Patent Application
20240336566
The disclosure provides novel salts and salt forms of Compound A:
and to processes for their preparation. The disclosure is also directed to pharmaceutical compositions containing at least one salt or salt form and to the therapeutic and/or prophylactic use of such salts, salt forms, and compositions thereof. These salts and salt forms are useful as modulators of targeted ubiquitination, especially with respect to a variety of polypeptides and other proteins, which are degraded and/or otherwise inhibited by the salts and salt forms of the present disclosure.
Most small molecule drugs bind enzymes or receptors in tight and well-defined pockets. On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination, and are therefore attractive therapeutic targets. The development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands which bind to these ligases.
One E3 ubiquitin ligase with therapeutic potential is cereblon. Cereblon is a protein that in humans is encoded by the CRBN gene. Thalidomide and its analogs, e.g., pomalidomide and lenalidomide, are known to bind cereblon. These agents bind to cereblon, altering the specificity of the complex to induce the ubiquitination and degradation of transcription factors essential for multiple myeloma growth. Indeed, higher expression of cereblon has been linked to an increase in efficacy of imide drugs in the treatment of multiple myeloma.
Androgen Receptor (AR) belongs to a nuclear hormone receptor family that is activated by androgens, such as testosterone and dihydrotestosterone (Pharmacol. Rev. 2006, 58 (4), 782-97; Vitam. Horn. 1999, 55:309-52.). In the absence of androgens, AR is bound by Heat Shock Protein 90 (Hsp90) in the cytosol. When an androgen binds AR, its conformation changes to release AR from Hsp90 and to expose the Nuclear Localization Signal (NLS). The latter enables AR to translocate into the nucleus where AR acts as a transcription factor to promote gene expression responsible for male sexual characteristics (Endocr. Rev. 1987, 8 (1): 1-28; Mol. Endocrinol. 2002, 16 (10), 2181-7). AR deficiency leads to Androgen Insensitivity Syndrome, formerly termed testicular feminization.
While AR is responsible for development of male sexual characteristics, it is also a well-documented oncogene in certain forms of cancers including prostate cancers (Endocr. Rev. 2004, 25 (2), 276-308). A commonly measured target gene of AR activity is the secreted Prostate Specific Antigen (PSA) protein. The current treatment regimen for prostate cancer involves inhibiting the androgen-AR axis by two methods. The first approach relies on reduction of androgens, while 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. An alternative approach for the treatment of prostate cancer involves eliminating the AR protein.
Because AR is a critical driver of tumorigenesis in many forms of prostate cancers, its elimination should lead to a therapeutically beneficial response. There exists an ongoing need in the art for effective treatments for diseases, especially cancer, prostate cancer, and Kennedy's Disease.
However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage or potentiate cereblon's substrate specificity and, at the same time, are “tunable” such that a wide range of protein classes can be targeted and modulated with specificity would be very useful as a therapeutic.
The present disclosure is directed to Compound A:
and salts and solid forms thereof.
In some aspects, the present disclosure is directed to a free base form of Compound A.
In some embodiments, Compound A is crystalline.
In some embodiments, Compound A is amorphous.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, or forty-one XRPD signals selected from those set forth in Table 1.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, or forty XRPD signals selected from those set forth in Table 2.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, or nineteen XRPD signals selected from those set forth in Table 3.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, or twenty-four XRPD signals selected from those set forth in Table 4.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, or thirty-five XRPD signals selected from those set forth in Table 5.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, or thirty-six XRPD signals selected from those set forth in Table 6.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen XRPD signals selected from those set forth in Table 7.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or twenty-two XRPD signals selected from those set forth in Table 8.
In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation). In some embodiments, the solid form of Compound A is a crystalline polymorphic form 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 radiation).
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the solid form of Compound A is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, or forty-two XRPD signals selected from those set forth in Table 9.
In some aspects, the present disclosure is directed to a tosylate salt of Compound A.
In some embodiments, the tosylate salt is crystalline.
In some embodiments, the tosylate salt is amorphous.
