Crystalline form of compounds for targeted degradation of androgen receptors

Abstract

This disclosure provides a novel solid form of compound A, including its salt and the solid form: This disclosure relates to JPEG2026513793000093.jpg38170 and processes for their preparation. This disclosure also relates to pharmaceutical compositions containing at least one salt or salt form, as well as to the therapeutic and / or prophylactic use of such salts, salt forms, and compositions thereof.

Description

[Technical Field]

[0001] Related applications This application claims priority and interest to U.S. Provisional Application No. 63 / 493,245 filed on 30 March 2023, which is incorporated into this application by reference in its entirety for all purposes.

[0002] This disclosure relates to novel salts and salt forms of compound A: [ka] The disclosure also provides processes for the preparation thereof. The disclosure also relates to pharmaceutical compositions containing at least one salt or salt form, as well as the therapeutic and / or prophylactic use of such salts, salt forms, and compositions thereof. These salts and salt forms are useful as modifiers of targeted ubiquitination, and are particularly useful with respect to various polypeptides and other proteins that are degraded and / or otherwise inhibited by the salts and salt forms of the disclosure. [Background technology]

[0003] Most small molecule drugs bind to tight, well-defined pockets of enzymes or receptors. Protein-protein interactions, on the other hand, are known to be extremely difficult to target with small molecules, due to their large contact surfaces and the presence of shallow grooves or flat interfaces. E3 ubiquitin ligases (hundreds of which are known in humans) are attractive therapeutic targets because they confer substrate specificity to ubiquitination. The development of ligands for E3 ligases has proven difficult, for one thing, because they are supposed to inhibit protein-protein interactions. However, recent developments have yielded specific ligands that bind to these ligases.

[0004] One of the therapeutically relevant E3 ubiquitin ligases is cereblon. Cereblon is a protein encoded by the CRBN gene in humans. Thalidomide and its analogs, such as pomalidomide and lenalidomide, are known to bind to cereblon. These agents bind to cereblon, alter the specificity of the complex, and induce ubiquitination and degradation of transcription factors essential for the proliferation of multiple myeloma. Indeed, high expression of cereblon is associated with increased efficacy of imide drugs in the treatment of multiple myeloma.

[0005] The androgen receptor (AR) belongs to the nuclear hormone receptor family that is activated by androgens such as testosterone and dihydrotestosterone (Pharmacol Rev 2006, 58(4), 782 - 97; Vitam Horm 1999, 55: 309 - 52). In the absence of androgen, AR is bound by heat shock protein 90 (Hsp90) in the cytosol. When androgen binds to AR, its conformation changes, AR is released from Hsp90, and a nuclear localization signal (NLS) is exposed. The latter enables nuclear translocation of AR, where it acts as a transcription factor and promotes gene expression involved in male sexual characteristics (Endocr Rev 1987, 8(1): 1 - 28; Mol Endocrinol 2002, 16(10), 2181 - 7). AR deficiency causes androgen insensitivity syndrome, which was formerly called testicular feminization syndrome.

[0006] AR is involved in the development of male sexual characteristics and is also a well-established cancer gene in certain forms of cancer, including prostate cancer (Endocr. Rev. 2004, 25(2), 276 - 308). The target gene of AR activity that is commonly measured is the secreted prostate-specific antigen (PSA) protein. Current treatment regimens for prostate cancer involve inhibiting the androgen-AR axis in two ways. The first approach relies on reducing androgens, and the second strategy aims to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12, 823 - 824). Despite the development of effective targeted therapies, most patients develop resistance and the disease progresses. Alternative approaches for treating prostate cancer involve eliminating the AR protein.

[0007] Since AR is an important driver of tumorigenesis in many forms of prostate cancer, its elimination should lead to a beneficial response to treatment. In the art, there is a continuing need for effective treatments for diseases, particularly cancer, prostate cancer, and Kennedy disease.

[0008] However, non-specific effects and the inability to completely target and regulate certain classes of proteins, such as transcription factors, remain obstacles to the development of effective anti-cancer agents. Thus, small molecule therapeutics that are "tunable" to utilize or enhance the substrate specificity of cereblon while targeting and specifically regulating a broad range of protein classes would be highly useful as therapeutic agents. SUMMARY OF THE INVENTION

[0009] The present disclosure relates to Compound A:

Chemical formula

[0010] In some embodiments, the present disclosure relates to the free base form of Compound A.

[0011] In some embodiments, compound A is crystalline.

[0012] In some embodiments, compound A is amorphous.

[0013] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 18.6°2θ, 13.9°2θ, and 15.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0014] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 80 or Figure 86.

[0015] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41 XRPD signals selected from those listed in Table 1.

[0016] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 14.4°2θ, 19.1°2θ, and 15.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0017] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 87.

[0018] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 XRPD signals selected from those listed in Table 2.

[0019] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or more XRPD signals selected from the group consisting of 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, and 16.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0020] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 88.

[0021] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 XRPD signals selected from those listed in Table 3.

[0022] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 14.6°2θ, 17.7°2θ, and 16.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0023] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 89.

[0024] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 XRPD signals selected from those listed in Table 4.

[0025] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 14.9°2θ, 22.6°2θ, and 7.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0026] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 90.

[0027] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 XRPD signals selected from those listed in Table 5.

[0028] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 3.5°2θ, 3.6°2θ, and 15.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0029] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 91.

[0030] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 XRPD signals selected from those listed in Table 6.

[0031] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 4.8°2θ, 15.7°2θ, and 17.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0032] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 92.

[0033] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 XRPD signals selected from those listed in Table 7.

[0034] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 4.9°2θ, 15.9°2θ, and 18.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0035] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 93.

[0036] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 XRPD signals selected from those listed in Table 8.

[0037] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 17.2°2θ, 21.0°2θ, and 24.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0038] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 94.

[0039] In some embodiments, the solid form of compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 XRPD signals selected from those listed in Table 9.

[0040] In some embodiments, this disclosure relates to a tosylate of compound A.

[0041] In some embodiments, the tosylate is crystalline.

[0042] In some embodiments, the tosylate is amorphous.

[0043] In some embodiments, the tosylate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 3.5°2θ, 22.0°2θ, and 23.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0044] In some embodiments, the tosylate is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 95.

[0045] In some embodiments, the tosylate is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 XRPD signals selected from those listed in Table 10.

[0046] In some embodiments, the tosylate is a salt in which tosylate:compound A is in a 1:1 ratio.

[0047] In some embodiments, the tosylate is a salt in which tosylate:compound A is in a 2:1 ratio.

[0048] In some embodiments, the tosylate is a salt in which tosylate:compound A is in a 1:2 ratio.

[0049] In some embodiments, this disclosure relates to a phosphate of compound A.

[0050] In some embodiments, the phosphate is crystalline.

[0051] In some embodiments, the phosphate is amorphous.

[0052] In some embodiments, the phosphate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 23.6°2θ, 3.3°2θ, and 19.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0053] In some embodiments, the phosphate is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 96.

[0054] In some embodiments, the phosphate is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 XRPD signals selected from those listed in Table 11.

[0055] In some embodiments, the phosphate is a phosphate:compound A salt in a 1:1 ratio, i.e., a monophosphate of compound A.

[0056] In some embodiments, the phosphate is a salt of compound A in a phosphate:compound A ratio of 2:1, i.e., a diphosphate of compound A.

[0057] In some embodiments, the phosphate is a phosphate:compound A salt in a 1:1 ratio, or a phosphate:compound A salt in a 2:1 ratio.

[0058] In some embodiments, the phosphate is a salt of compound A in a phosphate:compound A ratio of 1:2, i.e., a hemiphosphate of compound A.

[0059] In some embodiments, this disclosure relates to a besylate of compound A.

[0060] In some embodiments, the besylate is crystalline.

[0061] In some embodiments, the besylate is amorphous.

[0062] In some embodiments, the besilate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 18.5°2θ, 18.3°2θ, and 22.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0063] In some embodiments, the besylate is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 97.

[0064] In some embodiments, the besylate is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 XRPD signals selected from those listed in Table 12.

[0065] In some embodiments, the besylate is a salt in which besylate:compound A is in a 1:1 ratio.

[0066] In some embodiments, the besylate salt is a salt in which besylate:compound A is in a 2:1 ratio.

[0067] In some embodiments, the besylate salt is a salt in which besylate:compound A is in a 1:2 ratio.

[0068] In some embodiments, this disclosure relates to a chloride salt of compound A.

[0069] In some embodiments, the chloride salt is a salt with a chloride:compound A ratio of 1:1.

[0070] In some embodiments, the chloride salt is a salt with a chloride:compound A ratio of 2:1.

[0071] In some embodiments, the chloride salt is a salt with a chloride:compound A ratio of 1:1 or a salt with a chloride:compound A ratio of 2:1.

[0072] In some embodiments, the chloride salt is a salt with a chloride:compound A ratio of 1:2.

[0073] In some embodiments, the Disclosure relates to a method for treating prostate cancer in a subject requiring treatment for prostate cancer, comprising administering a therapeutically effective amount of compound A in solid form or a salt thereof to the subject.

[0074] In some embodiments, the method further includes administering an effective dose of at least one additional anticancer agent to the subject.

[0075] In some embodiments, the prostate cancer is metastatic prostate cancer.

[0076] In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0077] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer.

[0078] In some embodiments, prostate cancer is castration-sensitive prostate cancer.

[0079] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer.

[0080] In some embodiments, prostate cancer has not been previously treated with second-generation antiandrogens. In some embodiments, prostate cancer has not been previously treated with either androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, prostate cancer has not been previously treated with androgen biosynthesis inhibitors. In some embodiments, prostate cancer has not been previously treated with androgen receptor blockers. In some embodiments, prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide. In some embodiments, the subject has not been previously administered second-generation antiandrogens. In some embodiments, the subject has not been previously administered either androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the subject has not been previously administered an androgen biosynthesis inhibitor. In some embodiments, the subject has not been previously administered an androgen receptor blocker. In some embodiments, the subjects have not been previously administered abiraterone acetate. In some embodiments, the subjects have not been previously administered an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0081] In some embodiments, the prostate cancer is novel hormone (NHA) naive. In some embodiments, the novel hormone (NHA) naive prostate cancer has not been previously treated with one or more second-generation antiandrogens. In some embodiments, the novel hormone (NHA) naive prostate cancer has not been previously treated with either an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the novel hormone (NHA) naive prostate cancer has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the novel hormone (NHA) naive prostate cancer has not been previously treated with an androgen receptor blocker. In some embodiments, the novel hormone (NHA) naive prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, the novel hormone (NHA) naive prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0082] In some embodiments, the prostate cancer is metastatic prostate cancer naive to novel hormones (NHAs). In some embodiments, metastatic prostate cancer naive to novel hormones (NHAs) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, metastatic prostate cancer naive to novel hormones (NHAs) has not been previously treated with either androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, metastatic prostate cancer naive to novel hormones (NHAs) has not been previously treated with androgen biosynthesis inhibitors. In some embodiments, metastatic prostate cancer naive to novel hormones (NHAs) has not been previously treated with androgen receptor blockers. In some embodiments, metastatic prostate cancer naive to novel hormones (NHAs) has not been previously treated with abiraterone acetate. In some embodiments, metastatic prostate cancer naive to novel hormonal agents (NHAs) has not been previously treated with androgen receptor blockers selected from enzalutamide, darolutamide, and apalutamide.

[0083] In some embodiments, the prostate cancer is castration-resistant prostate cancer naive to novel hormones (NHAs). In some embodiments, castration-resistant prostate cancer naive to novel hormones (NHAs) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, castration-resistant prostate cancer naive to novel hormones (NHAs) has not been previously treated with either androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, castration-resistant prostate cancer naive to novel hormones (NHAs) has not been previously treated with androgen biosynthesis inhibitors. In some embodiments, castration-resistant prostate cancer naive to novel hormones (NHAs) has not been previously treated with either androgen receptor blockers. In some embodiments, castration-resistant prostate cancer naive to novel hormones (NHAs) has not been previously treated with either androgen receptor blockers. In some embodiments, castration-resistant prostate cancer naive to novel hormonal agents (NHAs) has not been previously treated with androgen receptor blockers selected from enzalutamide, darolutamide, and apalutamide.

[0084] In some embodiments, the prostate cancer is castration-sensitive prostate cancer naive to novel hormones (NHAs). In some embodiments, castration-sensitive prostate cancer naive to novel hormones (NHAs) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, castration-sensitive prostate cancer naive to novel hormones (NHAs) has not been previously treated with either androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, castration-sensitive prostate cancer naive to novel hormones (NHAs) has not been previously treated with either androgen biosynthesis inhibitors. In some embodiments, castration-sensitive prostate cancer naive to novel hormones (NHAs) has not been previously treated with either androgen receptor blockers. In some embodiments, castration-sensitive prostate cancer naive to novel hormones (NHAs) has not been previously treated with either abiraterone acetate. In some embodiments, castration-sensitive prostate cancer naive to novel hormonal agents (NHAs) has not been previously treated with androgen receptor blockers selected from enzalutamide, darolutamide, and apalutamide.

[0085] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer naive to novel hormone agents (NHAs). In some embodiments, metastatic castration-resistant prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, metastatic castration-resistant prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with either androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, metastatic castration-resistant prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with androgen biosynthesis inhibitors. In some embodiments, metastatic castration-resistant prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with either androgen receptor blockers. In some embodiments, metastatic castration-resistant prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with either androgen receptor blockers. In some embodiments, metastatic castration-resistant prostate cancer naive to novel hormonal agents (NHAs) has not been previously treated with androgen receptor blockers selected from enzalutamide, darolutamide, and apalutamide.

[0086] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer naive to novel hormone agents (NHAs). In some embodiments, metastatic castration-sensitive prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with one or more second-generation antiandrogens. In some embodiments, metastatic castration-sensitive prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with either androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, metastatic castration-sensitive prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with androgen biosynthesis inhibitors. In some embodiments, metastatic castration-sensitive prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with either androgen receptor blockers. In some embodiments, metastatic castration-sensitive prostate cancer naive to novel hormone agents (NHAs) has not been previously treated with abiraterone acetate. In some embodiments, metastatic castration-sensitive prostate cancer naive to novel hormonal agents (NHAs) has not been previously treated with androgen receptor blockers selected from enzalutamide, darolutamide, and apalutamide.

[0087] In some embodiments, the second-generation antiandrogenic agent is an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0088] In some embodiments, the androgen biosynthesis inhibitor is abiraterone acetate.

[0089] In some embodiments, the androgen receptor blocker is selected from enzalutamide, darolutamide, and apalutamide.

[0090] Additional features, advantages, and aspects of this disclosure are shown or become apparent by considering the following detailed description, drawings, and claims. Furthermore, it should be understood that both the above summary of this disclosure and the following detailed description are illustrative and intended to provide further explanation without limiting the claimed scope of this disclosure. [Brief explanation of the drawing]

