advance diffractometer or similar using a radiation tube, a scan scope of 4–40° 2θ, 15 rpm, and 10° / min.

[0086] Example 1: 5-Bromo-N 3- Synthesis of (phenylmethylene)pyridine-2,3-diamine (compound B) [ka]

[0087] 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 h, and benzaldehyde (56.4 g) was added dropwise over 2 h. Upon reaction completion (5-10 h), water (53 kg) was added over 2 h, and NaHCO3 solution (7% in water) was added dropwise over 2 h to maintain a low temperature (0-5°C). The mixture was stirred for 3 h. The solid was filtered, washed with 1:1 methanol / water, and then dried, leaving compound B in 94% yield and 99% purity by HPLC. 1 H-NMR (DMSO-d6): δ 8.75(1H), 8.04(2H), 7.93(1H), 7.65(1H), 7.50-7.60(3H). Example 2: N 3 Synthesis of -benzyl-5-bromopyridine-2,3-diamine (Compound C) [ka]

[0088] Compound B (17.1 kg) was dissolved in ethanol (140 kg) and NaBH4 (1.4 kg) was added in portions, maintaining the temperature at 15-25°C. The reaction mixture was stirred for 8-15 hours until the reaction was complete, as monitored by HPLC. HCl solution (2N, 12 kg) was added to adjust the pH to 6-7, followed by the dropwise addition of water (350 kg) over 5 hours, 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 solid was dried at approximately 60°C for 15-20 hours to give 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). Example 3: N 3 Synthesis of -benzyl-5(3,5-dimethyl-1,2-oxazol-4-yl)pyridine-2,3-diamine (Compound D) [ka]

[0089] Compound C (14.2 kg), compound G (14.8 kg), and potassium phosphate tribasic trihydrate (22.0 kg) were mixed, followed by the addition of 1,4-dioxane (145 kg) and water (28 kg) and stirring for 1–2 hours. The resulting mixture was thoroughly purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (2.9 kg) was added, and the solution was thoroughly purged with nitrogen and heated to 90–95°C until the ratio of compound C to compound D was 1% or less by HPLC (16–20 hours). After cooling to 20–30°C, the reaction mixture was filtered, the solid was 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, and the mixture was cooled to 20–25°C. The mixture was stirred for 1–2 hours until the amount of compound D remaining 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-butyl methyl ether (27 kg). The wet cake was mixed in methylene chloride (658 kg) at 40-45°C to dissolve all solids, 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-butyl methyl 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 with methylene chloride, t-butyl methyl ether, and until the moisture level was 0.5% or less to give 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 successive washes with 1,4-dioxane / water and MTBE is purified using an ethanol (5 vol) slurry at 30-40 °C for 1-3 h, followed by drying to a moisture level of 0.5% or less and an ethanol level of 0.5% or less. Example 4: Synthesis of 1-benzyl-6-(3,5-dimethyl-1,2-oxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-one (Compound E) [ka]

[0090] Solid carbonyldiimidazole (8.4 kg) was added to a stirred mixture of compound D (10.0 kg) and dimethyl sulfoxide (35 kg) (CDI can be added in portions). The mixture was heated at 35-40°C for 1-3 hours at 55-60°C or until the ratio of compound D to compound E was NMT 0.5%. 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. The dimethyl sulfoxide was verified to be NMT 0.5% before drying using heat and vacuum. Drying was complete when the moisture level was NMT 0.5%. Compound E was obtained. Yield: 9.8 kg, 94%, Purity: 99.9%. 1 H-NMR (DMSO-d6): δ 11.85(1H),7.90(1H),7.20-7.45(6H),5.05(2H),3.57(3H),2.35(3H),2.15(3H). Example 5: Synthesis of 4-[1-benzyl-2-chloro-1H-imidazo[4,5-b]pyridin-6-yl]-3,5-dimethyl-1,2-oxazole (Compound F) [ka]

[0091] Compound E (9.6 kg) and phosphorus oxychloride (40 kg) were mixed and then treated with diisopropylethylamine (DIPEA) (9.8 kg) dropwise at 50°C. The resulting mixture was heated to 95-100°C for 60-70 hours. After the reaction was complete, the mixture was concentrated and then cooled. Ethyl acetate was added, and the mixture was concentrated under vacuum three times and co-distilled with ethyl acetate. Ethyl acetate (EtOAc) (114 kg) was added to the concentrate, and the mixture was cooled to ambient temperature. It was then slowly added to aqueous sodium bicarbonate (7%), and the mixture was maintained at 15-25°C. The organic phase was separated, and the organic layer was washed twice with aqueous sodium bicarbonate (7%) and then with water. The organic phase was concentrated, ethyl acetate (288 kg) was added, and the mixture was concentrated to ensure the water 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). Example 6: 1-benzyl-6(3,5-dimethyl-1,2-oxazol-4yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2amine (Compound I) [ka]