In some embodiments, the tosylate salt is a crystalline polymorphic form 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 radiation). In some embodiments, the tosylate salt is a crystalline polymorphic form 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 radiation).
In some embodiments, the tosylate salt is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the tosylate salt is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen XRPD signals selected from those set forth in Table 10.
In some embodiments, the tosylate salt is a 1:1 tosylate:Compound A salt.
In some embodiments, the tosylate salt is a 2:1 tosylate:Compound A salt.
In some embodiments, the tosylate salt is a 1:2 tosylate:Compound A salt.
In some aspects, the present disclosure is directed to a phosphate salt of Compound A.
In some embodiments, the phosphate salt is crystalline.
In some embodiments, the phosphate salt is amorphous.
In some embodiments, the phosphate salt is a crystalline polymorphic form 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 radiation). In some embodiments, the phosphate salt is a crystalline polymorphic form 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 radiation).
In some embodiments, the phosphate salt is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the phosphate salt is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen XRPD signals selected from those set forth in Table 11.
In some embodiments, the phosphate salt is a 1:1 phosphate:Compound A salt, i.e., a monophosphate salt of Compound A.
In some embodiments, the phosphate salt is a 2:1 phosphate:Compound A salt, i.e., a bisphosphate salt of Compound A.
In some embodiments, the phosphate salt is a 1:1 phosphate:Compound A salt or a 2:1 phosphate:Compound A salt.
In some embodiments, the phosphate salt is a 1:2 phosphate:Compound A salt, i.e., a hemiphosphate salt of Compound A.
In some aspects, the present disclosure is directed to a besylate salt of Compound A.
In some embodiments, the besylate salt is crystalline.
In some embodiments, the besylate salt is amorphous.
In some embodiments, the besylate salt is a crystalline polymorphic form 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 radiation). In some embodiments, the besylate salt is a crystalline polymorphic form 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 radiation).
In some embodiments, the besylate salt is a crystalline polymorphic form characterized by an XRPD spectrum substantially similar to that shown in
In some embodiments, the besylate salt is a crystalline polymorphic form characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, or thirty XRPD signals selected from those set forth in Table 12.
In some embodiments, the besylate salt is a 1:1 besylate:Compound A salt.
In some embodiments, the besylate salt is a 2:1 besylate:Compound A salt.
In some embodiments, the besylate salt is a 1:2 besylate:Compound A salt.
In some aspects, the present disclosure is directed to a chloride salt of Compound A.
In some embodiments, the chloride salt is a 1:1 chloride:Compound A salt.
In some embodiments, the chloride salt is a 2:1 chloride:Compound A salt.
In some embodiments, the chloride salt is a 1:1 chloride:Compound A salt or a 2:1 chloride:Compound A salt.
In some embodiments, the chloride salt is a 1:2 chloride:Compound A salt.
In some aspects, the present disclosure is directed to a method of treating prostate cancer in a subject need thereof comprising administering to the subject a therapeutically effective amount of a solid form or salt of Compound A disclosed herein.
In some embodiments, the method further comprises administering an effective amount of at least one additional anti-cancer agent to the subject.
In some embodiments, the prostate cancer is metastatic prostate cancer.
In some embodiments, the prostate cancer is castrate-resistant prostate cancer.
In some embodiments, the prostate cancer is metastatic castrate-resistant prostate cancer.
In some embodiments, the prostate cancer is castrate-sensitive prostate cancer.
In some embodiments, the prostate cancer is metastatic castrate-sensitive prostate cancer.
In some embodiments, the prostate cancer has not been previously treated with a second generation antiandrogen. In some embodiments, the prostate cancer has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the prostate cancer has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the prostate cancer has not been previously treated with an androgen receptor blocker. In some embodiments, the prostate cancer has not been previously treated with abiraterone acetate. In some embodiments, the 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 a second generation antiandrogen. In some embodiments, the subject has not been previously administered an androgen biosynthesis inhibitor or an androgen receptor blocker. 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 subject has not been previously administered abiraterone acetate. In some embodiments, the subject has not been previously administered an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.