[0091] The accompanying drawings included to provide a further understanding of this disclosure are incorporated herein and constitute part of this specification, illustrate aspects of this disclosure, and, together with the detailed description, help to explain the principles of this disclosure. This patent or application document includes at least one drawing drawn in color. Copies of this patent or patent application publication including the color drawing(s) are available from the Patent Office upon request and payment of the necessary fees. [Figure 1] The XRPD pattern of compound A is shown. [Figure 2] The 1H-NMR spectrum of compound A recorded in DMSO-d6 is shown. [Figure 3] The 19F-NMR spectrum of compound A recorded in DMSO-d6 is shown. [Figure 4] The TG / DSC thermogram of compound A is shown. [Figure 5] The DSC thermogram of compound A (after the first heating cycle) is shown. [Figure 6] The DSC thermogram of compound A (after the first cooling cycle) is shown. [Figure 7] The DSC thermogram of compound A (second heating cycle) is shown. [Figure 8] The DSC thermogram of compound A (second cooling cycle) is shown. [Figure 9] The VT-XRPD pattern of compound A is shown. [Figure 10] The DVS isotherm plot for compound A is shown. [Figure 11] The DVS reaction kinetics plot for compound A is shown. [Figure 12] The image shows an overlay of the XRPD pattern of compound A (top) and the XRPD pattern of compound A after DVS analysis (bottom). [Figure 13] The TG / DSC thermogram of compound A is shown. [Figure 14] DCM: Shows the FT-IR spectrum of potential chloride pattern 2 from methanol (50:50% v / v). [Figure 15] This shows the TG / DSC thermogram of potential chloride pattern 2 from DCM. [Figure 16] DCM: Shows the TG / DSC thermogram of potential chloride pattern 2 from methanol (50:50% v / v). [Figure 17] The FT-IR spectrum of tosylate pattern 1 from THF is shown. [Figure 18] This shows a TG / DSC thermogram of tosylate pattern 1 from THF. [Figure 19] The 1H-NMR spectrum of tosylate pattern 1 from THF recorded in DMSO-d6 is shown. [Figure 20] THF: The FT-IR spectrum of besylate pattern 1 from water (98:2% v / v) is shown. [Figure 21] THF: Shows a TG / DSC thermogram of besylate pattern 1 from water (98:2% v / v). [Figure 22] The 1H-NMR spectrum of besylate pattern 1 from THF:water (98:2% v / v) recorded in DMSO-d6 is shown. [Figure 23] THF: Shows the FT-IR spectrum of phosphate pattern 1 from water (98:2% v / v). [Figure 24] THF: Shows a TG / DSC thermogram of phosphate pattern 1 from water (98:2% v / v). [Figure 25] The 1H-NMR spectrum of phosphate pattern 1 from THF:water (98:2% v / v) recorded in DMSO-d6 is shown. [Figure 26]The 31P-NMR spectrum of phosphate pattern 1 from THF:water (98:2% v / v) recorded in DMSO-d6 is shown. [Figure 27] The TG / DSC thermogram of amorphous chloride is shown. [Figure 28] This shows the DSC thermogram of amorphous chloride (first heating cycle). [Figure 29] This shows the DSC thermogram (cooling cycle) of amorphous chloride. [Figure 30] This shows the DSC thermogram of amorphous chloride (second heating cycle). [Figure 31] The additional DSC thermogram for amorphous chloride (first heating cycle) is shown. [Figure 32] The additional DSC thermogram (cooling cycle) for amorphous chloride is shown. [Figure 33] The additional DSC thermogram for amorphous chloride (second heating cycle) is shown. [Figure 34] The image shows the free base pattern 9 (top) from 1,4-dioxane / L-histidine, the free base pattern 4 (middle) after storage at 40°C / 75%RH, and an overlay of the XRPD pattern of the free base pattern 4 (bottom). [Figure 35] The TG / DSC thermogram for free base pattern 9 is shown. [Figure 36] The overlays of XRPD patterns of acetonitrile and anisole crystallization screening samples before and after temperature cycling are shown. [Figure 37] The overlays of XRPD patterns of ethyl formate and isopropyl acetate crystallization screening samples before and after temperature cycling are shown. [Figure 38] The overlays of XRPD patterns of THF and toluene crystallization screening samples before and after temperature cycling are shown. [Figure 39] The TG / DSC thermogram of free base pattern 1 from 2-ethoxyethanol is shown. [Figure 40]The FT-IR spectrum of free base pattern 1 from THF is shown. [Figure 41] DCM: Shows the TG / DSC thermogram of free base pattern 2 from methanol (50:50% v / v). [Figure 42] DCM: The FT-IR spectrum of free base pattern 2 from methanol (50:50% v / v) is shown. [Figure 43] The TG / DSC thermogram of free base pattern 3 from 1,4-dioxane and succinic acid is shown. [Figure 44] The FT-IR spectra of free base pattern 3 from 1,4-dioxane and hydrochloric acid are shown. [Figure 45] The TG / DSC thermogram of free base pattern 4 from 1,4-dioxane and malonic acid is shown. [Figure 46] The FT-IR spectra of free base pattern 4 from 1,4-dioxane and benzoic acid are shown. [Figure 47] The TG / DSC thermogram of free base pattern 6 from DCM after temperature cycling is shown. [Figure 48] The FT-IR spectrum of free base pattern 6 from DCM after temperature cycling is shown. [Figure 49] The TG / DSC thermogram of free base pattern 8 from anisole is shown. [Figure 50] The TG / DSC thermogram of the free base pattern 8 (further dried) from anisole is shown. [Figure 51] The TG / DSC thermogram of free base pattern 8 from toluene is shown. [Figure 52] The FT-IR spectrum of free base pattern 8 from anisole is shown. [Figure 53] The FT-IR spectrum of free base pattern 8 from toluene is shown. [Figure 54] The TG / DSC thermogram for free base pattern 1 is shown. [Figure 55] The 1H-NMR spectrum of free base pattern 1, recorded in DMSO-d6, is shown. [Figure 56] This shows the DSC thermogram of free base pattern 1 (first heating cycle). [Figure 57] This shows the DSC thermogram (cooling cycle) for free base pattern 1. [Figure 58] This shows the DSC thermogram of free base pattern 1 (second heating cycle). [Figure 59] This shows a modulated DSC thermogram of a 3-gram batch of free base pattern 1. [Figure 60] The DVS isotherm plot for free base pattern 1 is shown. [Figure 61] The DVS reaction kinetics plot for free base pattern 1 is shown. [Figure 62] The image shows an overlay of the XRPD pattern of free base pattern 1 (top) and the XRPD pattern of free base pattern 1 after DVS analysis (bottom). [Figure 63] The TG / DSC thermogram for free base pattern 2 is shown. [Figure 64] The 1H-NMR spectrum of free base pattern 2 recorded in DMSO-d6 is shown. [Figure 65] The TG / DSC thermogram for free base pattern 6 is shown. [Figure 66] The 1H-NMR spectrum of free base pattern 6 recorded in DMSO-d6 is shown. [Figure 67] The 1H-NMR spectrum of free base pattern 1, recorded in DMSO-d6 after heating to 250°C, is shown. [Figure 68] The 1H-NMR spectrum of tosylate pattern 1 recorded in DMSO-d6 is shown. [Figure 69] The TG / DSC thermogram for tosylate pattern 1 is shown. [Figure 70] The 1H-NMR spectrum of besylate pattern 1 recorded in DMSO-d6 is shown. [Figure 71] The TG / DSC thermogram for besylate pattern 1 is shown. [Figure 72] The 1H-NMR spectrum of phosphate pattern 1 recorded in DMSO-d6 is shown. [Figure 73] The 31P-NMR spectrum of phosphate pattern 1 recorded in DMSO-d6 is shown. [Figure 74] The TG / DSC thermogram for phosphate pattern 1 is shown. [Figure 75] The XRPD pattern overlay of free base pattern 1 after stability analysis is shown. [Figure 76] The XRPD pattern overlay of free base pattern 2 after stability analysis is shown. [Figure 77] This shows an overlay of the XRPD pattern of tosylate pattern 1 after stability analysis. [Figure 78] This shows an overlay of the XRPD pattern of besylate pattern 1 after stability analysis. [Figure 79] This shows an overlay of the XRPD pattern when attempting to scale up from ethanol. [Figure 80] The XRPD pattern of the scale-up batch of free base pattern 1 is shown. [Figure 81] The 1H-NMR spectrum of a 3-gram batch of free base pattern 1, recorded in DMSO-d6, is shown. [Figure 82] The TG / DSC thermogram of a 3-gram batch of free base pattern 1 is shown. [Figure 83] This shows the DSC thermogram (first heating cycle) of a 3-gram batch of free base pattern 1. [Figure 84] This shows the DSC thermogram (cooling cycle) of a 3-gram batch of free base pattern 1. [Figure 85] This shows the DSC thermogram (second heating cycle) of a 3-gram batch of free base pattern 1. [Figure 86] The XRPD pattern of free base pattern 1 is shown. [Figure 87] The XRPD pattern for free base pattern 2 is shown. [Figure 88] The XRPD pattern for free base pattern 3 is shown. [Figure 89] The XRPD pattern for free base pattern 4 is shown. [Figure 90] The XRPD pattern for free base pattern 5 is shown. [Figure 91] The XRPD pattern of free base pattern 6 is shown. [Figure 92] The XRPD pattern of free base pattern 7 is shown. [Figure 93] The XRPD pattern of free base pattern 8 is shown. [Figure 94] The XRPD pattern for free base pattern 9 is shown. [Figure 95] The XRPD pattern of tosylate pattern 1 is shown. [Figure 96] The XRPD pattern for phosphate pattern 1 is shown. [Figure 97] The XRPD pattern of besylate pattern 1 is shown. [Modes for carrying out the invention]

[0092] This disclosure provides salt and polymorphic salt forms of compound A that are useful in the preparation of pharmaceuticals and / or as pharmaceuticals. In some embodiments, one or more of the salts and / or salt forms described herein can be formulated into pharmaceutical compositions.

[0093] definition Compound A of the present disclosure is 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-N-((S)-2,6-dioxopiperidine-3-yl)-2-fluorobenzamide, and has the following structure: [ka]

[0094] In some embodiments, compound A may be prepared as described in U.S. Patent Application Publication No. 2021 / 0196710A1, which is incorporated herein by reference.

[0095] The terms “powder X-ray diffraction pattern,” “PXRD pattern,” “powder X-ray diffraction pattern,” and “XRPD pattern” are used interchangeably and refer to experimentally observed diffractograms or parameters derived therefrom. Powder X-ray diffraction patterns are typically characterized by peak positions (horizontal coordinates) and peak intensities (vertical coordinates). The term “peak intensity” refers to the relative signal intensity within a given X-ray diffraction pattern. Factors that can affect relative peak intensity include the thickness of the sample and preferred orientation (i.e., whether the crystal grains are randomly distributed). As used herein, the term “peak position” refers to the X-ray reflection position measured and observed in a powder X-ray diffraction experiment. Peak positions are directly related to the dimensions of the unit cell. Peaks are identified by their respective peak positions and extracted from the diffraction patterns of various polymorphic forms of salts of compound A.

[0096] The terms “2-theta value,” “2θ,” “2 θ,” “°2θ,” or “°2 θ” refer to the peak position expressed in degrees, based on the experimental setup of an X-ray diffraction experiment, and are the common transverse coordinate units in diffraction patterns. Generally, in an experimental setup, if reflection is diffracted when the incident beam forms an angle theta (θ) with a particular lattice plane, the reflected beam should be recorded at an angle of 2-theta (2 θ). When a specific 2θ value for a particular polymorph is referred to herein, it should be understood that this refers to the 2θ value (in degrees) measured using the X-ray diffraction experimental conditions described herein.

[0097] "Preferred orientation effects" refer to variations in peak intensity or relative intensity differences between different PXRD measurements of the same sample, which may be due to particle orientation. While we do not wish to be bound by theory, in PXRD, it is sometimes desirable to have a sample with randomly oriented particles (e.g., powder). However, achieving truly random particle orientation in practice can be difficult, or in some cases impossible. As particle size increases, the randomness of particle orientation decreases, and the challenge of preferred orientation may increase. While we do not wish to be bound by theory, reducing particle size can mitigate the technical challenges associated with preferred orientation, allowing for more accurate peak representation. However, those skilled in the art will understand how to reduce or mitigate preferred orientation effects and will recognize that preferred orientation effects may exist even between two different measurements of the same sample. For example, in some embodiments, differences in resolution or relative peak intensity may be due to preferred orientation effects.

[0098] As used herein, the term “substantially pure” with respect to a particular salt (or mixture of two or more salts) of a compound means that the salt (or mixture) contains impurities, including other salt forms of the compound, in amounts less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.2% by weight, or less than 0.1% by weight. Such purity can be determined, for example, by powder X-ray diffraction.

[0099] As used herein, the terms “polymorph” or “salt form” refer to different crystalline forms of the same compound, as well as other solid-state molecular forms of the same compound, including pseudopolymorphs such as hydrates (e.g., those bound with water present in the crystal structure) and solvates (e.g., those bound with solvents other than water). Different crystalline polymorphs result in different crystalline structures due to different packing of molecules within the lattice. This results in different crystal symmetry and / or unit cell parameters, which directly affect physical properties such as the X-ray diffraction characteristics of the crystal or powder. For example, different polymorphs generally diffract at different sets of angles and yield different intensity values. Therefore, powder X-ray diffraction can be used to identify solid morphologies containing different polymorphs or multiple polymorphs in a reproducible and reliable manner (S. Byrn et al, Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations, Pharmaceutical research, Vol. 12, No. 7, p. 945-954, 1995; JK Haleblian and W. McCrone, Pharmaceutical Applications of Polymorphism, Journal of Pharmaceutical Sciences, Vol. 58, No. 8, p. 91-929, 1969).

[0100] Crystalline polymorphisms are of interest to the pharmaceutical industry and, in particular, to those involved in the development of suitable dosage forms. If polymorphisms are not kept constant during clinical or stability studies, it may be impossible to compare the exact dosage form used or studied between lots. Furthermore, since present impurities can cause undesirable toxic effects, it is desirable to have a process for producing compounds with selected polymorphisms in high purity when the compound is used in clinical studies or commercial products. Certain polymorphisms may be more suitable for inclusion in pharmaceutical formulations because they may offer improved thermodynamic stability or be easier to produce in large quantities and with high purity. Certain polymorphs may exhibit other advantageous physical properties, such as the absence of hygroscopic tendencies due to different lattice energies, improved solubility, and increased dissolution rates.

[0101] The term "amorphous" refers to any solid material that (i) lacks three-dimensional order, or (ii) exhibits less than three-dimensional order, order only in the range of short distances (e.g., less than 10 Å), or both. Therefore, amorphous materials include partially crystalline materials and crystalline intermediate phases, such as those with one- or two-dimensional translational order (liquid crystals), orientation disorder (orientation disorder crystals), or stereochemical disorder (stereochemical disorder crystals). Amorphous solids can be characterized by known techniques, including powder X-ray diffraction (PXRD) crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or a combination of these techniques. Amorphous solids typically give a diffuse PXRD pattern consisting of one or two broad peaks (i.e., peaks with a base width of approximately 5°²θ or greater).

[0102] The term "crystalline" refers to any solid material that exhibits three-dimensional order, giving it a distinctive PXRD pattern with clearly defined peaks, in contrast to amorphous solids.

[0103] The term "ambient temperature" refers to the temperature conditions typically encountered in a laboratory environment. This includes an approximate temperature range of about 20°C to 30°C.

[0104] The term "detectable amount" refers to an amount or amount per unit volume that can be detected using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, HPLC, Fourier transform infrared spectroscopy (FT-IR), and Raman spectroscopy.

[0105] The term "solvate" refers to a molecular complex containing a drug substance and one or more solvent molecules (e.g., ethanol) in stoichiometric or non-stoichiometric amounts. When the solvent is tightly bound to the drug, the resulting complex has a clearly defined stoichiometricity that is independent of humidity. However, when the solvent is weakly bound, as in the case of channel solvates and hygroscopic compounds, the solvent content depends on humidity and dehydration conditions. In such cases, the complex may be non-stoichiometric.

[0106] The term "hydrate" refers to a solvate containing a drug substance in a stoichiometric or non-stoichiometric amount of water.

[0107] The term "relative humidity" refers to the ratio of the amount of water vapor in the air at a given temperature to the maximum amount of water vapor that can be held at that temperature and pressure, and is expressed as a percentage.

[0108] The term "relative intensity" refers to the intensity value obtained from the X-ray diffraction pattern of the feed. A value of 100 is assigned to the entire y-coordinate range scale of the diffraction pattern. On this intensity scale, peaks with intensities between approximately 50% and 100% are called very strong (vs), and peaks with intensities between approximately 50% and 25% are called strong (s). Additional weaker peaks are present in typical diffraction patterns and are characteristic of a given polymorphism, and these additional peaks are called moderate (m), weak (w), and very weak (vw).

[0109] The term "slurry" refers to a solid substance suspended in a liquid medium, typically water or an organic solvent.

[0110] The term "under vacuum" refers to the typical pressure obtained by an oil- or oil-free diaphragm vacuum pump used in a laboratory setting.

[0111] The term "pharmaceutical composition" refers to a composition comprising one or more polymorphic forms of a salt of compound A as described herein, and other chemical components, e.g., physiologically / pharmaceutically acceptable carriers, diluents, vehicles, and / or excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to living organisms such as humans or other mammals.

[0112] The terms “pharmaceutically acceptable,” “carrier,” “diluent,” “vehicle,” or “excipient” refer to any material(s) that may be included with a particular drug to form a pharmaceutical composition, and which may be solid or liquid. Exemplary solid carriers include lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Exemplary liquid carriers include syrup, peanut oil, olive oil, and water. Similarly, carriers or diluents may include, for example, glyceryl monostearate or glyceryl distearate alone or with wax, ethylcellulose, hydroxypropyl methylcellulose, and methyl methacrylate, which are time-delayed or time-release materials known in the art.

[0113] As used herein, the term “to treat” means, unless otherwise indicated, to reverse, alleviate, or prevent the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term “treatment” means, unless otherwise indicated, the act of “to treat” as defined immediately prior to it. For example, the terms “to treat,” “to treat,” and “treatment” may refer to a method of alleviating or suppressing one or more of a particular disorder and / or its associated symptoms.

[0114] As used herein, “subject” means human or animal (in the case of an animal, the subject may be a mammal). In one embodiment, the subject is human. In one embodiment, the subject is male.

[0115] Prostate cancer is the uncontrolled proliferation of cancerous cells in the prostate gland. In some embodiments, prostate cancer is metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, prostate cancer naive to novel hormones (NHA), metastatic prostate cancer naive to novel hormones (NHA), castration-resistant prostate cancer naive to novel hormones (NHA), metastatic castration-resistant prostate cancer naive to novel hormones (NHA), castration-sensitive prostate cancer naive to novel hormones (NHA), or metastatic castration-sensitive prostate cancer naive to novel hormones (NHA).

[0116] Metastatic prostate cancer, or metastatic cancer, refers to prostate cancer that has spread beyond the prostate to other parts of the body, such as the bones, lymph nodes, liver, lungs, or brain.

[0117] Castrate-resistant prostate cancer (or castration-resistant prostate cancer) is a type of prostate cancer that continues to grow even when the amount of testosterone in the body is very low.

[0118] Metastatic castration-resistant prostate cancer is a type of prostate cancer that has metastasized and continues to grow even when the amount of testosterone in the body has dropped to very low levels.

[0119] Castrate-sensitive prostate cancer (CSPC), or castration-sensitive prostate cancer, is a type of prostate cancer that can be controlled by reducing the amount of androgens (male hormones) in the body (e.g., through castration) and / or requires androgens to grow, and whose growth stops in the absence of androgens. CSPC is also called androgen-dependent prostate cancer, androgen-sensitive prostate cancer, or hormone-sensitive prostate cancer (HSPC).

[0120] Metastatic castration-sensitive prostate cancer is a type of castration-sensitive prostate cancer that has metastasized, requires androgens to grow, and can be controlled by stopping growth in the absence of androgens or by reducing the amount of androgens in the body (e.g., through castration).

[0121] Prostate cancer naive to novel hormonal agents (NHAs) is prostate cancer that has not been previously treated with one or more second-generation antiandrogens, e.g., androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the androgen biosynthesis inhibitor is abiraterone (e.g., abiraterone acetate). In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0122] Metastatic prostate cancer naive to novel hormonal agents (NHAs) is metastatic prostate cancer that has not been previously treated with second-generation antiandrogens, such as androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the androgen biosynthesis inhibitor is abiraterone (e.g., abiraterone acetate). In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0123] Novel hormone (NHA)-naive castration-resistant prostate cancer is castration-resistant prostate cancer that has not been previously treated with second-generation antiandrogens, such as androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the androgen biosynthesis inhibitor is abiraterone (e.g., abiraterone acetate). In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0124] Novel hormone (NHA)-naive castration-sensitive prostate cancer is castration-sensitive prostate cancer that has not been previously treated with second-generation antiandrogens, such as androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the androgen biosynthesis inhibitor is abiraterone (e.g., abiraterone acetate). In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0125] Metastatic castration-resistant prostate cancer naive to novel hormonal agents (NHAs) is metastatic castration-resistant prostate cancer that has not been previously treated with second-generation antiandrogens, such as androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the androgen biosynthesis inhibitor is abiraterone (e.g., abiraterone acetate). In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0126] Novel hormonal agent (NHA)-naive metastatic castration-sensitive prostate cancer is metastatic castration-sensitive prostate cancer that has not been previously treated with second-generation antiandrogens, such as androgen biosynthesis inhibitors or androgen receptor blockers. In some embodiments, the androgen biosynthesis inhibitor is abiraterone (e.g., abiraterone acetate). In some embodiments, the androgen receptor blocker is enzalutamide, darolutamide, or apalutamide.

[0127] As used herein, the term “anticancer agent” is used to refer to an anticancer agent, or a therapeutic agent administered concurrently with an anticancer agent (e.g., palonosetron), and together with these, the compounds of this disclosure may be co-administered and / or co-formulated to treat cancer and side effects associated with cancer treatment. These drugs include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, CDK inhibitors, and EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexed, azd2171, batablin, ofatumumab, zanorimumab, edtecalin, tetrandrin, rubican, tesmirifen, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Jaimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Lucanton, LY317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin,5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Sericiclib, PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, Disodium Salt, Heptahydrate, Camptothecin, PEG-labeled Irinotecan, Tamoxifen, Toremifene Citrate, Anastrozole, Exemestane, Letrozole, DES (Diethyl Stilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258), 3-[5-(methylsulfonylpiperazine methyl)-indolyl-quinolone, batalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptrelyn pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714, T AK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ronafarnib, BMS-214662, tipifurnib, amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrin, anagrelide, L-asparaginase, Calmette-Guérin (BCG) vaccine, Adriamycin, Bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisol, lomustine, mechloretamine, melphalan, 6-mercaptopurine, mesna,Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronic acid, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-cis-retinoic acid, Phenylalamine Nin mustard, uracil mustard, estramustine, altoretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mechatoprine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimustate, COL-3, neovastat, BMS-275291, squalane Min, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxyfene, Spironolactone, Finasteride, Cimetidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezimib, Paclitaxel, Cremophorfly - Paclitaxel, Docetaxel, Epithilone B, BMS-247550, BMS-310705, Doroxifen, 4-Hydroxytamoxifen, Pipendoxifen, ERA-923, Alzoxifen, Fulvestrant, Acorbifen, Lasofoxifen, Idoxifen, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, woltmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin,Pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans-retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab (tiuxetan), androgen, decitabine, hexamethylmelamine, bexarotene, tocitumomab, arsenic trioxide, cortisone, erythrocyte Examples include editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netsupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. In one embodiment, the anticancer agent is selected from the group consisting of abiraterone, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, and zoledronic acid. In another embodiment, the anticancer agent is selected from the group consisting of FLT-3 inhibitors, androgen receptor inhibitors, VEGFR inhibitors, EGFR TK inhibitors, aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, IGFR TK inhibitors, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase inhibitors, VEGF trap antibodies, and chemical castration agents.