[0092] Compound F (4.54 kg) was mixed with methylamine in tetrahydrofuran (THF) (31.9 kg, 2 M) and stirred at ambient temperature until the ratio of compound F to compound I was 0.1% NMT by HPLC. After completion of the reaction, the mixture was concentrated under vacuum, water (34 kg) was added dropwise to maintain ambient temperature, and the mixture was stirred for 1 to 1.5 hours. 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, and hydrochloric acid (36 kg, 35%) was added and stirred for 2 hours to dissolve the solids. The resulting solution was washed twice with methylene chloride to remove impurities. The aqueous solution was neutralized by adding sodium hydroxide solution (14.5 kg, 15%) dropwise over 1.5 hours and stirred for 5 hours. Compound I was isolated by filtration, washed with water, and dried under vacuum. If necessary to remove any residual hydrochloric acid, the dried material was dissolved in ethanol (13.4 kg), treated with a solution of sodium hydroxide 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.

[0093] Dry Compound I was dissolved in ethanol (16.2 kg), and the resulting solution was filtered in a clean room. The ethanol solution was azeotropically dried with absolute ethanol. The resulting mixture was heated to dissolve the product and concentrated. The mixture was heated to reflux to dissolve any solids and slowly cooled with seeding (Compound I - Form VII). 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. Solid XRPD indicated it was Form VII. T-butyl methyl 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 solid was filtered, washed with MTBE, and dried to give Compound I - Form VII (2.82 kg, 63%, purity >99%). 1H-NMR(DMSO-d6):δ 7.96(d,1H,J=2.0Hz),7.42(d,1H,J=2.0Hz),7.37(q,1H,J=4.2Hz),7.32(m,2H),7. 26(m,1H),7.24(m,2H),5.30(s,2H),3.00(d,3H,4.5Hz),2.34(s,3H),2.16(s,3H). C-NMR (DMSO-d): 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 may be added prior to seeding the mixture with Compound I - Form VII.

Claims

1. formula: 【Chemistry 1】 10. A solid form of a compound of formula: wherein said solid form is crystalline.

2. 10. The solid form of claim 1, which is anhydrous.

3. 2. The solid form of claim 1, wherein the solid form is Form VII.

4. It has three or more characteristic 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 degrees in terms of 2θ, each peak being a Cu—K α 4. The solid form of claim 3, having a refractive index of ±0.2°θ as determined on a diffractometer using a radiation tube.

5. It has six or more characteristic 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 degrees 2θ, each of which corresponds to a Cu—K α 4. The solid form of claim 3, having a refractive index of ±0.2°θ as determined on a diffractometer using a radiation tube.

6. 4. The solid form of any one of claims 1 to 3, having an XRPD pattern substantially similar to that shown in Figure 1.

7. 7. The solid form of any one of claims 1 to 6, having a DSC thermogram pattern with an endothermic peak at a temperature of about 205°C.

8. 8. The solid form of any one of claims 1 to 7, having a DSC thermogram substantially similar to that shown in Figure 2.

9. 9. The solid form of any one of claims 1 to 8, having a TGA thermogram substantially similar to that shown in Figure 3.

10. A pharmaceutical composition comprising the solid form of any one of claims 1 to 9 and at least one pharmaceutically acceptable carrier.

11. 11. A method for treating cancer, comprising administering to a subject in need of such treatment a therapeutically effective amount of the solid form of any one of claims 1 to 9, or the pharmaceutical composition of claim 10.

12. 12. The method of claim 11, wherein the cancer is B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, or neuroblastoma.

13. 13. The method of claim 12, wherein the cancer is prostate cancer.

14. 13. The method of claim 12, wherein the cancer is castration-resistant prostate cancer.

15. 13. The method of claim 12, wherein the cancer is metastatic castration-resistant prostate cancer.

16. 13. The method of claim 12, wherein the cancer is breast cancer.

17. 13. The method of claim 12, wherein the cancer is triple-negative breast cancer.

18. 13. The method of claim 12, wherein the cancer is estrogen receptor positive breast cancer.