In some embodiments, the prostate cancer is prostate cancer naïve to novel hormonal agents (NHA). In some embodiments, the prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with one or more second generation antiandrogens. In some embodiments, the prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.
In some embodiments, the prostate cancer is metastatic prostate cancer naïve to novel hormonal agents (NHA). In some embodiments, the metastatic prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with one or more second generation antiandrogens. In some embodiments, the metastatic prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the metastatic prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the metastatic prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the metastatic prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the metastatic prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.
In some embodiments, the prostate cancer is castrate-resistant prostate cancer naïve to novel hormonal agents (NHA). In some embodiments, the castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with one or more second generation antiandrogens. In some embodiments, the castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.
In some embodiments, the prostate cancer is castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA). In some embodiments, the castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with one or more second generation antiandrogens. In some embodiments, the castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.
In some embodiments, the prostate cancer is metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA). In some embodiments, the metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with one or more second generation antiandrogens. In some embodiments, the metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.
In some embodiments, the prostate cancer is metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA). In some embodiments, the metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with one or more second generation antiandrogens. In some embodiments, the metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor or an androgen receptor blocker. In some embodiments, the metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen biosynthesis inhibitor. In some embodiments, the metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker. In some embodiments, the metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with abiraterone acetate. In some embodiments, the metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) has not been previously treated with an androgen receptor blocker selected from enzalutamide, darolutamide, and apalutamide.
In some embodiments, the second generation antiandrogen is an androgen biosynthesis inhibitor or an androgen receptor blocker.
In some embodiments, the androgen biosynthesis inhibitor is abiraterone acetate.
In some embodiments, the androgen receptor blocker is selected from enzalutamide, darolutamide, and apalutamide.
Additional features, advantages, and aspects of the present disclosure are set forth or apparent from consideration of the following detailed description, drawings, and claims. Moreover, it is to be understood that both the foregoing summary of the present disclosure and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the present disclosure as claimed.
The accompanying drawings, which are included to provide a further understanding of the present disclosure, are incorporated in and constitute a part of this specification, illustrate aspects of the present disclosure and, together with the detailed description, serve to explain the principles of the present disclosure. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
The present disclosure provides salts and polymorphic salt forms of Compound A that are useful in the preparation of a medicament and/or as pharmaceutical agents. In some embodiments, one or more of the salts and/or salt forms described herein can be formulated into a pharmaceutical composition.
Compound A of the present disclosure refers to 4-(4-((1-(4-(((1R,3R)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl) carbamoyl)phenyl) piperidin-4-yl)methyl) piperazin-1-yl)-N—((S)-2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, which has the following structure:
In some embodiments, Compound A can be prepared as described in US Patent Application Publication No. 2021/0196710 A1, which is incorporated herein by reference.
The terms “powder X-ray diffraction pattern”, “PXRD pattern”, “X-ray powder diffraction pattern”, and “XRPD pattern” are used interchangeably and refer to the experimentally observed diffractogram or parameters derived therefrom. Powder X-ray diffraction patterns are typically characterized by peak position (abscissa) and peak intensities (ordinate). The term “peak intensities” refers to relative signal intensities within a given X-ray diffraction pattern. Factors which can affect the relative peak intensities are sample thickness and preferred orientation (i.e., the crystalline particles are not distributed randomly). The term “peak positions” as used herein refers to X-ray reflection positions as measured and observed in powder X-ray diffraction experiments. Peak positions are directly related to the dimensions of the unit cell. The peaks, identified by their respective peak positions, are extracted from the diffraction patterns for the various polymorphic forms of salts of Compound A.
The terms “2 theta value”, “2θ”, “2 θ”, “°2θ”, or “°2 θ” refer to the peak position in degrees based on the experimental setup of the X-ray diffraction experiment and is a common abscissa unit in diffraction patterns. In general, the experimental setup requires that if a reflection is diffracted when the incoming beam forms an angle theta (θ) with a certain lattice plane, the reflected beam is recorded at an angle 2 theta (2 θ). It should be understood that reference herein to specific 2θ values for a specific polymorphic form is intended to mean the 2θ values (in degrees) as measured using the X-ray diffraction experimental conditions as described herein.