[0128] In some embodiments, anticancer agents include temozolomide, capecitabine, irinotecan, tamoxifen, anastrazole, ecmestane, letrozole, DES, estradiol, estrogen, bevacizumab, goserelin acetate, leuprolide acetate, triptrelympamoate, medroxyprogesterone acetate, hydroprogesterone caproate, raloxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vinblastine, vinorelbine, topotecan, finasteride, aldoxifen, fulvestrant, prednisone, abiraterone, enzalutamide, apalutamide, darolutamide, ciplucel-T, pembrolizumab, nivolumab, semiplimab, and atezolizumab (Tecentriq). The following are selected from the group consisting of avelumab (Bavencio), durvalumab (Imfinzi), docetaxel (Taxotere), cabazitaxel (Jevtana), mitoxantrone (Novantrone), estramustine (Emcyt), docetaxel, ketoconazole, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, and zoledronic acid.

[0129] The term “approximately” is used herein to mean roughly, within a range, nearly, or near. When the term “approximately” is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the numerical value described. Generally, the term “approximately” is used herein to modify numerical values ​​above and below a specified value by a 20% variation, a 10% variation, a 5% variation, a 3% variation, or a 1% variation. When used in the context of XRPD peak values, the term “approximately” may indicate a peak value of ±0.20, ±0.15, ±0.10, ±0.05, or ±0.01°2θ. In some embodiments, when used in the context of XRPD peak values, “approximately” may indicate a peak value that substantially exactly matches the disclosed peak value.

[0130] The crystalline form of compound A. As shown below, compound A can form salts with various acids. In some embodiments, the salts of compound A described herein exist in various crystalline forms. All PXRD peaks described herein are indicated at °2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). Furthermore, all PXRD spectra are obtained using Cu Kα1 X-rays at a wavelength of 1.5406 Å.

[0131] Compound A free base pattern 1 In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 1. In some embodiments, the XRPD profile of compound A free base pattern 1 is substantially similar to that shown in Figure 80 or Figure 86. In some embodiments, the FT-IR spectrum of compound A free base pattern 1 is substantially similar to that shown in Figure 40. In some embodiments, the free base pattern of compound A 1 The 1H NMR spectrum is substantially similar to that shown in Figure 55 or Figure 81. In some embodiments, the TGA profile of compound A free base pattern 1 is substantially similar to that shown in Figures 13, 39, 54, or 82. In some embodiments, the DSC profile of compound A free base pattern 1 is substantially similar to that shown in Figures 13, 39, 54, or 82.

[0132] In some embodiments, the solid form of compound A free base pattern 1 is a crystalline compound A free base pattern 1 characterized by two or three XRPD signals selected from the group consisting of 18.6°2θ, 13.9°2θ, and 15.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0133] In some embodiments, the solid form of compound A free base pattern 1 is a crystalline compound A free base pattern 1 characterized by two or more XRPD signals selected from the group consisting of 18.6°2θ, 13.9°2θ, 15.3°2θ, 16.3°2θ, and 16.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 1 is a crystalline compound A free base pattern 1 characterized by XRPD signals at 18.6°2θ, 13.9°2θ, 15.3°2θ, 16.3°2θ, and 16.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0134] In some embodiments, the solid form of compound A free base pattern 1 is a crystalline compound A free base pattern 1 characterized by two or more XRPD signals selected from the group consisting of 18.6°2θ, 13.9°2θ, 15.3°2θ, 16.3°2θ, 16.0°2θ, 24.2°2θ, and 20.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 1 is a crystalline compound A free base pattern 1 characterized by XRPD signals at 18.6°2θ, 13.9°2θ, 15.3°2θ, 16.3°2θ, 16.0°2θ, 24.2°2θ, and 20.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0135] In some embodiments, the solid form of compound A free base pattern 1 is a crystalline compound A free base pattern 1 characterized by two or more XRPD signals selected from the group consisting of 18.6°2θ, 13.9°2θ, 15.3°2θ, 16.3°2θ, 16.0°2θ, 24.2°2θ, 20.8°2θ, 22.5°2θ, 14.9°2θ, and 3.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 1 is a crystalline compound A free base pattern 1 characterized by XRPD signals at 18.6°2θ, 13.9°2θ, 15.3°2θ, 16.3°2θ, 16.0°2θ, 24.2°2θ, 20.8°2θ, 22.5°2θ, 14.9°2θ, and 3.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0136] In some embodiments, the free base pattern 1 of crystalline compound A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41 XRPD signals selected from those listed in Table 1. [Table 1-1] [Table 1-2]

[0137] Compound A free base pattern 2 In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 2. In some embodiments, the XRPD profile of compound A free base pattern 2 is substantially similar to that shown in Figure 87. In some embodiments, the FT-IR spectrum of compound A free base pattern 2 is substantially similar to that shown in Figure 42. In some embodiments, the free base pattern of compound A 1 The 1H NMR spectrum is substantially similar to that shown in Figure 64. In some embodiments, the TGA profile of compound A free base pattern 2 is substantially similar to that shown in Figure 41 or Figure 63. In some embodiments, the DSC profile of compound A free base pattern 2 is substantially similar to that shown in Figure 41 or Figure 63.

[0138] In some embodiments, the solid form of compound A free base pattern 2 is a crystalline compound A free base pattern 2 characterized by two or three XRPD signals selected from the group consisting of 14.4°2θ, 19.1°2θ, and 15.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0139] In some embodiments, the solid form of compound A free base pattern 2 is a crystalline compound A free base pattern 2 characterized by two or more XRPD signals selected from the group consisting of 14.4°2θ, 19.1°2θ, 15.8°2θ, 16.2°2θ, and 23.5°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0140] In some embodiments, the solid form of compound A free base pattern 2 is a crystalline compound A free base pattern 2 characterized by two or more XRPD signals selected from the group consisting of 14.4°2θ, 19.1°2θ, 15.8°2θ, 16.2°2θ, 23.5°2θ, 15.1°2θ, and 20.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 2 is a crystalline compound A free base pattern 2 characterized by XRPD signals at 14.4°2θ, 19.1°2θ, 15.8°2θ, 16.2°2θ, 23.5°2θ, 15.1°2θ, and 20.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0141] In some embodiments, the solid form of compound A free base pattern 2 is a crystalline compound A free base pattern 2 characterized by two or more XRPD signals selected from the group consisting of 14.4°2θ, 19.1°2θ, 15.8°2θ, 16.2°2θ, 23.5°2θ, 15.1°2θ, 20.0°2θ, 18.9°2θ, 14.1°2θ, and 15.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 2 is a crystalline compound A free base pattern 2 characterized by XRPD signals at 14.4°2θ, 19.1°2θ, 15.8°2θ, 16.2°2θ, 23.5°2θ, 15.1°2θ, 20.0°2θ, 18.9°2θ, 14.1°2θ, and 15.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0142] In some embodiments, the free base pattern 2 of crystalline compound A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 XRPD signals selected from those listed in Table 2. [Table 2-1] [Table 2-2]

[0143] Compound A free base pattern 3 In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 3. In some embodiments, the XRPD profile of compound A free base pattern 3 is substantially similar to that shown in Figure 88. In some embodiments, the FT-IR spectrum of compound A free base pattern 3 is substantially similar to that shown in Figure 44. In some embodiments, the TGA profile of compound A free base pattern 3 is substantially similar to that shown in Figure 43. In some embodiments, the DSC profile of compound A free base pattern 3 is substantially similar to that shown in Figure 43.

[0144] In some embodiments, the solid form of compound A free base pattern 3 is a crystalline compound A free base pattern 3 characterized by two or three XRPD signals selected from the group consisting of 20.6°2θ, 16.1°2θ, and 16.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0145] In some embodiments, the solid form of compound A free base pattern 3 is a crystalline compound A free base pattern 3 characterized by two or more XRPD signals selected from the group consisting of 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, and 16.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 3 is a crystalline compound A free base pattern 3 characterized by XRPD signals at 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, and 16.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0146] In some embodiments, the solid form of compound A free base pattern 3 is a crystalline compound A free base pattern 3 characterized by two or more XRPD signals selected from the group consisting of 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, 16.8°2θ, 18.1°2θ, and 18.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 3 is a crystalline compound A free base pattern 3 characterized by XRPD signals at 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, 16.8°2θ, 18.1°2θ, and 18.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0147] In some embodiments, the solid form of compound A free base pattern 3 is a crystalline compound A free base pattern 3 characterized by two or more XRPD signals selected from the group consisting of 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, 16.8°2θ, 18.1°2θ, 18.7°2θ, 19.4°2θ, 15.2°2θ, and 22.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 3 is a crystalline compound A free base pattern 3 characterized by XRPD signals at 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, 16.8°2θ, 18.1°2θ, 18.7°2θ, 19.4°2θ, 15.2°2θ, and 22.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0148] In some embodiments, the free base pattern 3 of crystalline compound A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 XRPD signals selected from those listed in Table 3. [Table 3]

[0149] Compound A free base pattern 4 In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 4. In some embodiments, the XRPD profile of compound A free base pattern 4 is substantially similar to that shown in Figure 89. In some embodiments, the FT-IR spectrum of compound A free base pattern 4 is substantially similar to that shown in Figure 46. In some embodiments, the TGA profile of compound A free base pattern 4 is substantially similar to that shown in Figure 45. In some embodiments, the DSC profile of compound A free base pattern 4 is substantially similar to that shown in Figure 45.

[0150] In some embodiments, the solid form of compound A free base pattern 4 is a crystalline compound A free base pattern 4 characterized by two or three XRPD signals selected from the group consisting of 14.6°2θ, 17.7°2θ, and 16.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0151] In some embodiments, the solid form of compound A free base pattern 4 is a crystalline compound A free base pattern 4 characterized by two or more XRPD signals selected from the group consisting of 14.6°2θ, 17.7°2θ, 16.7°2θ, 15.5°2θ, and 18.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0152] In some embodiments, the solid form of compound A free base pattern 4 is a crystalline compound A free base pattern 4 characterized by two or more XRPD signals selected from the group consisting of 14.6°2θ, 17.7°2θ, 16.7°2θ, 15.5°2θ, 18.0°2θ, 17.2°2θ, and 20.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 4 is a crystalline compound A free base pattern 4 characterized by XRPD signals at 14.6°2θ, 17.7°2θ, 16.7°2θ, 15.5°2θ, 18.0°2θ, 17.2°2θ, and 20.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0153] In some embodiments, the solid form of compound A free base pattern 4 is a crystalline compound A free base pattern 4 characterized by two or more XRPD signals selected from the group consisting of 14.6°2θ, 17.7°2θ, 16.7°2θ, 15.5°2θ, 18.0°2θ, 17.2°2θ, 20.0°2θ, 15.9°2θ, 19.5°2θ, and 5.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 4 is a crystalline compound A free base pattern 4 characterized by XRPD signals at 14.6°2θ, 17.7°2θ, 16.7°2θ, 15.5°2θ, 18.0°2θ, 17.2°2θ, 20.0°2θ, 15.9°2θ, 19.5°2θ, and 5.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0154] In some embodiments, the free base pattern 4 of crystalline compound A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 XRPD signals selected from those listed in Table 4. [Table 4]

[0155] Compound A free base pattern 5 In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 5. In some embodiments, the XRPD profile of compound A free base pattern 5 is substantially similar to that shown in Figure 90.

[0156] In some embodiments, the solid form of compound A free base pattern 5 is a crystalline compound A free base pattern 5 characterized by two or three XRPD signals selected from the group consisting of 14.9°2θ, 22.6°2θ, and 7.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0157] In some embodiments, the solid form of compound A free base pattern 5 is a crystalline compound A free base pattern 5 characterized by two or more XRPD signals selected from the group consisting of 14.9°2θ, 22.6°2θ, 7.1°2θ, 15.1°2θ, and 20.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0158] In some embodiments, the solid form of compound A free base pattern 5 is a crystalline compound A free base pattern 5 characterized by two or more XRPD signals selected from the group consisting of 14.9°2θ, 22.6°2θ, 7.1°2θ, 15.1°2θ, 20.6°2θ, 24.4°2θ, and 16.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 5 is a crystalline compound A free base pattern 5 characterized by XRPD signals at 14.9°2θ, 22.6°2θ, 7.1°2θ, 15.1°2θ, 20.6°2θ, 24.4°2θ, and 16.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0159] In some embodiments, the solid form of compound A free base pattern 5 is a crystalline compound A free base pattern 5 characterized by two or more XRPD signals selected from the group consisting of 14.9°2θ, 22.6°2θ, 7.1°2θ, 15.1°2θ, 20.6°2θ, 24.4°2θ, 16.0°2θ, 16.5°2θ, 4.7°2θ, and 21.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 5 is a crystalline compound A free base pattern 5 characterized by XRPD signals at 14.9°2θ, 22.6°2θ, 7.1°2θ, 15.1°2θ, 20.6°2θ, 24.4°2θ, 16.0°2θ, 16.5°2θ, 4.7°2θ, and 21.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0160] In some embodiments, the free base pattern 5 of crystalline compound A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 XRPD signals selected from those listed in Table 5. [Table 5]

[0161] Compound A free base pattern 6 In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 6. In some embodiments, the XRPD profile of compound A free base pattern 6 is substantially similar to that shown in Figure 91. In some embodiments, the FT-IR spectrum of compound A free base pattern 6 is substantially similar to that shown in Figure 48. In some embodiments, the free base pattern of compound A 1 The 1H NMR spectrum is substantially similar to that shown in Figure 66. In some embodiments, the TGA profile of compound A free base pattern 6 is substantially similar to that shown in Figure 47 or Figure 65. In some embodiments, the DSC profile of compound A free base pattern 6 is substantially similar to that shown in Figure 47 or Figure 65.

[0162] In some embodiments, the solid form of compound A free base pattern 6 is a crystalline compound A free base pattern 6 characterized by two or three XRPD signals selected from the group consisting of 3.5°2θ, 3.6°2θ, and 15.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0163] In some embodiments, the solid form of compound A free base pattern 6 is a crystalline compound A free base pattern 6 characterized by two or more XRPD signals selected from the group consisting of 3.5°2θ, 3.6°2θ, 15.7°2θ, 18.9°2θ, and 23.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0164] In some embodiments, the solid form of compound A free base pattern 6 is a crystalline compound A free base pattern 6 characterized by two or more XRPD signals selected from the group consisting of 3.5°2θ, 3.6°2θ, 15.7°2θ, 18.9°2θ, 23.7°2θ, 16.2°2θ, and 19.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 6 is a crystalline compound A free base pattern 6 characterized by XRPD signals at 3.5°2θ, 3.6°2θ, 15.7°2θ, 18.9°2θ, 23.7°2θ, 16.2°2θ, and 19.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0165] In some embodiments, the solid form of compound A free base pattern 6 is a crystalline compound A free base pattern 6 characterized by two or more XRPD signals selected from the group consisting of 3.5°2θ, 3.6°2θ, 15.7°2θ, 18.9°2θ, 23.7°2θ, 16.2°2θ, 19.7°2θ, 14.6°2θ, 18.6°2θ, and 15.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 6 is a crystalline compound A free base pattern 6 characterized by XRPD signals at 3.5°2θ, 3.6°2θ, 15.7°2θ, 18.9°2θ, 23.7°2θ, 16.2°2θ, 19.7°2θ, 14.6°2θ, 18.6°2θ, and 15.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0166] In some embodiments, the free base pattern 6 of crystalline compound A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 XRPD signals selected from those listed in Table 6. [Table 6]

[0167] Free base pattern 7 of compound A In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 7. In some embodiments, the XRPD profile of compound A free base pattern 7 is substantially similar to that shown in Figure 92.

[0168] In some embodiments, the solid form of compound A free base pattern 7 is a crystalline compound A free base pattern 7 characterized by two or three XRPD signals selected from the group consisting of 4.8°2θ, 15.7°2θ, and 17.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0169] In some embodiments, the solid form of compound A free base pattern 7 is a crystalline compound A free base pattern 7 characterized by two or more XRPD signals selected from the group consisting of 4.8°2θ, 15.7°2θ, 17.9°2θ, 16.0°2θ, and 17.4°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0170] In some embodiments, the solid form of compound A free base pattern 7 is a crystalline compound A free base pattern 7 characterized by two or more XRPD signals selected from the group consisting of 4.8°2θ, 15.7°2θ, 17.9°2θ, 16.0°2θ, 17.4°2θ, 15.0°2θ, and 22.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 7 is a crystalline compound A free base pattern 7 characterized by XRPD signals at 4.8°2θ, 15.7°2θ, 17.9°2θ, 16.0°2θ, 17.4°2θ, 15.0°2θ, and 22.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0171] In some embodiments, the solid form of compound A free base pattern 7 is a crystalline compound A free base pattern 7 characterized by two or more XRPD signals selected from the group consisting of 4.8°2θ, 15.7°2θ, 17.9°2θ, 16.0°2θ, 17.4°2θ, 15.0°2θ, 22.7°2θ, 9.2°2θ, 16.4°2θ, and 7.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 7 is a crystalline compound A free base pattern 7 characterized by XRPD signals at 4.8°2θ, 15.7°2θ, 17.9°2θ, 16.0°2θ, 17.4°2θ, 15.0°2θ, 22.7°2θ, 9.2°2θ, 16.4°2θ, and 7.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0172] In some embodiments, the free base pattern 7 of crystalline compound A is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 XRPD signals selected from those listed in Table 7. [Table 7]

[0173] Free base pattern 8 of compound A In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 8. In some embodiments, the XRPD profile of compound A free base pattern 8 is substantially similar to that shown in Figure 93. In some embodiments, the FT-IR spectrum of compound A free base pattern 8 is substantially similar to that shown in Figure 52 or Figure 53. In some embodiments, the TGA profile of compound A free base pattern 8 is substantially similar to that shown in Figure 49, Figure 50, or Figure 51. In some embodiments, the DSC profile of compound A free base pattern 8 is substantially similar to that shown in Figure 49, Figure 50, or Figure 51.

[0174] In some embodiments, the solid form of compound A free base pattern 8 is a crystalline compound A free base pattern 8 characterized by two or three XRPD signals selected from the group consisting of 4.9°2θ, 15.9°2θ, and 18.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0175] In some embodiments, the solid form of compound A free base pattern 8 is a crystalline compound A free base pattern 8 characterized by two or more XRPD signals selected from the group consisting of 4.9°2θ, 15.9°2θ, 18.2°2θ, 9.3°2θ, and 17.4°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0176] In some embodiments, the solid form of compound A free base pattern 8 is a crystalline compound A free base pattern 8 characterized by two or more XRPD signals selected from the group consisting of 4.9°2θ, 15.9°2θ, 18.2°2θ, 9.3°2θ, 17.4°2θ, 16.7°2θ, and 23.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 8 is a crystalline compound A free base pattern 8 characterized by XRPD signals at 4.9°2θ, 15.9°2θ, 18.2°2θ, 9.3°2θ, 17.4°2θ, 16.7°2θ, and 23.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0177] In some embodiments, the solid form of compound A free base pattern 8 is a crystalline compound A free base pattern 8 characterized by two or more XRPD signals selected from the group consisting of 4.9°2θ, 15.9°2θ, 18.2°2θ, 9.3°2θ, 17.4°2θ, 16.7°2θ, 23.3°2θ, 12.8°2θ, 18.7°2θ, and 21.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 8 is a crystalline compound A free base pattern 8 characterized by XRPD signals at 4.9°2θ, 15.9°2θ, 18.2°2θ, 9.3°2θ, 17.4°2θ, 16.7°2θ, 23.3°2θ, 12.8°2θ, 18.7°2θ, and 21.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0178] In some embodiments, the free base pattern 8 of crystalline compound A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 XRPD signals selected from those listed in Table 8. [Table 8]

[0179] Free base pattern 9 of compound A In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A free base pattern 9. In some embodiments, the XRPD profile of compound A free base pattern 9 is substantially similar to that shown in Figure 94. In some embodiments, the TGA profile of compound A free base pattern 9 is substantially similar to that shown in Figure 35. In some embodiments, the DSC profile of compound A free base pattern 9 is substantially similar to that shown in Figure 35.