19. 10. A method for treating an inflammatory disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a solid form according to any one of claims 1 to 9.

20. 10. A method for treating cardiovascular disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a solid form according to any one of claims 1 to 9.

21. The method of claim 11 , wherein the subject is a human.

22. 1. A method for preparing Form VII of crystalline Compound I, comprising: 【Chemistry 2】 A method comprising precipitating Form VII from a solution comprising Compound I and ethanol, t-butyl methyl ether (MTBE), or a mixture thereof.

23. The precipitate (1) cooling the ethanol solution of Compound I; (2) adding seed crystals of Compound I-Form VII to the solution; (3) stirring the mixture for about 10 hours; (4) further cooling the mixture and adding MTBE; (5) The method of claim 22, wherein the method is carried out by stirring for about 3 to 5 hours to precipitate Compound I-Form VII.

24. Compound I 【Transformation 3】 A method for preparing a compound comprising steps (a) to (d): (a) 【Chemistry 4】 to compound G: 【Transformation 5】 to give Compound D: 【Transformation 6】 Generate (b) Compound D: 【Transformation 7】 is reacted with a first reagent to produce compound E: 【Transformation 8】 Generate (c) Compound E: 【Chemistry 9】 is reacted with a chlorinating agent to produce compound F: 【Chemistry 10】 Generate (d) Compound F: 【Chemistry 11】 with methylamine.

25. 25. The method of claim 24, wherein step (a) is carried out in the presence of a transition metal catalyst and a base.

26. 26. The method of claim 25, wherein the transition metal catalyst is a palladium catalyst.

27. The palladium catalyst is Pd(PPh ３ ) ４ 27. The method of claim 26, wherein:

28. 26. The method of claim 25, wherein the base is an alkali metal carbonate.

29. The base is K ３ P.O. ４ 26. The method of claim 25, wherein:

30. 25. The method of claim 24, wherein the first reagent in step (b) is carbonyldiimidazole (CDI) and step (b) is carried out in a solvent.

31. 31. The method of claim 30, wherein the solvent is an aprotic solvent.

32. 31. The method of claim 30, wherein the solvent is DMSO.

33. 31. The method of claim 30, wherein step (b) comprises adding water to the reaction mixture and precipitating compound E.

34. 25. The method of claim 24, wherein step (c) is carried out in the presence of a base.

35. The chlorinating agent is phosphoryl chloride (POCl ３ 35. The method of claim 34, wherein

36. 35. The method of claim 34, wherein the base is N,N-diidopropylethylamine (DIPEA).

37. 8 to 9 molar equivalents of POCl relative to compound E ３ and 2.5 molar equivalents of DIPEA are used.

38. NaHCO ３ 35. The method of claim 34, further comprising co-distilling with ethyl acetate before quenching the reaction with the solution.

39. 35. The method of claim 34, wherein compound F is isolated by crystallization from an ethyl acetate / n-heptane mixture.

40. 25. The method of claim 24, wherein step (d) is carried out using 2M methylamine in THF.

41. 25. The method of claim 24, wherein step (d) is carried out at 20-30°C.

42. 25. The method of claim 24, wherein step (d) further comprises a reaction work-up comprising dissolving the crude product in aqueous HCl and washing with a non-polar solvent, followed by neutralization with aqueous NaOH solution.

43. 25. The method of claim 24, wherein step (d) further comprises removing any remaining HCl by dissolving the dried material in ethanol and treating with a solution of sodium hydroxide in ethanol, followed by the addition of water to precipitate the product.

44. Compound C is (e) Compound B: 【Chemistry 12】 in a solvent. ４ 25. The method of claim 24, wherein the compound is prepared by reacting

45. 45. The method of claim 44, wherein the solvent is an alcohol.

46. 45. The method of claim 44, wherein the solvent is ethanol.

47. 0.6 molar equivalents of NaBH relative to compound B ４ 45. The method of claim 44, wherein

48. 45. The method of claim 44, further comprising work-up and isolation comprising adding an HCl solution to quench the reaction, followed by the addition of water to precipitate compound C.

49. Compound B is (f) Compound A: 【Chemistry 13】 45. The method of claim 44, wherein the compound is prepared by reacting with benzaldehyde in the presence of an acid.

50. 50. The method of claim 49, wherein the acid is acetic acid.

51. 50. The method of claim 49, further comprising a solvent, wherein the solvent is methanol.

52. After the reaction is complete, NaHCO ３ 50. The method of claim 49, further comprising adding a solution to the reaction mixture to precipitate Compound B.

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