“Preferred orientation effects” refer to variable peak intensities or relative intensity differences between different PXRD measurements of the same samples that can be due to the orientation of the particles. Without wishing to be bound by theory, in PXRD it can be desirable to have a sample in which particles are oriented randomly (e.g., a powder). However, it can be difficult or in some cases impossible to achieve truly random particle orientations in practice. As particle size increases, the randomness of particle orientation can decrease, leading to increased challenges with achieving a preferred orientation. Without wishing to be bound by theory, a smaller particle size can reduce technical challenges associated with preferred orientation and allow for more accurate representation of peaks. However, one of skill in the art will understand how to reduce or mitigate preferred orientation effects and will recognize preferred orientation effects that can exist even between two different measurements of the same sample. For instance, in some embodiments, differences in resolution or relative peak intensities can be attributed to preferred orientation effects.
As used herein, the term “substantially pure” with reference to a particular salt (or to a mixture of two or more salts) of a compound indicates the salt (or a mixture) includes less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% by weight of impurities, including other salt forms of the compound. Such purity may be determined, for example, by powder X-ray diffraction.
As used herein, the term “polymorph” or “salt form” refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo-polymorphs, such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound. Different crystalline polymorphs have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and/or unit cell parameters which directly influences its physical properties such as the X-ray diffraction characteristics of crystals or powders. A different polymorph, for example, will in general diffract at a different set of angles and will give different values for the intensities. Therefore, X-ray powder diffraction can be used to identify different polymorphs, or a solid form that comprises more than one polymorph, in a reproducible and reliable way (S. Byrn et al, Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations, Pharmaceutical research, Vol. 12, No. 7, p. 945-954, 1995; J. K. Haleblian and W. McCrone, Pharmaceutical Applications of Polymorphism, Journal of Pharmaceutical Sciences, Vol. 58, No. 8, p. 91 1-929, 1969).
Crystalline polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.
The term “amorphous” refers to any solid substance which (i) lacks order in three dimensions, or (ii) exhibits order in less than three dimensions, order only over short distances (e.g., less than 10 A), or both. Thus, amorphous substances include partially crystalline materials and crystalline mesophases with, e.g., one- or two-dimensional translational order (liquid crystals), orientational disorder (orientationally disordered crystals), or conformational disorder (conformationally disordered crystals). Amorphous solids may be characterized by known techniques, including powder X-ray diffraction (PXRD) crystallography, solid state nuclear magnet resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or some combination of these techniques. Amorphous solids give diffuse PXRD patterns, typically comprised of one or two broad peaks (i.e., peaks having base widths of about 5 °2θ or greater).
The term “crystalline” refers to any solid substance exhibiting three-dimensional order, which, in contrast to an amorphous solid substance, gives a distinctive PXRD pattern with sharply defined peaks.
The term “ambient temperature” refers to a temperature condition typically encountered in a laboratory setting. This includes the approximate temperature range of about 20 to about 30° C.
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), Raman spectroscopy, and the like.
The term “solvate” describes a molecular complex comprising the drug substance and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., ethanol). When the solvent is tightly bound to the drug the resulting complex will have a well-defined stoichiometry that is independent of humidity. When, however, the solvent is weakly bound, as in channel solvates and hygroscopic compounds, the solvent content will be dependent on humidity and drying conditions. In such cases, the complex may be non-stoichiometric.
The term “hydrate” describes a solvate comprising the drug substance and a stoichiometric or non-stoichiometric amount of water.
The term “relative humidity” refers to the ratio of the amount of water vapor in air at a given temperature to the maximum amount of water vapor that can be held at that temperature and pressure, expressed as a percentage.
The term “relative intensity” refers to an intensity value derived from a sample X-ray diffraction pattern. The complete ordinate range scale for a diffraction pattern is assigned a value of 100. A peak having intensity falling between about 50% to about 100% on this scale intensity is termed very strong (vs); a peak having intensity falling between about 50% to about 25% is termed strong(s). Additional weaker peaks are present in typical diffraction patterns and are also characteristic of a given polymorph, wherein the additional peaks are termed medium (m), weak (w) and very weak (vw).