[0180] In some embodiments, the solid form of compound A free base pattern 9 is a crystalline compound A free base pattern 9 characterized by two or three XRPD signals selected from the group consisting of 17.2°2θ, 21.0°2θ, and 24.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0181] In some embodiments, the solid form of compound A free base pattern 9 is a crystalline compound A free base pattern 9 characterized by two or more XRPD signals selected from the group consisting of 17.2°2θ, 21.0°2θ, 24.2°2θ, 17.8°2θ, and 19.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0182] In some embodiments, the solid form of compound A free base pattern 9 is a crystalline compound A free base pattern 9 characterized by two or more XRPD signals selected from the group consisting of 17.2°2θ, 21.0°2θ, 24.2°2θ, 17.8°2θ, 19.8°2θ, 5.3°2θ, and 21.5°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 9 is a crystalline compound A free base pattern 9 characterized by XRPD signals at 17.2°2θ, 21.0°2θ, 24.2°2θ, 17.8°2θ, 19.8°2θ, 5.3°2θ, and 21.5°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0183] In some embodiments, the solid form of compound A free base pattern 9 is a crystalline compound A free base pattern 9 characterized by two or three XRPD signals selected from the group consisting of 17.2°2θ, 21.0°2θ, 24.2°2θ, 17.8°2θ, 19.8°2θ, 5.3°2θ, 21.5°2θ, 18.9°2θ, 15.9°2θ, and 21.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A free base pattern 9 is a crystalline compound A free base pattern 9 characterized by XRPD signals at 17.2°2θ, 21.0°2θ, 24.2°2θ, 17.8°2θ, 19.8°2θ, 5.3°2θ, 21.5°2θ, 18.9°2θ, 15.9°2θ, and 21.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0184] In some embodiments, the free base pattern 9 of crystalline compound A is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 XRPD signals selected from those listed in Table 9.

Table 9-1

Table 9-2

[0185] [[ID=I3]]Compound A tosylate Pattern 1 In some embodiments, the present disclosure provides a solid form of Compound A, for example, a crystalline form of Compound A tosylate Pattern 1. In some embodiments, the XRPD profile of Compound A tosylate Pattern 1 is substantially similar to that shown in FIG. 95. In some embodiments, the FT-IR spectrum of Compound A tosylate Pattern I is substantially similar to that shown in FIG. 17. In some embodiments, the 1 1H NMR spectrum of Compound A tosylate Pattern 1 is substantially similar to that shown in FIG. 19 or FIG. 68. In some embodiments, the TGA profile of Compound A tosylate Pattern 1 is substantially similar to that shown in FIG. 18 or FIG. 69. In some embodiments, the DSC profile of Compound A tosylate Pattern 1 is substantially similar to that shown in FIG. 18 or FIG. 69.

[0186] In some embodiments, the solid form of Compound A tosylate Pattern 1 is a crystalline Compound A tosylate Pattern 1 characterized by two or three XRPD signals selected from the group consisting of 3.5° 2θ, 22.0° 2θ, and 23.0° 2θ (±0.2° 2θ, ±0.1° 2θ, or ±0.0° 2θ; Cu Kα1 line). In some embodiments, the solid form of Compound A tosylate Pattern 1 is a crystalline Compound A tosylate Pattern 1 characterized by the XRPD signals at 3.5° 2θ, 22.0° 2θ, and 23.0° 2θ (±0.2° 2θ, ±0.1° 2θ, or ±0.0° 2θ; Cu Kα1 line).

[0187] In some embodiments, the solid form of compound A tosylate pattern 1 is a crystalline compound A tosylate pattern 1 characterized by two or more XRPD signals selected from the group consisting of 3.5°2θ, 22.0°2θ, 23.0°2θ, 21.7°2θ, and 7.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0188] In some embodiments, the solid form of compound A tosylate pattern 1 is a crystalline compound A tosylate pattern 1 characterized by two or more XRPD signals selected from the group consisting of 3.5°2θ, 22.0°2θ, 23.0°2θ, 21.7°2θ, 7.2°2θ, 21.0°2θ, and 14.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A tosylate pattern 1 is a crystalline compound A tosylate pattern 1 characterized by XRPD signals at 3.5°2θ, 3.5°2θ, 22.0°2θ, 23.0°2θ, 21.7°2θ, 7.2°2θ, 21.0°2θ, and 14.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0189] In some embodiments, the solid form of compound A tosylate pattern 1 is a crystalline compound A tosylate pattern 1 characterized by two or more XRPD signals selected from the group consisting of 3.5°2θ, 22.0°2θ, 23.0°2θ, 21.7°2θ, 7.2°2θ, 21.0°2θ, 14.7°2θ, 10.7°2θ, 12.7°2θ, and 18.4°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A tosylate pattern 1 is a crystalline compound A tosylate pattern 1 characterized by XRPD signals at 3.5°2θ, 22.0°2θ, 23.0°2θ, 21.7°2θ, 7.2°2θ, 21.0°2θ, 14.7°2θ, 10.7°2θ, 12.7°2θ, and 18.4°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0190] In some embodiments, crystalline compound A tosylate pattern 1 is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 XRPD signals selected from those listed in Table 10. [Table 10]

[0191] Compound A phosphate pattern 1 In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A phosphate pattern 1. In some embodiments, the XRPD profile of compound A phosphate pattern 1 is substantially similar to that shown in Figure 96. In some embodiments, the FT-IR spectrum of compound A phosphate pattern 1 is substantially similar to that shown in Figure 23. In some embodiments, the FT-IR spectrum of compound A phosphate pattern 1 is substantially similar to that shown in Figure 23. 1 The 1H NMR spectrum is substantially similar to that shown in Figure 25 or Figure 72. In some embodiments, the compound A phosphate pattern 1 31The P NMR spectrum is substantially similar to that shown in Figure 26 or Figure 73. In some embodiments, the TGA profile of compound A phosphate pattern 1 is substantially similar to that shown in Figure 24 or Figure 74. In some embodiments, the DSC profile of compound A phosphate pattern 1 is substantially similar to that shown in Figure 24 or Figure 74.

[0192] In some embodiments, the solid form of compound A phosphate pattern 1 is a crystalline compound A phosphate pattern 1 characterized by two or three XRPD signals selected from the group consisting of 23.6°2θ, 3.3°2θ, and 19.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0193] In some embodiments, the solid form of compound A phosphate pattern 1 is a crystalline compound A phosphate pattern 1 characterized by two or more XRPD signals selected from the group consisting of 23.6°2θ, 3.3°2θ, 19.9°2θ, 14.6°2θ, and 18.4°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0194] In some embodiments, the solid form of compound A phosphate pattern 1 is a crystalline compound A phosphate pattern 1 characterized by two or more XRPD signals selected from the group consisting of 23.6°2θ, 3.3°2θ, 19.9°2θ, 14.6°2θ, 18.4°2θ, 20.6°2θ, and 16.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A phosphate pattern 1 is a crystalline compound A phosphate pattern 1 characterized by XRPD signals at 23.6°2θ, 3.3°2θ, 19.9°2θ, 14.6°2θ, 18.4°2θ, 20.6°2θ, and 16.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0195] In some embodiments, the solid form of compound A phosphate pattern 1 is a crystalline compound A phosphate pattern 1 characterized by two or more XRPD signals selected from the group consisting of 23.6°2θ, 3.3°2θ, 19.9°2θ, 14.6°2θ, 18.4°2θ, 20.6°2θ, 16.1°2θ, 11.9°2θ, 5.0°2θ, and 10.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A phosphate pattern 1 is a crystalline compound A phosphate pattern 1 characterized by XRPD signals at 23.6°2θ, 3.3°2θ, 19.9°2θ, 14.6°2θ, 18.4°2θ, 20.6°2θ, 16.1°2θ, 11.9°2θ, 5.0°2θ, and 10.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0196] In some embodiments, crystalline compound A phosphate pattern 1 is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 XRPD signals selected from those listed in Table 11. [Table 11]

[0197] Compound A besylate pattern 1 In some embodiments, the disclosure provides a solid form of compound A, for example, a crystalline form of compound A besylate pattern 1. In some embodiments, the XRPD profile of compound A besylate pattern 1 is substantially similar to that shown in Figure 97. In some embodiments, the FT-IR spectrum of compound A besylate pattern 1 is substantially similar to that shown in Figure 20. In some embodiments, the FT-IR spectrum of compound A besylate pattern 1 is substantially similar to that shown in Figure 20. 1 The 1H NMR spectrum is substantially similar to that shown in Figure 22 or Figure 70. In some embodiments, the TGA profile of compound A besylate pattern 1 is substantially similar to that shown in Figure 21 or Figure 71. In some embodiments, the DSC profile of compound A besylate pattern 1 is substantially similar to that shown in Figure 21 or Figure 71.

[0198] In some embodiments, the solid form of compound A besilate pattern 1 is a crystalline compound A besilate pattern 1 characterized by two or three XRPD signals selected from the group consisting of 18.5°2θ, 18.3°2θ, and 22.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0199] In some embodiments, the solid form of compound A besylate pattern 1 is a crystalline compound A besylate pattern 1 characterized by two or more, or three or more, XRPD signals selected from the group consisting of 18.5°2θ, 18.3°2θ, 22.6°2θ, 11.1°2θ, and 14.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A besylate pattern 1 is a crystalline compound A besylate pattern 1 characterized by XRPD signals at 18.5°2θ, 18.3°2θ, 22.6°2θ, 11.1°2θ, and 14.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0200] In some embodiments, the solid form of compound A besylate pattern 1 is a crystalline compound A besylate pattern 1 characterized by two or more XRPD signals selected from the group consisting of 18.5°2θ, 18.3°2θ, 22.6°2θ, 11.1°2θ, 14.6°2θ, 23.5°2θ, and 13.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line). In some embodiments, the solid form of compound A besylate pattern 1 is a crystalline compound A besylate pattern 1 characterized by XRPD signals at 18.5°2θ, 18.3°2θ, 22.6°2θ, 11.1°2θ, 14.6°2θ, 23.5°2θ, and 13.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0201] In some embodiments, the solid form of Compound A besylate Pattern 1 is a crystalline Compound A besylate Pattern 1 characterized by two or more, or three or more XRPD signals selected from the group consisting of 18.5° 2θ, 18.3° 2θ, 22.6° 2θ, 11.1° 2θ, 14.6° 2θ, 23.5° 2θ, 13.3° 2θ, 11.3° 2θ, 17.8° 2θ, and 4.8° 2θ (±0.2° 2θ, ±0.1° 2θ, or ±0.0° 2θ; Cu Kα1 line). In some embodiments, the solid form of Compound A besylate Pattern 1 is a crystalline Compound A besylate Pattern 1 characterized by XRPD signals at 18.5° 2θ, 18.3° 2θ, 22.6° 2θ, 11.1° 2θ, 14.6° 2θ, 23.5° 2θ, 13.3° 2θ, 11.3° 2θ, 17.8° 2θ, and 4.8° 2θ (±0.2° 2θ, ±0.1° 2θ, or ±0.0° 2θ; Cu Kα1 line).

[0202] In some embodiments, the crystalline Compound A besylate Pattern 1 is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 XRPD signals selected from those listed in Table 12.

Table 12

[0203] Method for ubiquitinating / degrading target proteins in cells The present disclosure provides a method for ubiquitinating / degrading target proteins in cells.

[0204] In some embodiments, the method comprises administering a solid form of Compound A of the present disclosure or a salt form of Compound A of the present disclosure, wherein Compound A is a bifunctional compound comprising an E3 ubiquitin ligase binding moiety and a protein targeting moiety linked via a linker moiety.

[0205] [[ID=Z3]] In some embodiments, the E3 ubiquitin ligase binding moiety binds to a protein targeting moiety, the E3 ubiquitin ligase binding moiety recognizes a protein in the ubiquitin pathway (e.g., ubiquitin ligase, preferably E3 ubiquitin ligase), the protein targeting moiety recognizes a target protein, and degradation of the target protein occurs when the target protein is positioned in close proximity to the ubiquitin ligase, resulting in degradation / inhibition of the target protein's action and control of its protein level. The control of protein levels brought about by this disclosure provides treatment for a disease or condition regulated via a target protein by reducing the level of the target protein in the patient's cells.

[0206] In some embodiments, the application provides a solid form or a salt form of compound A of the disclosure that degrades androgen receptor (AR) proteins.

[0207] In some embodiments, the present disclosure relates to a method for treating a patient who requires treatment for a medical condition or state regulated via a protein, wherein the degradation of the protein brings about a therapeutic effect in the patient, and the method comprises administering an effective amount of compound A of the present disclosure in solid form or a salt form of compound A of the present disclosure, optionally in combination with other anticancer agents, to the patient in need. The medical condition or state may be a disease caused by the overexpression of a protein that gives rise to the medical condition and / or state.

[0208] Treatment methods In one embodiment, the present application relates to a method for treating and / or preventing cancer, comprising administering a therapeutically effective amount of compound A of the present disclosure in solid form or in salt form to a subject in need thereof.

[0209] In one embodiment, the present application relates to a method for treating and / or preventing cancer, comprising administering a therapeutically effective amount of Compound A of the present disclosure in solid form or salt form to a subject in need, in combination with one or more additional anticancer agents.

[0210] The cancer treatment methods described herein result in a reduction in tumor size. Alternatively or additionally, if the cancer is metastatic cancer, these treatment methods involve inhibition of the invasion of metastatic cancer cells.

[0211] In some embodiments, the cancer is prostate cancer.

[0212] In some embodiments, the cancer is metastatic prostate cancer.

[0213] In some embodiments, the cancer is castration-resistant prostate cancer.

[0214] In some embodiments, the cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0215] In some embodiments, prostate cancer is castration-sensitive prostate cancer.

[0216] In some embodiments, the prostate cancer is metastatic castration-sensitive prostate cancer.

[0217] In some embodiments, prostate cancer is a type of prostate cancer that is naive to novel hormonal agents (NHAs).

[0218] In some embodiments, the prostate cancer is metastatic prostate cancer that is naive to novel hormonal agents (NHAs).

[0219] In some embodiments, the prostate cancer is castration-resistant prostate cancer that is naive to novel hormonal agents (NHAs).

[0220] In some embodiments, prostate cancer is castration-sensitive prostate cancer that is naive to novel hormonal agents (NHAs).

[0221] In some embodiments, the prostate cancer is metastatic castration-resistant prostate cancer that is naive to novel hormonal agents (NHAs).

[0222] In some embodiments, prostate cancer is metastatic castration-sensitive prostate cancer that is naive to novel hormonal agents (NHAs).

[0223] In some embodiments, the prostate cancer is not naive to novel hormones (NHAs). In some embodiments, the prostate cancer that is not naive to novel hormones (NHAs) is also metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0224] In one embodiment, the present application relates to treating prostate cancer using a solid form of Compound A of the present disclosure or a salt form of Compound A of the present disclosure in combination with another anticancer agent. In some embodiments, the prostate cancers treated by the solid form of Compound A of the present disclosure or a salt form of Compound A of the present disclosure in combination with other anticancer agents are metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), castration-sensitive prostate cancer, metastatic castration-sensitive prostate cancer, prostate cancer naive to novel hormones (NHA), metastatic prostate cancer naive to novel hormones (NHA), castration-resistant prostate cancer naive to novel hormones (NHA), castration-sensitive prostate cancer naive to novel hormones (NHA), metastatic castration-resistant prostate cancer naive to novel hormones (NHA), or metastatic castration-sensitive prostate cancer naive to novel hormones (NHA).

[0225] In some embodiments, prostate cancer treated with a combination of compound A of the Disclosure in solid form or a salt form of compound A of the Disclosure and other anticancer agents is not novel hormone (NHA) naive prostate cancer. In some embodiments, prostate cancer that is not novel hormone (NHA) naive is also metastatic prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, castration-sensitive prostate cancer, or metastatic castration-sensitive prostate cancer.

[0226] In some embodiments, other anticancer agents include abiraterone, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronic acid, zoledronic acid, or pharmaceutically acceptable salts thereof.

[0227] In some embodiments, cancer treatment reduces tumor size. This reduction in tumor size may also be referred to as "tumor regression." Preferably, the tumor size after treatment is reduced by 5% or more compared to the tumor size before treatment; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. Tumor size can be measured by any reproducible measuring means. In one preferred embodiment, tumor size can be measured as tumor diameter.

[0228] In some embodiments, cancer treatment reduces tumor volume. Preferably, the tumor volume after treatment is reduced by 5% or more compared to the tumor volume before treatment; more preferably, it is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. Tumor volume can be measured by any reproducible measurement means.

[0229] In some embodiments, cancer treatment reduces the number of tumors. Preferably, the number of tumors after treatment is reduced by 5% or more compared to the number of tumors before treatment; more preferably, it is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of tumors can be measured by any reproducible measuring means. In one preferred embodiment, the number of tumors can be measured by counting tumors that can be seen with the naked eye or at a specific magnification. In some embodiments, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0230] In some embodiments, cancer treatment reduces the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, the number of metastatic lesions after treatment is reduced by 5% or more compared to the number before treatment; more preferably, the number of metastatic lesions is reduced by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measuring means. In some embodiments, the number of metastatic lesions can be measured by counting metastatic lesions that can be seen with the naked eye or at a specific magnification. In some embodiments, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0231] In some embodiments, cancer treatment increases the mean survival time of the treated population compared to the population administered only the carrier. Preferably, the mean survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in mean survival time of the population can be measured by any reproducible means. In some embodiments, the increase in mean survival time of the population can be measured, for example, by calculating the mean survival time of the population after the initiation of treatment with the active agent or compound of the disclosure. In some embodiments, the increase in mean survival time of the population can also be measured, for example, by calculating the mean survival time of the population after the completion of the first round of treatment with the active agent or compound of the disclosure.

[0232] In some embodiments, cancer treatment increases the mean survival time of a treated population compared to an untreated population. Preferably, the mean survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in mean survival time of the population can be measured by any reproducible means. In some embodiments, the increase in mean survival time of the population can be measured by calculating the mean survival time of the population after the initiation of treatment with the active agent or compound of the Disclosure. In some embodiments, the increase in mean survival time of the population can be measured by calculating the mean survival time of the population after the completion of the first round of treatment with the compound of the Disclosure.

[0233] In some embodiments, cancer treatment reduces the tumor growth rate. Preferably, the tumor growth rate after treatment is reduced by at least 5% compared to the growth rate before treatment; more preferably, the tumor growth rate is reduced by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. The tumor growth rate can be measured by any reproducible measuring means. In some embodiments, the tumor growth rate is measured by the change in tumor diameter per unit time.

[0234] In some embodiments, cancer treatment reduces tumor regrowth. Preferably, tumor regrowth after treatment is less than 5%; more preferably less than 10%; more preferably less than 20%; more preferably less than 30%; more preferably less than 40%; more preferably less than 50%; even more preferably less than 50%; and most preferably less than 75%. Tumor regrowth can be measured by any reproducible measuring means. In some embodiments, tumor regrowth is measured by measuring the increase in tumor diameter from the previous tumor reduction after treatment. In some embodiments, the reduction in tumor regrowth is indicated by the absence of tumor recurrence after the completion of treatment.

[0235] The dosage of Compound A in solid form or salt form of Compound A in this disclosure for any of the methods and uses described herein will vary depending on the drug, the age, weight, and clinical condition of the recipient, as well as the experience and judgment of the treating clinician or physician, among other factors that may influence the selected dosage.