The term “slurry” refers to a solid substance suspended in a liquid medium, typically water or an organic solvent.
The term “under vacuum” refers to typical pressures obtainable by a laboratory oil or oil-free diaphragm vacuum pump.
The term “pharmaceutical composition” refers to a composition comprising one or more of the polymorphic forms of salts of Compound A described herein, and other chemical components, such as physiologically/pharmaceutically acceptable carriers, diluents, vehicles and/or excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, such as a human or other mammals.
The term “pharmaceutically acceptable” “carrier”, “diluent”, “vehicle”, or “excipient” refers to a material (or materials) that may be included with a particular pharmaceutical agent to form a pharmaceutical composition, and may be solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like.
Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropyl methylcellulose, methylmethacrylate and the like.
The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of “treating” as defined immediately above. For example, the terms “treat”, “treating” and “treatment” can refer to a method of alleviating or abrogating a particular disorder and/or one or more of its attendant symptoms.
As used herein, “subject” means a human or animal (in the case of an animal, the subject can be a mammal). In one aspect, the subject is a human. In one aspect, the subject is a male.
Prostate cancer is the uncontrolled growth of cancerous cells in the prostate gland. In some embodiments, the prostate cancer is metastatic prostate cancer, castrate-resistant prostate cancer, metastatic castrate-resistant prostate cancer, castrate-sensitive prostate cancer, metastatic castrate-sensitive prostate cancer, prostate cancer naïve to novel hormonal agents (NHA), metastatic prostate cancer naïve to novel hormonal agents (NHA), castrate-resistant prostate cancer naïve to novel hormonal agents (NHA), metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA), castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA), or metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA).
Metastatic prostate cancer, or metastases, refers to prostate cancer that has spread beyond the prostate to other parts of the body, e.g., bones, lymph nodes, liver, lungs, brain.
Castrate-resistant prostate cancer or castration-resistant prostate cancer (or prostate cancer that is castrate- or castration-resistant) is a type of prostate cancer that keeps growing even when the amount of testosterone in the body is reduced to very low levels.
Metastatic castrate-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 is reduced to very low levels.
Castrate-sensitive prostate cancer or castration-sensitive prostate cancer (CSPC), or prostate cancer that is castrate- or castration-sensitive, is prostate cancer that can be controlled by reducing the amount of androgens (male hormones) in the body (e.g., through castration) and/or prostate cancer that requires androgens to grow and stops growing when androgens are not present. CSPC is also referred to as androgen-dependent prostate cancer, androgen-sensitive prostate cancer, or hormone-sensitive prostate cancer (HSPC).
Metastatic castrate-sensitive prostate cancer is a type of castrate-sensitive prostate cancer that has metastasized and requires androgens to grow and stops growing when androgens are not present, or can be controlled by reducing the amount of androgens in the body (e.g., through castration).
Prostate cancer naïve to novel hormonal agents (NHA) is prostate cancer that has not been previously treated with one or more 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.
Metastatic prostate cancer naïve to novel hormonal agents (NHA) 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.
Castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) is castrate-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.
Castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) is castrate-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.
Metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA) is metastatic castrate-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.
Metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA) is metastatic castrate-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.
As used herein, the term “anti-cancer agent” is used to describe an anti-cancer agent, or a therapeutic agent administered concurrently with an anti-cancer agent (e.g., palonosetron), with which may be co-administered and/or co-formulated with a compound of the disclosure to treat cancer, and the side effects associated with the cancer treatment. These agents 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, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a CDK inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKT inhibitor, an mTORC1/2 inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone, 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, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (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, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, 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, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. In one embodiment, the anti-cancer agent is selected from the group consisting of abiraterone, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, and zolendronate. In one embodiment, the anti-cancer agent is selected from the group consisting of FLT-3 inhibitor, androgen receptor inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4/6 inhibitor, anti-HGF antibody, IGFR TK inhibitor, PI3 kinase inhibitor, AKT inhibitor, JAK/STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, focal adhesion kinase inhibitor, Map kinase inhibitor, VEGF trap antibody, and chemical castration agent.
In some embodiments, the anti-cancer agent is selected from the group consisting of temozolomide, capecitabine, irinotecan, tamoxifen, anastrazole, exemestane, letrozole, DES, Estradiol, estrogen, bevacizumab, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroprogesterone caproate, raloxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vinblastine, vinorelbine, topotecan, finasteride, arzoxifene, fulvestrant, prednisone, abiraterone, enzalutamide, apalutamide, darolutamide, sipuleucel-T, pembrolizumab, nivolumab, cemiplimab, atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), docetaxel (Taxotere), cabazitaxel (Jevtana), mitoxantrone (Novantrone), estramustine (Emcyt), docetaxel, ketoconazole, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, and zolendronate.
The term “about” is used herein to mean approximately, in the region of, roughly or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%, a variance of 10%, a variance of 5%, a variance of 3%, or a variance of 1%. When used in the context of XRPD peak values, the term “about” can indicate a peak value ±0.20, ±0.15, ±0.10, ±0.05, or ±0.01 °2θ. In some embodiments, when used in the context of XRPD peak values “about” can indicate a peak value at substantially exactly the disclosed peak value.
As set forth below, Compound A can form salts with different acids. In some embodiments, the salts of Compound A described herein exist in various crystalline forms. All PXRD peaks described herein are in ° 2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). Additionally, all PXRD spectra are obtained using Cu Kα1 X-rays at a wavelength of 1.5406 Å.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 1. In some embodiments, the Compound A free base Pattern 1 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 1 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 1 is crystalline Compound A free base Pattern 1 characterized by 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 1 is crystalline Compound A free base Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 1 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 1 is crystalline Compound A free base Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 1 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 1 is crystalline Compound A free base Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 1 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 1 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, or forty-one XRPD signals selected from those set forth in Table 1.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 2. In some embodiments, the Compound A free base Pattern 2 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 2 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 2 is crystalline Compound A free base Pattern 2 characterized by 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 2 is crystalline Compound A free base Pattern 2 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 2 is crystalline Compound A free base Pattern 2 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 2 is crystalline Compound A free base Pattern 2 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 2 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 2 is crystalline Compound A free base Pattern 2 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 2 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 2 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, or forty XRPD signals selected from those set forth in Table 2.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 3. In some embodiments, the Compound A free base Pattern 3 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 3 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 3 is crystalline Compound A free base Pattern 3 characterized by XRPD signals at 20.6 °2θ, 16.1 °2θ, and 16.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).
In some embodiments, the solid form of Compound A free base Pattern 3 is crystalline Compound A free base Pattern 3 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 3 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 3 is crystalline Compound A free base Pattern 3 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 3 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 3 is crystalline Compound A free base Pattern 3 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 3 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 3 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, or nineteen XRPD signals selected from those set forth in Table 3.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 4. In some embodiments, the Compound A free base Pattern 4 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 4 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 4 is crystalline Compound A free base Pattern 4 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 4 is crystalline Compound A free base Pattern 4 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 4 is crystalline Compound A free base Pattern 4 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 4 is crystalline Compound A free base Pattern 4 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 4 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 4 is crystalline Compound A free base Pattern 4 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 4 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 4 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, or twenty-four XRPD signals selected from those set forth in Table 4.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 5. In some embodiments, the Compound A free base Pattern 5 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 5 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 5 is crystalline Compound A free base Pattern 5 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 5 is crystalline Compound A free base Pattern 5 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 5 is crystalline Compound A free base Pattern 5 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 5 is crystalline Compound A free base Pattern 5 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 5 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 5 is crystalline Compound A free base Pattern 5 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 5 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 5 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, or thirty-five XRPD signals 10 selected from those set forth in Table 5.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 6. In some embodiments, the Compound A free base Pattern 6 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 6 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 6 is crystalline Compound A free base Pattern 6 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 6 is crystalline Compound A free base Pattern 6 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 6 is crystalline Compound A free base Pattern 6 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 6 is crystalline Compound A free base Pattern 6 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 6 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 6 is crystalline Compound A free base Pattern 6 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 6 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 6 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, or thirty-six XRPD signals selected from those set forth in Table 6.