[0236] A therapeutically effective dose of compound A in its solid form or salt form may be administered at least once daily for a maximum of 30 days or more, followed by a day or more without administration of the compound. This type of treatment plan, i.e., daily administration of compound A in its solid form or salt form, followed by a day without administration of the solid / salt, can be called a treatment cycle. A treatment cycle can be repeated as many times as necessary to achieve the intended effect.

[0237] In some embodiments, the therapeutically effective amounts of Compound A of the Disclosure in solid form or salt form are 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 4 4, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 ,205,210,215,220,225,230,235,240,245,250,255,260,265,270,275,280,285,290,295,300,305,310,315,320,325,330,335,340,345,350,355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 5 15, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 67 0, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825,830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg, once a day, 2 It is administered once, three, four, or more times a day for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30 consecutive days, or once, two, three, four, or more times a day, in single doses or divided doses, for 2, 3, 4, 5, 6 months, or longer.

[0238] In some embodiments, therapeutically effective doses of compound A of the Disclosure in solid form or salt form are approximately 10 to approximately 40 mg, approximately 20 to approximately 50 mg, approximately 30 to approximately 60 mg, approximately 40 to approximately 70 mg, approximately 50 to approximately 80 mg, approximately 60 to approximately 90 mg, approximately 70 to approximately 100 mg, approximately 80 to approximately 110 mg, approximately 90 to approximately 120 mg, approximately 100 to approximately 130 mg, approximately 110 to approximately 140 mg, approximately 120 to approximately 150 mg, approximately 130 to approximately 160 mg, approximately 140 to approximately 170 mg, approximately 150 to approximately 180 mg, approximately 160 to approximately 190 mg, approximately 170 to approximately 200 mg, approximately 180 to approximately 210 mg, About 190 to about 220 mg, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 230 to about 260 mg, about 240 to about 270 mg, about 250 to about 280 mg, about 260 to about 290 mg, about 270 to about 300 mg, about 280 to about 310 mg, about 290 ~320mg, 300~330mg, 310~340mg, 320~350mg, 330~360mg, 340~370mg, 350~380mg, 360~390mg, 370~400mg, 380~410mg, 390~42 0mg, approximately 400-430mg, approximately 410-440mg, approximately 420-450mg, approximately 430-460mg, approximately 440-470mg, approximately 450-480mg, approximately 460-490mg, approximately 470-500mg, approximately 480-510mg, approximately 490-520mg, approximately 500-530mg, approximately 510-540mg, approximately 520-550mg, approximately 530-560mg, approximately 540-570mg, approximately 550-580mg, approximately 560-590mg, approximately 570-600mg, approximately 580-610mg, approximately 590-620mg, approximately 600 ~630mg, 610~640mg, 620~650mg, 630~660mg, 640~670mg, 650~680mg, 660~690mg, 670~700mg, 680~710mg, 690~720mg, 700~73 0 mg, about 710 to about 740 mg, about 720 to about 750 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg, about 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg,About 810 to about 840 mg, about 820 to about 850 mg, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg, and is administered once, twice, three times, four times or more per day, either as a single dose or divided doses (the dose can be adjusted according to the patient's body weight (kg), body surface area (m, 2 ), and / or age).

[0239] In some embodiments, the therapeutically effective amount of the solid form of Compound A of the present disclosure or the salt form of Compound A of the present disclosure is about 70 mg to about 1000 mg, and is administered once, twice, three times, four times or more per day, either as a single dose or divided doses (the dose can be adjusted according to the patient's body weight (kg), body surface area (m 2 ), and / or age).

[0240] In some embodiments, the therapeutically effective amount of the solid form of Compound A of the present disclosure or the salt form of Compound A of the present disclosure is about 70 mg, 100 mg, 105 mg, 140 mg, 150 mg, 175 mg, 210 mg, 245 mg, 280 mg, 300 mg, 315 mg, 350 mg, 385 mg, 420 mg, 455 mg, 490 mg, 525 mg, 560 mg, 595 mg, 630 mg, 665 mg, or 700 mg, and is administered once, twice, three times, four times or more per day, either as a single dose or divided doses (the dose can be adjusted according to the patient's body weight (kg), body surface area (m 2 ), and / or age).

[0241] In some embodiments, a therapeutically effective dose of compound A of the Disclosure in solid form or salt form is administered to a subject once daily. In some embodiments, this daily dose of compound A of the Disclosure in solid form or salt form may be administered to the subject in its entirety at once. In some embodiments, this daily dose of compound A of the Disclosure in solid form or salt form may be administered to the subject in two divided doses (i.e., split doses). In some embodiments, this daily dose of compound A of the Disclosure in solid form or salt form may be administered to the subject in three split doses. In some embodiments, this daily dose of compound A of the Disclosure in solid form or salt form may be administered to the subject in four split doses. In some embodiments, this daily dose of compound A of the Disclosure in solid form or salt form may be administered to the subject in five or more split doses. In some embodiments, these partial or divided doses are administered to the subject at regular intervals throughout the day, such as every 12 hours, every 8 hours, every 6 hours, every 5 hours, or every 4 hours.

[0242] The therapeutically effective dose of compound A in solid form or salt form of compound A in this disclosure can first be estimated using a cell culture assay or an animal model, typically a rat, mouse, rabbit, dog, or pig. The animal model may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for human administration. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED 50 (Therapeutic dose effective in 50% of the population) and LD 50 This can be determined by the dose (the dose that is lethal to 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, or LD50. 50 / ED 50 It can be expressed as a ratio. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0243] Dosage and administration are adjusted to provide a sufficient level of compound A in solid form or salt form, or to maintain the desired effect. Factors to be considered include the severity of the condition, the subject's overall health status, age, weight and sex, diet, time and frequency of administration, drug combination(s), sensitivity to response, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered once every 3-4 days, weekly, or every 2 weeks, depending on the half-life and clearance rate of the particular formulation.

[0244] In some embodiments, with respect to methods for treating prostate cancer with a combination of Compound A of the Disclosure in solid form or a salt form of Compound A of the Disclosure and another anticancer agent, the therapeutic effective amounts of Compound A of the Disclosure in solid form or a salt form of Compound A of the Disclosure are described herein, and the therapeutic effective amounts of the other anticancer agent are 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16 ,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,5 8, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 2 55, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 41 0, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565 ,570,575,580,585,590,595,600,605,610,615,620,625,630,635,640,645,650,655,660,665,670,675,680,685,690,695,700,705,710,715,720,725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965 The dosage is 970, 975, 980, 985, 990, 995, or 1,000 mg, administered once, twice, three, four or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 30 consecutive days, or once, twice, three, four or more times daily, in single doses or divided doses, for 2, 3, 4, 5, 6 months, or longer.

[0245] In some embodiments, the solid form of compound A of the disclosure or the salt form of compound A of the disclosure and other anticancer agents are administered to the subject simultaneously. In some embodiments, the solid form of compound A of the disclosure or the salt form of compound A of the disclosure and other anticancer agents are administered to the subject sequentially.

[0246] In some embodiments, the solid form of compound A of the Disclosure or the salt form of compound A of the Disclosure and other anticancer agents are administered to the subject in close proximity in time.

[0247] In some embodiments, “temporal proximity” means that the administration of the solid form of Compound A or the salt form of Compound A of the Disclosure is performed within a period before or after the administration of an additional anticancer agent, such that the therapeutic effect of the solid form of Compound A of the Disclosure or the salt form of Compound A of the Disclosure overlaps with the therapeutic effect of an additional anticancer agent. In some embodiments, the therapeutic effect of the solid form of Compound A of the Disclosure or the salt form of Compound A of the Disclosure completely overlaps with the therapeutic effect of an additional anticancer agent. In some embodiments, “temporal proximity” means that the administration of the solid form of Compound A of the Disclosure or the salt form of Compound A of the Disclosure is performed within a period before or after the administration of an anticancer agent, such that there is a synergistic effect between the solid form of Compound A of the Disclosure or the salt form of Compound A of the Disclosure and the additional anticancer agent.

[0248] "Temporal proximity" can vary depending on various factors, including, but are not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the recipient of the therapeutic agent; the disease or condition being treated or improved; the therapeutic outcome to be achieved; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration of the therapeutic agent. In some embodiments, "temporal proximity" means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, multiple administrations of one therapeutic agent may occur in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may be altered during a treatment cycle or within a dosing regimen. [Examples]

[0249] Example 1. General analytical method X-ray powder diffraction (XRPD) XRPD analysis was performed using a PANalytical X'pert pro with a PIXcel detector (128 channels), scanning the sample between 3 and 35°²θ. The material was gently ground to release aggregates and loaded into a multiwell plate using Kapton or Mylar polymer film to support the sample. The multiwell plate was then placed in a diffractometer and operated in transmission mode (step size 0.0130°²θ, step time 18.87 sec) using a 40kV / 40mA generator setting, and analyzed using the Cu K line (α1λ=1.54060Å; α2=1.54443Å; β=1.39225Å; α1:α2 ratio=0.5). Data visualization and image generation were performed using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0250] Spinning stage X-ray powder diffraction (XRPD) XRPD analysis of the second set of competitive slurry experiments was performed using a Philips X'Pert Pro multi-purpose diffractometer equipped with a spinning stage autosampler. The samples were manipulated using a Bragg-Brentano centrifugation optical system (Bragg-Brentano geometry) (step size 0.008 °2θ, step time 10.160 sec, rotation period 2 sec) with a 40 kV / 40 mA generator setting, and scanned between 5 and 34.997°2θ using the Cu K line (α1λ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5). Data visualization and image generation were performed using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0251] Polarizing microscope (PLM) The presence of crystallinity (birefringence) was measured using an Olympus BX50 microscope equipped with a cross-polarizing lens and a Motic camera. Images were captured using Motic Imaging Plus 2.0. Unless otherwise specified, all images were recorded using a 20× objective lens.

[0252] Thermogravimetric / differential thermal analysis (TG / DTA) Approximately 5 mg of the material was weighed and placed in an aluminum open pan, then loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and kept at room temperature. Next, the sample was heated from 20°C to 300°C at a rate of 10°C / min, during which the change in sample weight was recorded along with the differential thermal event (DTA). Nitrogen was used as a purge gas at 300 cm³. 3 It was used at a flow rate of [number] minutes.

[0253] Differential Scanning Calorimetry (DSC) Approximately 5 mg of the material was weighed and placed in an aluminum DSC pan, which was then sealed airtight with a perforated aluminum lid. Next, the sample pan was loaded into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with an RC90 condenser. The sample and reference material were heated to 270°C at a scanning rate of 10°C / min, and the resulting heat flow response was obtained. The samples were monitored. The samples were recooled to 20°C, and then reheated to 270°C at a rate of 10°C / min. Nitrogen was used as a purge gas at a flow rate of 50 cm³ / min.

[0254] Infrared spectroscopy (IR) Infrared spectroscopy was performed using a Bruker ALPHA P spectrometer. Sufficient material was placed in the center of the spectrometer plate, and spectra were acquired using the following parameters: Resolution: 4cm -1 Background scan time: 16 scans Sample scanning time: 16 scans Data acquisition: 4000~400cm -1 Resulting spectrum: transmittance Software: OPUS version 6

[0255] nuclear magnetic resonance (NMR) NMR experiments were performed using a Bruker AVIIIHD spectrometer operating at 400 MHz for protons. The experiments were conducted in deuterated DMSO, and each sample was prepared to a concentration of approximately 10 mM.

[0256] Dynamic vapor sorption (DVS) 10–20 mg of sample was placed in a wire mesh vapor sorbent balance pan and loaded into a DVS-1 dynamic water vapor sorbent balance using Surface Measurement Systems. The sample was subjected to a gradient profile of relative humidity (RH) from 40–90% in 10% increments at 25°C, maintaining the sample at each step (dm / dt 0.004%, minimum step length 30 min, maximum step length 500 min) until a stable weight was achieved. After completion of the sorbent cycle, the sample was dried to 0% RH using the same procedure, and then returned to 40% RH in a second sorbent cycle. Two cycles were performed. The weight change during the sorbent / desorbent cycle was plotted to determine the hygroscopicity of the sample. Next, XRPD analysis was performed on one of the retained solids.

[0257] Temperature-Variable Powder X-ray Diffraction (VT-XRPD) VT-XRPD analysis was performed using a Philips X'Pert Pro multi-purpose diffractometer equipped with a temperature chamber. The sample was manipulated with a Bragg-Brentano focusing optical system (Bragg-Brentano geometry) (step size 0.008 °2θ) using a 40kV / 40mA generator setting, and scanned between 4 and 35.99° 2θ using the Cu K line (α1λ=1.54060Å; α2=1.54443Å; β=1.39225Å; α1:α2 ratio=0.5). The sample was heated at a heating rate of 10°C / min and held for 3 minutes at each temperature before XRPD analysis. Measurements were performed at 25°C, 164°C, 180°C, 203°C, 216°C, 234°C, 250°C, and again at 25°C.

[0258] High-performance liquid chromatography-ultraviolet detection (HPLC-UV) Equipment:Waters H-Class UPLC Column: ACQUITY UPLC BEH C18 1.7μm 2.1×50mm (Part number 186002350) Column temperature: 45℃ Autosampler temperature: Ambient UV wavelength: 254nm Injection volume: 2μL Flow rate: 0.8mL / min Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Diluent: 0.1% TFA in water:acetonitrile (50:50% v / v) Gradient program: [Table 13]

[0259] Example 2. Characterization of Compound A Compound A was characterized by the following techniques: XRPD, PLM, multinuclear NMR, TG / DSC, VT-XRPD, DSC, DSV, and HPLC.

[0260] • In the initial characterization of compound A, the material was determined to be amorphous by XRPD. See Figure 1. This was confirmed by PLM, and no birefringent solids were observed. The particles are approximately 5 μm in size and have a plate-like morphology. · Multinuclear NMR ( 1 H NMR, C HSQC and 19 F) revealed that this data is consistent with the structure of compound A. -74.5 ppm 19 A peak of approximately 1% impurity is present in the F spectrum, which is highly likely to be due to TFA. See Figures 2 and 3. • TG / DSC analysis revealed a mass loss of 0.8 wt.% (0.36 equivalents) of water in the TG trace at the start of the experiment, which is likely due to surface moisture. Decomposition was observed above 300°C. In the DSC trace, an endothermic melting event starting at 236°C was observed. See Figure 4. DSC analysis revealed three events during the first heating cycle. A small endothermic event starting at 164°C may be caused by the melting of a small amount of crystalline material in the bulk sample. This is followed by a broad exothermic event starting at 203°C due to material recrystallization, and a sharp endothermic event starting at 235°C due to melting. See Figure 5. This data is in good agreement with the data obtained by TG / DSC. Glass transitions were observed during the cooling cycle, the second heating cycle, and the second cooling cycle, with midpoints at 123°C, 129°C, and 128°C, respectively. See Figures 6-8. • VT-XRPD analysis showed no change in crystallinity of compound A when heated to 164°C, the temperature at which a small endothermic event was observed in DSC. When heated to the onset temperature of the exothermic event observed in DSC (203°C), recrystallization to pattern 1 was observed—this was slightly shifted compared to the reference diffractogram collected in permeation mode. When pattern 1 was heated to the endothermic event observed by DSC (presumably due to melting), a slight decrease in crystallinity was observed. Further heating resulted in melting. Recrystallization during cooling was not evident. See Figure 9. • DVS analysis revealed that the material is hygroscopic, absorbing an average mass of 4.08 wt.% (1.91 equivalents) of water at 90% humidity. See Figure 10 for isotherm plots and Figure 11 for kinetic plots. No crystallization was observed in XRPD after DVS. See Figure 12. [Table 14]

[0261] Example 3. Solvent solubility screening of compound A Approximately 5 mg of compound A was added to a known volume aliquot of solvent (usually 5 times the volume). See Table 14 for the solvents selected for solvent solubility screening. [Table 15-1] [Table 15-2]

[0262] While adding each solvent, confirm that the mixture was dissolved. If dissolution was not apparent, heat the mixture to approximately 40°C and check again. Continue this procedure until dissolution was observed or until 100 times the volume of solvent had been added.

[0263] If dissolution was not observed, the solid was isolated by centrifugation and analyzed by XRPD. Solubility was obtained by analyzing the saturated solution by HPLC.

[0264] If dissolution was observed, the clear solution was evaporated under ambient conditions, and the resulting solid was analyzed by XRPD. • High solubility of compound A (over 100 mg / mL) was observed in 1,4-dioxane, DMSO, DMA, DMF, and DCM:methanol (75:25% v / v). The moderately high solubility of compound A (between 100 and 50 mg / mL) was observed in DCM, NMP, THF, THF:water (98:2% v / v), and DCM:methanol (50:50% v / v). Regarding anisole, a moderate solubility (between 50 and 25 mg / mL) was observed in compound A. The material was insoluble in the remaining 25 solvent systems tested (<5 mg / mL). During solvent screening, two new crystalline XRPD patterns were obtained, which were named Free Base Pattern 1 and Free Base Pattern 2.

[0265] For an overview of solvent solubility screening, please refer to Table 15. [Table 16-1] [Table 16-2] A: Amorphous, P1: Pattern 1, P2: Pattern 2, *Poor crystallinity, + p1: Some peaks of Pattern 1

[0266] Example 4. Salt screening of compound A For 96 experiments, 30 mg of compound A sample was weighed and placed in a 2 mL screw-cap sample vial. 200 μL of a suitable solvent system was added to these vials to dissolve the material or form a slurry. See Table 16 for the solvent systems selected for primary salt screening. [Table 17] • 1.05 equivalents of solid counterions were weighed and placed into six separate vials. A 1-molar stock solution was then prepared in 5 mL of THF for use with liquid counterions. See Table 17 for the selected counterions and the mass / volume required to add 1.05 equivalents. • 100 μL of a suitable solvent was added to the solid counterion. [Table 18]

[0267] The counterion solution / slurry was added to the free base material solution / slurry. This was mixed using a vortex mixer, and the results were recorded. See Table 18. [Table 19]

[0268] The sample was placed in an incubator shaker and subjected to a temperature cycle between ambient temperature and 40°C for 4-hour cycles. After approximately 72 hours of temperature cycling, the observation results were recorded. See Table 19. [Table 20]

[0269] • If a slurry was obtained, the solid was isolated by centrifugation. The solid and gel were analyzed by XRPD.

[0270] All samples that were clear solutions after temperature cycling were evaporated under ambient conditions. See Table 20 for observations made after evaporation. The solids obtained by evaporation were analyzed by XRPD. [Table 21-1] [Table 21-2]

[0271] Samples obtained from temperature cycling were dried under vacuum at approximately 40°C for approximately 20 hours, while samples obtained from evaporation were dried under vacuum at approximately 40°C for approximately 4 hours. Next, the samples were analyzed using XRPD. The XRPD plates were then stored at 40°C / 75%RH for approximately 20 hours and re-analyzed using XRPD. • After initial XRPD analysis of solids obtained during primary salt screening, potential salt forms were obtained for hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, and fumaric acid. • Potential fumarates became amorphous after drying. • Potential maleates became amorphous after the humidity increased. • CAD analysis of potential chloride salts revealed only trace amounts of chloride. Tosylates, besylates, and phosphates are all considered to be stable hydrates. Furthermore, two possible new free base patterns were obtained from the 1,4-dioxane sample. Pattern 3 from hydrochloric acid, l-glutamic acid, succinic acid, and acetic acid. • Pattern 4 from malonic acid and benzoic acid.

[0272] For an overview of the XRPD results from the primary salt screening, please refer to Tables 21-23. [Table 22] [Table 23] [Table 24]

[0273] Example 5. Characterization of a Novel Form Potential chloride salt pattern 2, tosylate pattern 1, besylate pattern 1, and phosphate pattern 1 were characterized using the following techniques: PLM FT-IR · TG / DSC • CAD (if applicable) · 1 1H NMR (if applicable) · 31 P NMR (if applicable)

[0274] Potential chloride salt pattern 2 • Potential chloride salt pattern 2 was observed after drying potential chloride salt pattern 1 obtained from DCM and DCM:methanol. Drying was carried out in an oven at 40°C for approximately 20 hours. PLM demonstrated birefringent rod-shaped particles. • FT-IR analysis showed a slight peak shift compared to amorphous free bases. The peak of the CC triple bond was at 2218 cm⁻¹. -1 This was evident. Amide peaks and the possibility of water presence were observed at higher wavenumbers. See Figure 14. • TG / DSC analysis of the sample from DCM showed no significant mass loss in the TG trace before decomposition above 292°C, indicating the material was anhydrous. The DSC trace showed a sharp endothermic event starting at 241°C, which may be due to melting and is similar to the melting observed in free base pattern 1. See Figure 15. • TG / DSC analysis was repeated on samples from DCM: methanol. No significant mass loss was observed in the TG traces before decomposition above 310°C. The DSC traces showed a broad endothermic melting event starting at 243°C, which is in good agreement with the previously obtained thermogram. See Figure 16. CAD analysis of two potential chloride salt samples (from DCM and from DCM:methanol (50:50% v / v)) determined that only trace amounts of chloride were present. • Potential chloride salt pattern 2 was not a salt.

[0275] Tosylate Pattern 1 In PLM, no clear morphology was observed, but aggregation was noted. The material appeared to be birefringent under polarized light. FT-IR analysis determined that there were some slight differences in the spectrum, which are likely due to the presence of p-toluenesulfonic acid. The peak for the CC triple bond is at 2220 cm⁻¹. -1 This was clear. No clear presence of water in the hydrate was observed. See Figure 17. • TG / DSC analysis revealed a gradual mass loss of 1.8 wt.% (0.25 equivalents of THF or 1 equivalent of water) in the TG trace from the start of heating to the potential melting event. Decomposition was observed above 278°C. An endothermic event, likely due to melting, was observed in the DSC trace, starting at 195°C. See Figure 18. · 1 1H NMR showed that the ratio of p-toluenesulfonic acid to compound A was 1:1. 1 1H NMR did not reveal any significant amount of THF, suggesting that the mass loss from TG / DSC was likely due to water. No peak shift was observed compared to free base. See Figure 19. ○ Tosylate pattern 1 was a hydrated salt of p-toluenesulfonic acid with a stoichiometric ratio of 1:1 to compound A.

[0276] Besilate pattern 1 PLM revealed large, pink, plate-like particles. The material appeared to exhibit weak birefringence under polarized light. FT-IR analysis determined that there were some slight differences in the spectrum, which is likely due to the presence of benzenesulfonic acid. The peak for the CC triple bond is at 2222 cm⁻¹. -1 This was evident in [the relevant section]. See Figure 20. • TG / DSC revealed two mass losses in the TG trace from the start of heating up to approximately 277°C: a 4.2 wt.% mass loss (0.6 equivalents of THF or 2.4 equivalents of water) and a 3.7 wt.% mass loss (0.5 equivalents of THF or 2.1 equivalents of water). Decomposition was observed above 277°C. There was no clear evidence of melting in the DSC trace. A broad endothermic reaction was observed during the first mass loss, which is likely related to desolvation. See Figure 21. · 1 ¹H NMR showed a 1:1 ratio of benzenesulfonic acid to compound A. 0.85 wt.% (0.11 equivalents) of THF 1 Observed in 1H NMR. A slight peak shift was observed compared to the free base of compound A. See Figure 22. 〇 Besylate pattern 1 was a hydrated salt of p-toluenesulfonic acid with a stoichiometric ratio of 1:1 with respect to compound A.

[0277] Phosphate pattern 1 PLM analysis did not reveal any clear morphology. Aggregation was observed, and the material appeared to be weakly birefringent under polarized light. FT-IR analysis determined that the spectra were equivalent, with some slight peak shifts likely due to the presence of phosphate. The peak for the CC triple bond was at 2221 cm⁻¹. -1 This was clear. No clear presence of water in the hydrate was observed in the spectrum. See Figure 23. • TG / DSC analysis revealed a gradual mass loss of 5.8 wt.% (3 equivalents of water or 0.8 equivalents of THF) in the TG trace from the start up to approximately 170°C. Decomposition was observed above 249°C. In the DSC trace, a broad endothermic event occurred after the mass loss between 165°C and 245°C. See Figure 24. · 1 The 1H NMR spectrum was consistent with the structure. No significant amount of THF was observed, suggesting that the mass loss from TG / DSC was likely due to water. Compared to the free base of compound A, a slight peak shift was observed, and a broad water peak was present, both indicating salt formation. 31 A peak was observed in PNMR, confirming the presence of phosphate. See Figures 25 and 26. CAD analysis revealed 22.9 wt.% of phosphate, corresponding to approximately 2 equivalents (1 equivalent = 10.5 wt.% and 2 equivalents = 18.9 wt.%). 〇 Phosphate pattern 1 was a hydrated salt with a stoichiometric ratio of phosphate to compound A free base of 2:1. [Table 25-1] [Table 25-2]

[0278] Water solubility • The water solubility of promising salts was determined in unbuffered water. • Slurries were prepared by adding 0.5 mL of unbuffered water to 2.2 mg of tosylate, and 5 mg each of besylate and phosphate. See Table 25. Each sample was capped, sealed in Parafilm, and placed in an incubator shaker at 25°C for approximately 24 hours. After 24 hours, the observation results were recorded (see Table 25), and the slurry was filtered by centrifugal filtration. The saturated solution was subjected to HPLC analysis and injected directly due to its low solubility. [Table 26]

[0279] Unfortunately, the solubility of all three samples was below the LOQ (Low-Level of Solubility), so quantification was not possible.

[0280] Example 6. Additional Chloride Salt Formation Experiment Despite the large pKa difference between compound A and hydrochloric acid, the possibility of stable chloride salt formation seemed unlikely. However, to further investigate this possibility, three additional chloride salt formation experiments were conducted. (Table 26) [Table 27]

[0281] Experiment 1: 30 mg of free base was dissolved in 400 μL of DCM:methanol (50:50% v / v). A clear purple solution was observed. 1.05 equivalents of 1 M HCl in THF were added to the clear solution. No change was observed. The solution was capped and sealed in Parafilm, then placed in the incubator's shaker and temperature cycled between ambient temperature and 50°C for 72 hours in 4-hour cycles. An orange solution was obtained, and the sample was removed and evaporated. Experiment 2: 30 mg of free base was dissolved in 400 μL of DCM. A clear purple solution was observed. 2.1 equivalents of 1 M HCl were added in THF. No change was observed. The solution was capped and sealed in Parafilm, then placed in the incubator's shaker and temperature cycled between ambient temperature and 40°C for 72 hours in 4-hour cycles. A yellow solution was obtained, and the sample was removed from the cap and evaporated. Experiment 3 followed the following method: 200 mg of free base was dissolved in 2 mL of DCM:methanol in a 9:1 ratio. A clear purple solution was obtained. An additional 1 mL of DCM was added. • 0.8 mL of 1.25 M HCl was added to methanol. The solution was stirred on a hot plate in a stirrer at room temperature for 1 hour. The solvent was removed using a rotary evaporator on a 40°C water bath. A brown gel was obtained. 5 mL of ethanol was added to obtain an off-white slurry. The slurry was stirred at room temperature for approximately 2.5 hours. The slurry was filtered by Buchner filtration, and the material was dried on the filter bed for approximately 5 minutes. Next, the off-white solid was placed in a scintillation vial, covered with tissue paper, and dried in a 40°C oven for approximately 96 hours. The materials obtained from these experiments were analyzed by XRPD to obtain amorphous materials, and amorphous monochloride salts were obtained from the solid obtained from Experiment 1, where the chloride content was determined by CAD analysis. These samples were further analyzed by TG / DSC and DSC. Experiment 1, performed at high temperature, yielded pattern 2 of free bases. Amorphous materials were obtained from the other two samples. CAD analysis revealed 0.8 wt.% chloride in Experiment 2. ○ Trace amounts outside the calibration curve range CAD analysis revealed 7.7 wt.% chloride in Experiment 3, which is approximately equivalent to 2 equivalents of chloride (1 equivalent = 4.2 wt.%, 2 equivalents = 8.0 wt.%). • TG / DSC analysis of amorphous chloride from Experiment 3 revealed a mass loss of 7.97 wt.% (4.23 equivalents of water, 0.90 equivalents of DCM, 2.38 equivalents of methanol, 1.66 equivalents of ethanol, or 2.09 equivalents of HCl) from the start of the experiment to approximately 110°C. A gradual mass loss of 10.15 wt.% (5.52 equivalents of water, 1.17 equivalents of DCM, 3.11 equivalents of methanol, 2.16 equivalents of ethanol, or 2.73 equivalents of HCl) was observed from 110°C to approximately 300°C, before decomposition, which is likely due to sample decomposition. This data suggests that chloride anions were lost at the start of the experiment. DSC traces showed two broad endothermic events with peaks at 186°C and 232°C. (Figures 27-33) • In the first heating cycle with DSC, two endothermic events were observed. The broad endothermic event, starting at 45°C and with a peak at 99°C, corresponds to the mass loss observed in TG / DSC. The second endothermic event was sharp, starting at 184°C and likely corresponding to melting with a peak at 189°C. ○ This melting was lower than any previously obtained free base melting, so the temperature was confirmed by repeating the DSC. The same result was obtained with repeated DSCs. During the cooling cycle, a glass transition with an intermediate point of 148°C was observed. • In the second heating cycle, a glass transition with an intermediate temperature of 154°C was observed.

[0282] Example 7. Cocrystal screening of compound A Dry milling Approximately 30 mg of compound A was weighed and placed in a 48 x 2 mL bead mill vial. • 1.05 equivalents of each co-forming agent were added to six bead mill vials. Two stainless steel bead milling balls were added to each vial, and the samples were dry-milled using the following procedure: • 6500 RPM • 40 x 60 second cycle (Total milling time: 40 minutes) • 10-second pause By-samples from each co-forming agent were analyzed by XRPD after dry milling.

[0283] Temperature cycling Each sample was dissolved in an appropriate solvent. The solution was temperature-cycled between ambient temperature and 40°C for approximately 72 hours in a 4-hour cycle using an incubator shaker. Three days later, the slurry was centrifuged and filtered, and all obtained solids were analyzed by XRPD. After XRPD analysis, the XRPD plates were left at 40°C / 75%RH for approximately 30 hours, and then the samples were re-analyzed using XRPD. • Samples that yielded novel XRPD patterns were analyzed by TG / DSC and PLM.

[0284] Store at 40°C / 75%RH XRPD plates containing co-crystal screen samples were stored in a 40°C / 75%RH humidity chamber for approximately 24 hours, after which the samples were re-analyzed using XRPD.

[0285] result Cocrystal screening yielded free base patterns 1, 2, 4, and a novel pattern. • A novel pattern was obtained from five different co-forming agents in 1,4-dioxane, suggesting that this is likely a novel free base pattern. We named it Potential Free Base Pattern 9. See Table 27 for an overview of XRPD after temperature cycling. Pattern 9 was converted to free base pattern 4 after storage at 40°C / 75%RH. For an overview of XRPD after storage at 40°C / 75%RH, please refer to Table 28. [Table 28] [Table 29]

[0286] Characterization of free base pattern 9 • The novel free base pattern 9 is converted to pattern 4 after storage at 40°C / 75%RH. See Figure 34. • Very small (approximately 5 μm) weakly birefringent particles were observed by PLM. Aggregation was observed. • TG / DSC determined that there were two mass losses in the TG trace. The first was a mass loss of 8.2 wt.% (4 equivalents of water, 0.82 equivalents of 1,4-dioxane, or 0.5 equivalents of L-histidine) that occurred between 55°C and 175°C. The second was a mass loss of 3.8 wt.% (1.75 equivalents of water, 0.36 equivalents of 1,4-dioxane, or 0.2 equivalents of L-histidine) that occurred between 255°C and 290°C. Decomposition began above 289°C. Several events were observed in the DSC trace. An exothermic event with an onset at 146°C and a peak at 164°C. A second exothermic event with an onset at 187°C and a peak at 195°C. An endothermic event with an onset at 238°C and a peak at 243°C. A second endothermic event with an onset at 264°C and a peak at 271°C. For TG / DSC, please refer to Figure 35.

[0287] Example 8. Crystallization screening of compound A • 34 × 40 mg of compound A was weighed and placed in a vial. If possible, the selected solvent was then added to prepare the slurry. See Table 29 for a list of the solvent systems and volumes used. A stirring rod was added to the vial, the vial was then sealed, and the temperature was cycled between 5°C and 40°C while stirring. The heating rate was 0.1°C / min, and the sample was held at 5°C and 40°C for 2 hours. Observations were made after a 4-day temperature cycle (see Table 29). The slurry was centrifuged and filtered, and the solid was analyzed by XRPD. The solid was dried at 40°C for approximately 18 hours and then re-analyzed by XRPD. Next, for the following experiment, the saturated solution was divided into three vials. • Evaporation at ambient temperature · Cooling (5℃) If a solid was not obtained after 72 hours, the sample was transferred to a -20°C freezer and cooled further. If further cooling did not yield a solid, the sample was evaporated at ambient temperature. • Addition of poor solvent at ambient temperature If a solid was not obtained after 72 hours, the sample was moved to a -20°C freezer to promote crystallization. If a solid was not obtained by cooling, the sample was evaporated at ambient temperature.

[0288] The free base forms are PLM, TG / DSC, and 1 The samples were characterized by 1H NMR. [Table 30-1] [Table 30-2]

[0289] • Primary crystallization screening revealed six free base patterns. Patterns 1 and 2 had been observed previously. Patterns 5-8 were newly obtained. Patterns 3 and 4 obtained from salt screening, and pattern 9 obtained from cocrystal screening, were not observed in crystallization screening. Experiments showed that free base pattern 1 was the most commonly recovered. Patterns 5 and 7 were converted to pattern 8 when dried at 40°C.

[0290] See Table 30 for an overview of the XRPD patterns obtained during the primary crystallization screening. [Table 31-1] [Table 31-2] [Table 32-1] [Table 32-2] [Table 32-3] [Table 32-4] [Table 32-5]

[0291] Free base pattern 1 • A 0.6% mass loss related to melting was observed in the TG trace – likely due to the release of trapped solvent during melting. Decomposition was observed above approximately 295°C. A sharp endothermic event was observed in the DSC trace (starting at 240°C), likely due to melting. See Figure 39. • No clear morphology was observed by PLM. Aggregates were visible. The material appeared to be weakly birefringent under polarized light. • FT-IR analysis revealed that the spectrum of free base pattern 1 was very similar to that of amorphous free bases. The CC triple bond peak was at 2214 cm⁻¹. -1 This was evident. Several potential THF peaks were observed at higher wavenumbers. See Figure 40.

[0292] Free base pattern 2 • TG / DSC analysis determined that there was an initial 1.1% loss of mass in the TG trace from the start of heating, which is likely due to the observed unbound solvent (0.3 equivalents methanol, 0.1 equivalents DCM, or 0.5 equivalents water). Decomposition was evident at approximately 314°C. In the DSC trace, a sharp endothermic event due to melting, which began at 243°C, was observed. Melting occurred at a temperature similar to that of Pattern 1. See Figure 41. PLM analysis determined the morphology of free base pattern 2, which consists of needle-shaped and lath-shaped particles of various sizes. The material appeared to be birefringent under polarized light, indicating that it is a crystalline material. • FT-IR analysis revealed that the spectrum of free base pattern 2 was very similar to that of amorphous free bases. The peak of the CC triple bond was at 2220 cm⁻¹. -1 This was evident. There was no clear evidence of solvent or water. See Figure 42.

[0293] Free base pattern 3 • TG / DSC analysis determined a gradual mass loss of 2.3% from the start of heating up to approximately 150°C, as observed in the TG trace. This mass loss is likely the result of unbonded solvent loss (0.2 or 1 equivalent of 1,4-dioxane or water, respectively). A second stepwise mass loss (6.1%) was observed between 150°C and 240°C (0.6 or 2.9 equivalents of 1,4-dioxane or water, respectively). DSC traces appeared to show possible melting / recrystallization events occurring during this mass loss, starting at 178°C and 198°C. Following the recrystallization events, an endothermic event associated with melting (starting at 236°C) was observed, similar to Pattern 1. See Figure 43. PLM analysis determined that the morphology appeared to consist of rod-like structures and aggregates. The material appeared to be birefringent under polarized light. • FT-IR analysis revealed that the spectrum of free base pattern 3 was very similar to that of amorphous free bases, but with several additional weak peaks at high wavenumbers. These may be due to the presence of 1,4-dioxane and / or water. The peak for the CC triple bond was at 2222 cm⁻¹. -1 This was clear. See Figure 44.

[0294] Free base pattern 4 • In TG / DSC, a gradual mass loss of 1.0% was observed in the TG trace from the start of heating up to approximately 50°C – this is likely the result of unbonded solvent loss. Between 60°C and 150°C (0.5 or 2.6 equivalents of 1,4-dioxane or water, respectively), a second stepwise mass loss of 5.4% was observed. This indicated that pattern 4 is a possible dioxane solvate. Following this potential desolvation, potential melting / recrystallization events were observed in the DSC trace, starting at 169°C and 192°C. Following the recrystallization events, an endothermic event associated with melting (starting at 235°C) was observed, similar to pattern 1. See Figure 45. PLM analysis determined that the morphology appeared to consist of rod-like, lath-like, and aggregate-like structures. The material appeared to exhibit birefringence under polarized light. • FT-IR analysis revealed that the spectrum of free base pattern 4 was very similar to that of amorphous free bases, but with several additional weak peaks at high wavenumbers, which may be due to the presence of 1,4-dioxane and / or water. The peak for the CC triple bond was at 2223 cm⁻¹. -1 This was clear. See Figure 46.

[0295] Free base pattern 6 • TG / DSC analysis revealed a 2.1% mass loss in the TG trace from the start to approximately 120°C (0.2 equivalents of DCM or 1 equivalent of water). Decomposition was observed above 306°C. In the DSC trace, a sharp endothermic event due to melting was observed, similar to pattern 1 (starting at 242°C). Furthermore, a 0.3% mass loss was observed in the TG trace during melting (likely due to solvent trapping). See Figure 47. PLM analysis revealed that the material consisted of needle-shaped particles, with some aggregates visible. The material appeared to be weakly birefringent under polarized light. • FT-IR analysis revealed that the spectrum of free base pattern 6 was very similar to that of amorphous free bases. The peak of the CC triple bond was at 2221 cm⁻¹. -1This was clear. See Figure 48.