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 7. In some embodiments, the Compound A free base Pattern 7 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 7 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 7 is crystalline Compound A free base Pattern 7 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 7 is crystalline Compound A free base Pattern 7 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 7 is crystalline Compound A free base Pattern 7 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 7 is crystalline Compound A free base Pattern 7 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 7 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 7 is crystalline Compound A free base Pattern 7 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 7 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 7 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen XRPD signals selected from those set forth in Table 7.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 8. In some embodiments, the Compound A free base Pattern 8 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 8 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 8 is crystalline Compound A free base Pattern 8 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 8 is crystalline Compound A free base Pattern 8 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 8 is crystalline Compound A free base Pattern 8 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 8 is crystalline Compound A free base Pattern 8 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 8 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 8 is crystalline Compound A free base Pattern 8 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 8 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 8 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or twenty-two XRPD signals selected from those set forth in Table 8.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A free base Pattern 9. In some embodiments, the Compound A free base Pattern 9 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A free base Pattern 9 is 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 9 is crystalline Compound A free base Pattern 9 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 9 is crystalline Compound A free base Pattern 9 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 9 is crystalline Compound A free base Pattern 9 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 9 is crystalline Compound A free base Pattern 9 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 9 is 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 radiation).
In some embodiments, the solid form of Compound A free base Pattern 9 is crystalline Compound A free base Pattern 9 characterized by two or more, or three 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, 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 radiation). In some embodiments, the solid form of Compound A free base Pattern 9 is 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 radiation).
In some embodiments, the crystalline Compound A free base Pattern 9 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, or forty-two XRPD signals selected from those set forth in Table 9.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A tosylate Pattern 1. In some embodiments, the Compound A tosylate Pattern 1 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A tosylate Pattern 1 is 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 radiation). In some embodiments, the solid form of Compound A tosylate Pattern 1 is crystalline Compound A tosylate Pattern 1 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 radiation).
In some embodiments, the solid form of Compound A tosylate Pattern 1 is crystalline Compound A tosylate Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A tosylate Pattern 1 is crystalline Compound A tosylate Pattern 1 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A tosylate Pattern 1 is crystalline Compound A tosylate Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A tosylate Pattern 1 is 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, and 14.7 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation).
In some embodiments, the solid form of Compound A tosylate Pattern 1 is crystalline Compound A tosylate Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A tosylate Pattern 1 is 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 radiation).
In some embodiments, the crystalline Compound A tosylate Pattern 1 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen XRPD signals selected from those set forth in Table 10.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A phosphate Pattern 1. In some embodiments, the Compound A phosphate Pattern 1 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A phosphate Pattern 1 is 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 radiation). In some embodiments, the solid form of Compound A phosphate Pattern 1 is crystalline Compound A phosphate Pattern 1 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 radiation).
In some embodiments, the solid form of Compound A phosphate Pattern 1 is crystalline Compound A phosphate Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A phosphate Pattern 1 is crystalline Compound A phosphate Pattern 1 characterized by XRPD signals at 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 radiation).
In some embodiments, the solid form of Compound A phosphate Pattern 1 is crystalline Compound A phosphate Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A phosphate Pattern 1 is 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 radiation).
In some embodiments, the solid form of Compound A phosphate Pattern 1 is crystalline Compound A phosphate Pattern 1 characterized by two or more, or three 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 radiation). In some embodiments, the solid form of Compound A phosphate Pattern 1 is 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 radiation).
In some embodiments, the crystalline Compound A phosphate Pattern 1 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen XRPD signals selected from those set forth in Table 11.
In some embodiments, the present disclosure provides solid forms of Compound A, e.g., crystalline forms of Compound A besylate Pattern 1. In some embodiments, the Compound A besylate Pattern 1 XRPD profile is substantially similar to that shown in
In some embodiments, the solid form of Compound A besylate Pattern 1 is crystalline Compound A besylate 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 radiation). In some embodiments, the solid form of Compound A besylate Pattern 1 is crystalline Compound A besylate Pattern 1 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 radiation).