[0296] Free base pattern 8 • TG / DSC analysis of a dried sample from anisole revealed a 14% mass loss from the start of heating up to 100°C (1.2 equivalents of anisole - presumably a solvate). Decomposition was observed above 307°C. DSC tracing showed a series of weak thermal events following possible desolvation, similar to pattern 1, before a sharp endothermic event (starting at 237°C) was observed. See Figure 49. The anisole sample was further dried and then reanalyzed by TG / DSC. The TG trace showed a 12.4% mass loss (1.1 equivalents of anisole—presumably solvate) from the start of heating up to 100°C. Decomposition was observed above 291°C. The DSC trace showed a potential recrystallization event after desolvation (starting at 192°C) and a sharp endothermic event due to melting (starting at 238°C). See Figure 50. • TG / DSC analysis of the dried toluene sample revealed two mass losses of 1% and 1.1% (0.2 equivalents of toluene) from the start of heating up to 125°C. Decomposition was observed above 290°C. A potential recrystallization event (starting at 193°C) was observed in the DSC trace after solvent loss. Finally, a sharp endothermic event due to melting (starting at 238°C) was observed in the DSC trace, and a small mass loss associated with melting was observed in the TG trace. See Figure 51. PLM analysis revealed no clear morphology, but aggregation was present. The material appeared to be birefringent under polarized light. • FT-IR analysis revealed that the free base pattern 8 spectrum from anisole was very similar to that of amorphous free bases, although there was a slight shift. The CC triple bond peak was at 2220 cm⁻¹. -1 This was evident. Several peaks, possibly attributable to anisole, were observed at 3000 cm. -1 It was present in a slightly greater quantity than that. See Figure 52. • FT-IR analysis revealed that the spectrum of free base pattern 8 from toluene was very similar to that of amorphous free bases, although some shift was observed. The peak for the CC triple bond was at 2220 cm⁻¹. -1 This was clear. See Figure 53.

[0297] Example 9. Secondary crystallization screening of compound A Scaling up of free base patterns 1, 2, and 6 Approximately 250 mg of compound A was weighed and placed in three scintillation vials. • Dissolve the sample in the appropriate solvent and record the observation results; see the table below. A magnetic stirring rod was added to each sample, and the solution was heated at a rate of 0.1°C / min between 5°C and 40°C, holding each temperature for 2 hours, for a total of 72 hours of temperature cycling. After approximately 72 hours, the observation results were recorded, the cap on the sample was removed, and it was allowed to evaporate under ambient conditions for approximately 20 hours. See Table 31 for details and observations of the experiments conducted during the first trial of scaling up with free base patterns 1, 2, and 6. [Table 33]

[0298] Although the correct morphology was obtained, the samples did not have the desired degree of crystallinity. Therefore, 1 mL of an appropriate solvent was added to each sample to re-slurry it and improve the crystallinity of the solid. The slurry was temperature-cycled between ambient temperature and 40°C in an incubator shaker for 4-hour cycles. Approximately 72 hours later, observations were made, and the solid was isolated by centrifugation. The solid was analyzed using XRPD, and then gently dried in an oven at approximately 40°C for about 20 hours. • Once dried, the material can be processed using XRPD, TG / DSC, and 1 The samples were characterized by 1H NMR. • Free base pattern 1 was further characterized by DSC, DVS, and optical activity. See Table 32 for details and observations of the experiments conducted during the first trial to scale up with free base patterns 1, 2, and 6. [Table 34]

[0299] Characterization of free base patterns 1, 2, and 6 XRPD analysis of the dried free base morphology determined that the morphology was preserved.

[0300] Free base pattern 1 PLM analysis revealed needle-shaped small particles. Aggregation was observed. The material appeared to be slightly birefringent under polarized light. • In TG / DSC analysis, no significant mass loss was observed in the TG trace before decomposition (above 310°C). Endothermic events due to melting were observed in the DSC trace (start temperature 239°C). See Figure 54. · 1 The 1H NMR spectrum was consistent with the structure. 0.32 wt.% (0.04 equivalents) of THF was present in the sample. See Figure 55. Compound A 1 No peak shift was observed compared to 1H NMR. • DSC analysis of free base pattern 1 revealed a sharp endothermic event in the first heating cycle, starting at 239°C and peaking at 242°C, which was attributed to material melting. See Figure 56. • During the cooling cycle, an exothermic event was observed, starting at 164°C and peaking at 158°C. A glass transition was also observed with an intermediate point at 119°C. See Figure 57. • The fever phenomenon was also observed in DSC analysis of a 3g batch of compound A pattern 1, thus confirming that it is inherent to that morphology. • In the second heating cycle, a glass transition with an intermediate point of 123°C and a broad endothermic event starting at 147°C were observed. See Figure 58. The endothermic phenomenon was also observed in DSC analysis of a 3g batch of compound A pattern 1, thus confirming its inherent properties for that morphology. See Figures 83-85. Modulated DSC analysis was performed on a 3g batch of compound A pattern 1. Endothermic melting events were observed in both reversible and irreversible heat flows, with slightly different onset temperatures at 239°C and 237°C, respectively. Furthermore, an exothermic event starting at 245°C was observed in the irreversible heat flow, which is likely due to decomposition. (Figure 59) • DVS analysis of free base pattern 1 determined that the material is slightly hygroscopic, with a water absorption mass of 1.17 wt.% (0.53 equivalents). The isotherm plot was of type 1. See Figure 60. No morphological changes were observed in the reaction kinetic plot. See Figure 61. XRPD analysis confirmed no morphological changes after DVS. See Figure 62. • For optical rotation, the sample and blank were prepared in DCM. Optical rotation revealed a relative rotation of -11.460° at 0.00969 g / mL in DCM for free base pattern 1.

number

[0301] Free base pattern 2 PLM analysis revealed small particles with indistinct morphologies. Aggregation was observed. The material appeared to be birefringent under polarized light. • In the TG / DSC of free base pattern 2, a small mass loss of 0.97 wt.% was found in the TG trace at the start of the experiment, which is likely due to surface moisture. Decomposition was observed above 305°C. In the DSC trace, a small exothermic event was observed (starting at 222°C). An endothermic event due to melting followed (starting at 242°C). · 1The 1H NMR spectrum was consistent with its structure. No residual solvent was observed in the sample. Compound A 1 No peak shift was observed compared to 1H NMR.

[0302] Free base pattern 6 PLM analysis revealed very small particles with indistinct morphology. Aggregation was observed. The material exhibited weak birefringence under polarized light. • TG / DSC analysis revealed a small mass loss of 1.3 wt.% in the TG trace at the start of the experiment, which is likely due to surface moisture. Decomposition was observed above 305°C. Endothermic events due to melting were observed in the DSC trace (starting temperature 241°C). See Figure 65. · 1 The 1H NMR spectrum was consistent with the structure. 0.67 wt.% (0.08 equivalents) of THF was present in the sample. See Figure 66. Compound A 1 No peak shift was observed compared to 1H NMR.

[0303] Competitive slurry experiment Eight samples were prepared, each containing 10 mg of free base patterns 1, 2, and 6. • An appropriate solvent system was added, and the observation results were recorded. After shaking at ambient temperature or 40°C, observations were recorded, and the sample was centrifuged and filtered. The resulting solid was analyzed by XRPD. See Table 33 for details of the experiment and observations. [Table 35]

[0304] Since no definitive results were obtained, the solids were returned to the sample vials, and 100 μL of a suitable solvent was added to each sample. The samples were then capped and sealed with Parafilm, and shaken at ambient temperature or at 40°C as before. • After shaking for 72 hours, the solid was analyzed using XRPD.

[0305] Competitive slurry in ethanol • A competitive slurry experiment was prepared by combining approximately 5 mg each of compound A patterns 1, 2, and 6. 200 μL of ethanol was added to obtain an off-white slurry. The sample was shaken at 40°C for approximately 72 hours. After 72 hours, an off-white slurry was obtained, which was filtered by centrifugal filtration. • The solid was analyzed using XRPD. • Free base pattern 1 was obtained from a competitive slurry in ethanol.

[0306] Competitive slurries in DCM / ethanol A 1:1 mixture of 5 mg of compound A patterns 1 and 2 was prepared in a 2 mL screw-cap sample vial. A mixture of 1 mg of compound A pattern 1 and 4 mg of compound A pattern 2 was prepared in a 2 mL screw-cap sample vial. Because the remaining material for Pattern 1 after scaling up was insufficient, the material was recovered from the primary crystallization screen and dried at 40°C for approximately 3 hours. • 500 μL of 5% DCM in ethanol was added to a 1:1 mixture, and 500 μL of 10% DCM in ethanol was added to a 1:4 mixture to form a slurry. Both samples were capped, sealed in Parafilm, and shaken around over the weekend. After approximately 72 hours, the solid was isolated by centrifuging at 7500 rpm for 60 seconds and analyzed by XRPD. • Compound A pattern 1 was obtained from the sample in ethanol with 5% DCM, and compound A pattern 2 was obtained from the sample in ethanol with 10% DCM. • Although free base pattern 1 was determined to be the thermodynamic form, it was shown that DCM prefers free base pattern 2. [Table 36] [Table 37]

[0307] Heating experiment of compound A free base pattern 1 Approximately 4 mg of compound A pattern 1 was heated to 250°C using TG / DSC. Next, the sample, 1 Analysis was performed using 1HNMR. • After heating the sample to 250°C, 1 No changes were observed in the 1H NMR spectrum. This indicates that the sample did not decompose after being heated to this temperature. (Figure 67) [Table 38] [Table 39] [Table 40] [Table 41]

[0308] Example 10. Secondary salt screening of compound A Scale up • 250 mg of three free base samples were dissolved in a suitable solvent system to obtain a clear purple solution. • 1.05 equivalents of an appropriate acid were added to each sample. See Table 40 for details on the scale-up experiment. [Table 42] The sample vials were capped and sealed in Parafilm, then temperature-cycled between ambient temperature and 40°C for approximately 72 hours in 4-hour cycles. Observations were recorded before and after the temperature cycle. See Table 41. [Table 43] The sample was centrifuged and filtered, and the solid obtained from the slurry was analyzed using XRPD. The solid and gel were dried under vacuum at 40°C for approximately 20 hours. • The dried solid was analyzed by XRPD and then subjected to NMR analysis. The sample was re-slurred in 1.5 mL of a suitable solvent system. A further 1.05 equivalents of a stock solution of phosphoric acid was added to the phosphate sample. Next, the samples were subjected to a temperature cycle of 4 hours between ambient temperature and 40°C for a total of one week. • After one week, the sample was isolated by centrifugation, and the solid was analyzed using XRPD. For details and observations made during the second trial, please refer to Table 42. [Table 44] Next, the solid was gently dried at approximately 40°C for about 20 hours. • The dried solid was analyzed by XRPD, multinuclear NMR, CAD (where applicable), and TG / DSC.

[0309] NMR analysis of the material after the initial scale-up trial. • Tosylate sample before reslurrying 1 ¹H NMR spectroscopy determined that the ratio of p-toluenesulfonic acid to the free base of compound A was 1:1. 0.32 wt.% (0.04 equivalents) of THF was present in the sample. 1 A slight peak shift was observed compared to 1H NMR. • Besilate sample 1 The 1H NMR spectrum was consistent with the structure, and a 1:1 ratio of benzenesulfonic acid to the free base of compound A was observed. 4.04 wt.% (0.5 equivalents) of THF was present in the sample. 1 A slight peak shift was observed compared to 1H NMR. • Phosphate samples 1The 1H NMR spectrum was consistent with the structure. No solvent was observed in the sample. 31 No phosphorus peak was observed in the P NMR spectrum of compound A. 1 Compared to 1H NMR, no peak shift was observed. Since this was not a phosphate, additional phosphate was added to the sample.

[0310] Scaled-up salt characterization Tosylate Pattern 1 • The scaled-up sample matched the target pattern obtained by XRPD. PLM analysis revealed very small particles, whose morphology was indistinct due to their small size. Aggregation was observed. The material appeared to be weakly birefringent under polarized light. A 1:1 ratio of compound A to p-toluenesulfonic acid was observed in the spectrum. Approximately 0.24 wt% (0.03 equivalents) of THF was present in the sample. See Figure 68. 1 A slight peak shift was observed compared to 1H NMR. • In the TG trace, a mass loss of 3.1 wt.% (1.23 equivalents of water or 0.31 equivalents of THF) was observed between approximately 90°C and 220°C. Decomposition was observed above 280°C. In the DSC trace, an endothermic melting event starting at 197.5°C was observed. See Figure 69.

[0311] Besilate pattern 1 • The scaled-up sample matched the target pattern obtained by XRPD. PLM analysis revealed very small particles with indistinct morphology. Aggregation was observed. The material appeared to be weakly birefringent under polarized light. · 1 ¹H NMR spectroscopy determined that the ratio of compound A to benzenesulfonic acid was 1:1. 3.02 wt.% (0.4 equivalents) of THF was observed in the sample. See Figure 70. 1 A slight peak shift was observed compared to 1H NMR. • In the TG trace, a mass loss of 0.9 wt.% (0.5 equivalents of water or 0.12 equivalents of THF) was observed from the start of the experiment, which is likely surface moisture. A second mass loss of 0.9 wt. (0.5 equivalents of water or 0.12 equivalents of THF) was observed between 45°C and 90°C. A third, larger mass loss of 1.45 wt.% (0.79 equivalents of water or 0.20 equivalents of THF) was observed between 100°C and 175°C. Decomposition was observed above 210°C. Two endothermic events were observed in the DSC trace: the first started at 184°C (melting) and the second started at 261°C. See Figure 71.

[0312] Phosphate pattern 1 • The scaled-up sample matched the target pattern obtained by XRPD. PLM analysis revealed very small particles with indistinct morphology. Aggregation was observed. The material appeared to be weakly birefringent under polarized light. · 1 The 1H NMR spectrum was consistent with the structure and contained a broad water peak indicating salt formation. No residual solvent was observed in the sample. See Figure 72. Compound A 1 No peak shift was observed compared to 1H NMR. 31 A phosphorus peak was observed in the 3P NMR spectrum. See Figure 73. • In the TG trace, a mass loss of 0.5 wt.% (0.24 equivalents of water or 0.06 equivalents of THF) was observed from the start of the experiment. Another mass loss of 6.5 wt.% (3.5 equivalents of water or 0.9 equivalents of THF) was observed between 70°C and 160°C. Decomposition was observed above 270°C. Broad endothermic events were observed in the DSC trace related to the mass loss between 50°C and 160°C. See Figure 74. CAD analysis revealed the presence of 22.2% w / w of phosphate, which corresponds to approximately 2 equivalents of phosphate (1 equivalent = 10.8 wt.%, 2 wt. = 19.5 wt.%). [Table 45]

[0313] Example 11. Determination of thermodynamic solubility The solubility of compound A free base pattern 1, compound A tosylate, compound A besylate, and compound A phosphate was determined using the following procedure. Approximately 5 mg of the selected compound A was weighed and placed in a clear glass vial, and 2 mL of buffer was added. In both cases, the slurry persisted. The pH of the solution was determined and then adjusted as needed. The slurry was stirred at 25°C. • At each time point, aliquots were isolated, filtered through a 0.22 μm nylon filter, and then injected into HPLC without dilution. The LOQ (Low-Level Quantity) determined by HPLC was 0.00025 mg / mL. • All data were reported in terms of the concentration of free base of compound A. Unfortunately, the solubility was too low to detect any of the samples at pH 3.0 and pH 4.0 by HPLC. These were reported to have a solubility of <0.00025 mg / mL, which was the LOQ for the experiment. Free base pattern 1 had the highest solubility at pH 1.2 after 24 hours, at 0.0693 mg / mL. • Of the salts, the phosphate showed the highest solubility at pH 1.2 after 24 hours, at 0.0306 mg / mL. No clear solubility advantage of the salt over compound A free base was observed. For a complete summary of the thermodynamic solubility determination results, see Table 44. [Table 46]

[0314] Example 12. 7-day stability evaluation Three samples were prepared: 10-15 mg each of compound A free base patterns 1 and 2, and compound A tosylate and besylate. These were stored under the following stability conditions: • 40℃ / 75%RH (Opened vial) • 80℃ (sealed vial) • Ambient light (sealed vial) • The appearance of the sample was recorded daily to monitor color changes. • After 7 days, the samples were analyzed by HPLC and XRPD. • In addition, HPLC analysis was performed before the stability test. The appearance of the samples remained unchanged after 7 days under each stability condition. They all remained white or off-white solids. • XRPD analysis determined that the pattern was preserved. Additional peaks were obtained in the tosylate sample. See Figures 75-78. • High purity was maintained in all samples. 〇 Relative area of ​​free base pattern 1 > 99% 〇 Relative area of ​​free base pattern 2 > 98% ○ Relative area of ​​tosylate pattern 1 > 96% ○ Relative area of ​​besylate pattern 1 > 97% For a summary of the results and a table of impurity peaks, please refer to the following. [Table 47] [Table 48] [Table 49] [Table 50] [Table 51] [Table 52] [Table 53] [Table 54] [Table 55] [Table 56] [Table 57] [Table 58] [Table 59] [Table 60] [Table 61] [Table 62] [Table 63]

[0315] Example 13. 3G scale-up of Compound A Pattern 1 Approximately 3 g of amorphous compound A was added to a pre-weighed scintillation vial. 5 mL of THF was added to obtain a purple slurry. A magnetic stirring rod was added, and the sample was subjected to a temperature cycle at a heating rate of 0.1 °C / min between 20 °C and 40 °C, holding at 20 °C and 40 °C for 2 hours. After approximately 3 hours, the sample was examined, and a thick off-white slurry was observed. An additional 5 mL of THF was added to obtain a mobile slurry. After approximately 72 hours, the sample was a thick, off-white slurry. It was filtered through a Buchner funnel and dried on a filter bed for about 5 minutes. Secondary samples were analyzed by XRPD. Pattern 1 was found to be poorly crystallin. The samples were gently dried at 40°C for about 20 hours and then re-analyzed by XRPD. • 25 mg of free base pattern 1 seed crystal material was added to the material, and the sample was re-slurred in 7 mL of ethanol. The slurry was temperature-cycled between ambient temperature and 40°C for approximately 24 hours in 4-hour cycles. Secondary samples were analyzed by XRPD, and then the material was gently dried at 40°C and re-analyzed by XRPD. • Samples exhibiting poor crystallinity (Pattern 1) were re-slurred in 10 mL of methanol:DCM (90:10% v / v) using 5 mg of free basic Pattern 1 seed crystals, and then temperature-cycled between ambient temperature and 40°C for approximately 72 hours in 4-hour cycles. A mixture of free base patterns 2 and 7 was obtained. The sample was filtered by Buchner filtration and then completely dried in the open at room temperature under vacuum for approximately 3 hours. The dried sample was re-slurried in 10 mL of ethanol using a 3.5 mg seed crystal of free basicity pattern 1, and then temperature-cycled between ambient temperature and 40°C for approximately 48 hours in 4-hour cycles. After 48 hours, a concentrated slurry was obtained and dried by Buchner filtration. By-samples were analyzed by XRPD, confirming the successful conversion of the sample to pattern 1. The materials were placed in pre-weighed scintillation vials, covered with tissue paper, and gently dried in a 40°C oven for approximately 20 hours. • Dry materials, XRPD, PLM, TG / DSC, DSC, Modulated DSC, 1 Analysis was performed by 1H NMR and HPLC.

[0316] result • Samples from THF yielded pattern 1, indicating poor crystallinity. This pattern was retained after reslurrying in ethanol using a seed crystal of pattern 1. Analysis of this sample by PLM revealed very small, weakly birefringent particles with indistinct morphology. The small particle size likely contributed to the appearance of the XRPD pattern. A mixture of free base patterns 2 and 7 was obtained after temperature cycling in methanol:DCM (90:10 %v / v) for approximately 72 hours. • Free base pattern 1 was successfully scaled up by slurrying the materials of free base patterns 2 and 7 in ethanol using the seed crystal material of pattern 1. • A 3g scale-up of compound A pattern 1 yielded 2.68g (90.2% yield).

[0317] Characterization of compound A in 3g scale-up pattern 1 • The XRPD pattern matched previously identified free base pattern 1. See Figure 80. PLM analysis detected small birefringent particles approximately 5 μm in size. Their morphology was indistinct. · 1 The 1H NMR spectrum matched the free base spectrum. 0.6 wt.% (0.1 equivalent) of ethanol and 1.1 wt.% (0.1 equivalent) of IPA were observed in the spectrum. See Figure 81. No peak shift was observed compared to compound A. • In the TG trace, no mass loss was observed until decomposition at approximately 310°C. In the DSC trace, a sharp endothermic event corresponding to melting was observed, starting at 240°C. See Figure 82. • DSC analysis was performed on this batch, and the exothermic and endothermic events observed during the cooling and second heating cycles, respectively, were consistent with the batch's morphology and not artifacts. During the first heating cycle, a sharp endothermic melting was observed, starting at 241°C, which was consistent with previous data. See Figure 83. • In the DSC cooling cycle, an exothermic event was observed, starting at 168°C and peaking at 167°C (previous batches had a broader event, starting at 164°C and peaking at 158°C). A glass transition was also observed with an intermediate point at 118°C (previously 119°C). See Figure 84. • In the second heating cycle, a glass transition was observed with an intermediate point at 123°C (the same temperature as before), and an endothermic event was observed that began at 166°C with a peak at 168°C, and this event had a shoulder at the peak of 156°C. (Previously, it began at 147°C and a peak was observed at 162°C. See Figure 85.) • Exothermic and endothermic events were observed in DSC analysis of this batch and previous batches, and were therefore confirmed to be due to the free base morphology. See Figures 56-58 for previous batches. • HPLC analysis determined the batch purity to be 97.35% based on relative area.

[0318] Equal portions While the present invention has been described in conjunction with the specific embodiments described above, many alternatives, modifications, and other variations thereto will be apparent to those skilled in the art. All such alternatives, modifications, and variations are intended to be within the spirit and scope of the present invention.

[0319] List of embodiments Aspects of this disclosure will be further described with reference to the following embodiments:

[0320] A. Solid form of compound A: [ka]

[0321] B. The solid form described in Embodiment A, wherein the solid form is crystalline.

[0322] C. The solid form described in Embodiment A, wherein the solid form is amorphous.

[0323] D. A solid-state according to any of the prior embodiments, characterized by a crystalline polymorphism comprising two or three XRPD signals selected from the group consisting of 18.6°2θ, 13.9°2θ, and 15.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0324] E. A solid-state according to any of the prior embodiments, characterized by a crystalline polymorphism with XRPD signals at 18.6°2θ, 13.9°2θ, and 15.3°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0325] F. The solid form described in any of the prior embodiments, which is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 80 or Figure 86.

[0326] G. A solid form according to any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41 XRPD signals selected from those listed in Table 1.

[0327] H. A solid-state according to any of the prior embodiments, characterized by a crystalline polymorphism comprising two or three XRPD signals selected from the group consisting of 14.4°2θ, 19.1°2θ, and 15.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0328] I. A solid-state according to any of the prior embodiments, characterized by a crystalline polymorphism with XRPD signals at 14.4°2θ, 19.1°2θ, and 15.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0329] J. The solid form described in any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 87.

[0330] K. A solid form according to any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 XRPD signals selected from those listed in Table 2.

[0331] L. A solid form according to any of the prior embodiments, characterized by a crystalline polymorphism comprising two or more XRPD signals selected from the group consisting of 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, and 16.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0332] M. A solid form according to any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by XRPD signals at 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, and 16.8°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0333] N. The solid form described in any of the prior embodiments, which is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 88.

[0334] O. The solid form described in any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 XRPD signals selected from those listed in Table 3.

[0335] P. A solid-state according to any of the prior embodiments, characterized by a crystalline polymorphism comprising two or three XRPD signals selected from the group consisting of 14.6°2θ, 17.7°2θ, and 16.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0336] Q. The solid form described in any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by XRPD signals at 14.6°2θ, 17.7°2θ, and 16.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0337] R. The solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 89, as described in any of the prior embodiments.

[0338] S. A solid form according to any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 XRPD signals selected from those listed in Table 4.

[0339] T. A solid-state according to any of the prior embodiments, characterized by a crystalline polymorphism comprising two or three XRPD signals selected from the group consisting of 14.9°2θ, 22.6°2θ, and 7.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0340] U. A solid-state according to any of the prior embodiments, wherein the solid-state is a crystalline polymorph characterized by XRPD signals at 14.9°2θ, 22.6°2θ, and 7.1°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0341] V. The solid form described in any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 90.

[0342] W. A solid form according to any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 XRPD signals selected from those listed in Table 5.

[0343] X. A solid-state according to any of the prior embodiments, characterized by a crystalline polymorphism comprising two or three XRPD signals selected from the group consisting of 3.5°2θ, 3.6°2θ, and 15.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0344] Y. A solid-state according to any of the prior embodiments, wherein the solid-state is a crystalline polymorph characterized by XRPD signals at 3.5°2θ, 3.6°2θ, and 15.7°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0345] Z. The solid form described in any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 91.

[0346] AA. A solid form according to any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 XRPD signals selected from those listed in Table 6.

[0347] BB. A solid-state according to any of the prior embodiments, characterized by a crystalline polymorphism comprising two or three XRPD signals selected from the group consisting of 4.8°2θ, 15.7°2θ, and 17.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0348] CC. A solid-state according to any of the prior embodiments, wherein the solid-state is a crystalline polymorph characterized by XRPD signals at 4.8°2θ, 15.7°2θ, and 17.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0349] DD. The solid-state form described in any of the prior embodiments, wherein the solid-state form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 92.

[0350] EE. A solid-state form according to any of the prior embodiments, wherein the solid-state form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 XRPD signals selected from those listed in Table 7.

[0351] FF. A solid-state form according to any of the prior embodiments, characterized by a crystalline polymorphism comprising two or three XRPD signals selected from the group consisting of 4.9°2θ, 15.9°2θ, and 18.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0352] GG. A solid-state according to any of the prior embodiments, wherein the solid-state is a crystalline polymorph characterized by XRPD signals at 4.9°2θ, 15.9°2θ, and 18.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0353] HH. The solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 93, as described in any of the prior embodiments.

[0354] II. A solid form according to any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 XRPD signals selected from those listed in Table 8.

[0355] JJ. A solid-state form according to any of the prior embodiments, characterized by a crystalline polymorphism having two or three XRPD signals selected from the group consisting of 17.2°2θ, 21.0°2θ, and 24.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0356] KK. A solid-state according to any of the prior embodiments, wherein the solid-state is a crystalline polymorph characterized by XRPD signals at 17.2°2θ, 21.0°2θ, and 24.2°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0357] LL. The solid-state form described in any of the prior embodiments, wherein the solid-state form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 94.

[0358] MM. A solid form according to any of the prior embodiments, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 XRPD signals selected from those listed in Table 9.

[0359] NN. Tosylate of compound A: [ka]

[0360] OO. The tosylate salt described in Embodiment 40, wherein the tosylate salt is crystalline.

[0361] PP. The tosylate described in Embodiment 40, wherein the tosylate is amorphous.

[0362] QQ. A tosylate according to any of the prior embodiments, wherein the tosylate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 3.5°2θ, 22.0°2θ, and 23.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0363] RR. A tosylate according to any of the prior embodiments, wherein the tosylate is a crystalline polymorph characterized by XRPD signals at 3.5°2θ, 22.0°2θ, and 23.0°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0364] SS. A tosylate according to any of the prior embodiments, wherein the tosylate is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 95.

[0365] TT. A tosylate according to any of the prior embodiments, wherein the tosylate is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 XRPD signals selected from those listed in Table 10.

[0366] UU. A tosylate according to any of the prior embodiments, wherein the tosylate:compound A is a 1:1 salt.

[0367] VV. A tosylate according to any of the prior embodiments, wherein the tosylate:compound A is a 2:1 salt.

[0368] WW. A tosylate according to any of the prior embodiments, wherein the tosylate:compound A is a salt in a 1:2 ratio.

[0369] XX. Phosphate of compound A: [ka]

[0370] YY. The phosphate according to Embodiment 50, wherein the phosphate is crystalline.

[0371] ZZ. The phosphate according to Embodiment 50, wherein the phosphate is amorphous.

[0372] AAA. A phosphate according to any of the prior embodiments, wherein the phosphate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 23.6°2θ, 3.3°2θ, and 19.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0373] BBB. A phosphate according to any of the prior embodiments, wherein the phosphate is a crystalline polymorph characterized by XRPD signals at 23.6°2θ, 3.3°2θ, and 19.9°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0374] CCC. The phosphate according to any of the prior embodiments, wherein the phosphate is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 96.

[0375] DDD. A phosphate according to any of the prior embodiments, wherein the phosphate is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 XRPD signals selected from those listed in Table 11.

[0376] EEE. A phosphate according to any of the prior embodiments, wherein the phosphate:compound A is a 1:1 salt.

[0377] FFF. A phosphate according to any of the prior embodiments, wherein the phosphate:compound A is a salt in a 2:1 ratio.

[0378] GGG. A phosphate according to any of the prior embodiments, wherein the phosphate:compound A is a salt in a 1:2 ratio.

[0379] HHH. Besylate of compound A: [ka]

[0380] III. The besilate salt described in Embodiment 60, wherein the besilate salt is crystalline.

[0381] A besilate salt according to Embodiment 60 of JJJ, wherein the besilate salt is amorphous.

[0382] KKK. A besilate according to any of the prior embodiments, wherein the besilate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 18.5°2θ, 18.3°2θ, and 22.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0383] LLL. A besylate according to any of the prior embodiments, wherein the besylate is a crystalline polymorph characterized by XRPD signals at 18.5°2θ, 18.3°2θ, and 22.6°2θ (±0.2°2θ, ±0.1°2θ, or ±0.0°2θ; Cu Kα1 line).

[0384] MMM. A besylate described in any of the prior embodiments, wherein the besylate is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 97.

[0385] NNN. A besilate according to any of the prior embodiments, wherein the besilate is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 XRPD signals selected from those listed in Table 12.

[0386] OOO. A besilate according to any of the prior embodiments, wherein the besilate is a salt in a 1:1 ratio with compound A.

[0387] PPP. A besilate according to any of the prior embodiments, wherein the besilate:compound A is a 2:1 salt.

[0388] QQQ. A besylate according to any of the prior embodiments, wherein the besylate:compound A is a 1:2 salt.

[0389] RRR. A method for treating prostate cancer in a subject requiring treatment for prostate cancer, comprising administering to the subject a therapeutically effective amount of a solid form or salt described in any one of the prior embodiments.

[0390] SSS. The method according to any one of the prior embodiments, further comprising administering an effective dose of at least one further anticancer agent to the subject.

[0391] TTT. The method according to any one of the prior embodiments, wherein the prostate cancer is metastatic prostate cancer.

[0392] UUU. The method according to any one of the prior embodiments, wherein the prostate cancer is castration-resistant prostate cancer.

[0393] VVV. The method according to any one of the prior embodiments, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

[0394] WWW. The method according to any one of the prior embodiments, wherein the prostate cancer is castration-sensitive prostate cancer.

[0395] XXX. The method according to any one of the prior embodiments, wherein the prostate cancer is metastatic castration-sensitive prostate cancer.

[0396] YYY. The method according to any one of the prior embodiments, wherein the prostate cancer is a prostate cancer that is naive to a novel hormonal agent (NHA).

[0397] ZZZ. The method according to the prior claim, wherein the prostate cancer is naive to the novel hormonal agent (NHA) and has not been previously treated with a second-generation anti-androgen agent.

[0398] AAAA. The method according to any one of the prior embodiments, wherein the metastatic prostate cancer is a metastatic prostate cancer that is naive to a novel hormonal agent (NHA).

[0399] BBBB. The method according to any one of the prior embodiments, wherein the prostate cancer is a castration-resistant prostate cancer naive to a novel hormonal agent (NHA).

[0400] CCCC. The method according to the prior claim, wherein castration-resistant prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation antiandrogen.

[0401] DDDD. The method according to any one of the prior embodiments, wherein the prostate cancer is a castration-sensitive prostate cancer that is naive to a novel hormonal agent (NHA).

[0402] EEEE. The method according to the prior claim, wherein castration-sensitive prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation antiandrogen.

[0403] FFFF. The method according to any one of the prior embodiments, wherein the prostate cancer is metastatic castration-resistant prostate cancer naive to a novel hormonal agent (NHA).

[0404] GGGG. The method according to the prior claim, wherein metastatic castration-resistant prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation antiandrogen.

[0405] HHHH. The method according to any one of the prior embodiments, wherein the prostate cancer is metastatic castration-sensitive prostate cancer naive to a novel hormonal agent (NHA).

[0406] IIII. The method according to the prior claim, wherein metastatic castration-sensitive prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation antiandrogen.

[0407] JJJJ. The method according to any one of the prior embodiments, wherein the prostate cancer has not been previously treated with either an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0408] KKKK. The method according to any one of the prior embodiments, wherein the prostate cancer has not been previously treated with abiraterone acetate.

[0409] LLLL. The method according to any one of the prior embodiments, wherein the prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

[0410] MMMM. The method according to one of the prior embodiments, wherein the subject has not previously been administered either an androgen biosynthesis inhibitor or an androgen receptor blocker.

[0411] NNNN. The method according to one of the prior embodiments, wherein the subject has not been previously administered abiraterone acetate.

[0412] OOOO. The method according to any one of the prior embodiments, wherein the subject has not previously been administered an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

Claims

1. Solid form of compound A: 【Chemistry 1】 The solid form is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 18.6°2θ, 13.9°2θ, and 15.3°2θ (±0.2°2θ Cu Kα1 line).

2. The solid form according to claim 1, wherein the solid form is a crystalline polymorph characterized by XRPD signals at 18.6°2θ, 13.9°2θ, and 15.3°2θ (±0.2°2θ Cu Kα1 line).

3. Solid form of compound A: 【Chemistry 2】 The solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 80 or Figure 86.

4. Solid form of compound A: 【Transformation 3】 The solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41 XRPD signals selected from those listed in Table 1.

5. Solid form of compound A: 【Chemistry 4】

6. The solid form according to claim 5, wherein the solid form is crystalline.

7. The solid form according to claim 5, wherein the solid form is amorphous.

8. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 14.4°2θ, 19.1°2θ, and 15.8°2θ (±0.2°2θ Cu Kα1 line).

9. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 87.

10. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 XRPD signals selected from those listed in Table 2.

11. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by two or more XRPD signals selected from the group consisting of 20.6°2θ, 16.1°2θ, 16.3°2θ, 17.3°2θ, and 16.8°2θ (±0.2°2θ Cu Kα1 line).

12. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 88.

13. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 XRPD signals selected from those listed in Table 3.

14. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 14.6°2θ, 17.7°2θ, and 16.7°2θ (±0.2°2θ Cu Kα1 line).

15. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 89.

16. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 XRPD signals selected from those listed in Table 4.

17. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 14.9°2θ, 22.6°2θ, and 7.1°2θ (±0.2°2θ Cu Kα1 line).

18. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 90.

19. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 XRPD signals selected from those listed in Table 5.

20. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 3.5°2θ, 3.6°2θ, and 15.7°2θ (±0.2°2θ Cu Kα1 line).

21. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 91.

22. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 XRPD signals selected from those listed in Table 6.

23. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 4.8°2θ, 15.7°2θ, and 17.9°2θ (±0.2°2θ Cu Kα1 line).

24. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 92.

25. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 XRPD signals selected from those listed in Table 7.

26. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 4.9°2θ, 15.9°2θ, and 18.2°2θ (±0.2°2θ Cu Kα1 line).

27. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 93.

28. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 XRPD signals selected from those listed in Table 8.

29. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 17.2°2θ, 21.0°2θ, and 24.2°2θ (±0.2°2θ Cu Kα1 line).

30. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by an XRPD spectrum substantially similar to that shown in Figure 94.

31. The solid form according to claim 5 or 6, wherein the solid form is a crystalline polymorph characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 XRPD signals selected from those listed in Table 9.

32. Tosylate of compound A: 【Transformation 5】

33. The tosylate salt according to claim 32, wherein the tosylate salt is crystalline.

34. The tosylate salt according to claim 32, wherein the tosylate salt is amorphous.

35. The tosylate according to claim 32 or 33, wherein the tosylate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 3.5°2θ, 22.0°2θ, and 23.0°2θ (±0.2°2θ Cu Kα1 line).

36. Phosphate of compound A: 【Transformation 6】

37. The phosphate according to claim 36, wherein the phosphate is crystalline.

38. The phosphate according to claim 36, wherein the phosphate is amorphous.

39. The phosphate according to claim 36 or 37, wherein the phosphate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 23.6°2θ, 3.3°2θ, and 19.9°2θ (±0.2°2θ Cu Kα1 line).

40. Besylate of compound A: 【Transformation 7】

41. The besilate salt according to claim 40, wherein the besilate salt is crystalline.

42. The besilate salt according to claim 40, wherein the besilate salt is amorphous.

43. The besilate according to claim 40 or 41, wherein the besilate is a crystalline polymorph characterized by two or three XRPD signals selected from the group consisting of 18.5°2θ, 18.3°2θ, and 22.6°2θ (±0.2°2θ Cu Kα1 line).

44. A method for treating prostate cancer in a subject requiring treatment for prostate cancer, comprising administering to the subject a therapeutically effective amount of a solid form or salt according to any one of claims 1-43.

45. The method according to claim 44, wherein the prostate cancer is metastatic prostate cancer.

46. The method according to claim 44, wherein the prostate cancer is castration-resistant prostate cancer.

47. The method according to claim 44, wherein the prostate cancer is metastatic castration-resistant prostate cancer.

48. The method according to claim 44, wherein the prostate cancer is castration-sensitive prostate cancer.

49. The method according to claim 44, wherein the prostate cancer is metastatic castration-sensitive prostate cancer.

50. The method according to claim 44, wherein the prostate cancer is a prostate cancer that is naive to a novel hormonal agent (NHA).

51. The method according to claim 50, wherein the prostate cancer is naive to the novel hormonal agent (NHA) and has not been previously treated with a second-generation anti-androgen agent.

52. The method according to claim 45, wherein the metastatic prostate cancer is a metastatic prostate cancer that is naive to a novel hormonal agent (NHA).

53. The method according to claim 52, wherein metastatic prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation antiandrogen.

54. The method according to claim 46, wherein the castration-resistant prostate cancer is a castration-resistant prostate cancer that is naive to a novel hormonal agent (NHA).

55. The method according to claim 54, wherein castration-resistant prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation anti-androgen agent.

56. The method according to claim 48, wherein the castration-sensitive prostate cancer is a castration-sensitive prostate cancer that is naive to a novel hormonal agent (NHA).

57. The method according to claim 56, wherein castration-sensitive prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation antiandrogen.

58. The method according to claim 47, wherein the metastatic castration-resistant prostate cancer is a metastatic castration-resistant prostate cancer that is naive to a novel hormonal agent (NHA).

59. The method according to claim 58, wherein metastatic castration-resistant prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation antiandrogen.

60. The method according to claim 49, wherein the metastatic castration-sensitive prostate cancer is a metastatic castration-sensitive prostate cancer that is naive to a novel hormonal agent (NHA).

61. The method according to claim 60, wherein metastatic castration-sensitive prostate cancer naive to the novel hormonal agent (NHA) has not been previously treated with a second-generation antiandrogen.

62. The method according to any one of claims 44-61, wherein the prostate cancer has not been previously treated with either an androgen biosynthesis inhibitor or an androgen receptor blocker.

63. The method according to any one of claims 44-62, wherein the prostate cancer has not been previously treated with abiraterone acetate.

64. The method according to any one of claims 44-62, wherein the prostate cancer has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

65. The method according to any one of claims 44-62, wherein the subject has not previously been administered either an androgen biosynthesis inhibitor or an androgen receptor blocker.

66. The method according to any one of claims 44-62, wherein the subject has not previously been administered abiraterone acetate.

67. The method according to any one of claims 44-62, wherein the subject has not previously been administered an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.

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