In some embodiments, the solid form of Compound A besylate Pattern 1 is 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 radiation). In some embodiments, the solid form of Compound A besylate Pattern 1 is 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 radiation).
In some embodiments, the solid form of Compound A besylate Pattern 1 is 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, and 13.3 °2θ (±0.2 °2θ; ±0.1 °2θ; or ±0.0 °2θ; Cu Kα1 radiation). In some embodiments, the solid form of Compound A besylate Pattern 1 is 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 radiation).
In some embodiments, the solid form of Compound A besylate Pattern 1 is 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 radiation). In some embodiments, the solid form of Compound A besylate Pattern 1 is 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 radiation).
In some embodiments, the crystalline Compound A besylate Pattern 1 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, or thirty XRPD signals selected from those set forth in Table 12.
The present disclosure provides a method of ubiquitinating/degrading a target protein in a cell.
In some embodiments, the method comprises administering a solid form of Compound A of the disclosure or a salt form of Compound A of the 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.
In some embodiments, the E3 ubiquitin ligase binding moiety is coupled to the protein targeting moiety and wherein the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, preferably an E3 ubiquitin ligase) and the protein targeting moiety recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in proximity to the ubiquitin ligase, thus resulting in degradation/inhibition of the effects of the target protein and the control of protein levels. The control of protein levels afforded by the present disclosure provides treatment of a disease state or condition, which is modulated through the target protein by lowering the level of that protein in the cells of a patient.
In some embodiments, this application provides a solid form of Compound A of the disclosure or a salt form of Compound A of the disclosure that degrades the androgen receptor (AR) protein.
In some embodiments, the present disclosure is directed to a method of treating a patient in need for a disease state or condition modulated through a protein where the degradation of that protein will produce a therapeutic effect in that patient, the method comprising administering to a patient in need an effective amount of a solid form of Compound A of the disclosure or a salt form of Compound A of the disclosure, optionally in combination with another anti-cancer agent. The disease state or condition may be a disease caused by overexpression of a protein, which leads to a disease state and/or condition.
In one aspect, the present application pertains to a method of treating and/or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a solid form of Compound A of the disclosure or a salt form of Compound A of the disclosure.
In one aspect, the present application pertains to a method of treating and/or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a solid form of Compound A of the disclosure or a salt form of Compound A of the disclosure, in combination with one or more additional anti-cancer agents.
The methods of treating cancer described herein result in a reduction in tumor size. Alternatively, or in addition, the cancer is metastatic cancer and this method of treatment includes inhibition of metastatic cancer cell invasion.
In some embodiments, the cancer is prostate cancer.
In some embodiments, the cancer is metastatic prostate cancer.
In some embodiments, the cancer is castrate-resistant prostate cancer.
In some embodiments, the cancer is metastatic castrate-resistant prostate cancer (mCRPC).
In some embodiments, the prostate cancer is castrate-sensitive prostate cancer.
In some embodiments, the prostate cancer is metastatic castrate-sensitive prostate cancer.
In some embodiments, the prostate cancer is prostate cancer naïve to novel hormonal agents (NHA).
In some embodiments, the prostate cancer is metastatic prostate cancer naïve to novel hormonal agents (NHA).
In some embodiments, the prostate cancer is castrate-resistant prostate cancer naïve to novel hormonal agents (NHA).
In some embodiments, the prostate cancer is castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA).
In some embodiments, the prostate cancer is metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA).
In some embodiments, the prostate cancer is metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA).
In some embodiments, the prostate cancer is not prostate cancer naïve to novel hormonal agents (NHA). In some embodiments, the prostate cancer that is not prostate cancer naïve to novel hormonal agents (NHA) is also metastatic prostate cancer, castrate-resistant prostate cancer, metastatic castrate-resistant prostate cancer, castrate-sensitive prostate cancer, or metastatic castrate-sensitive prostate cancer.
In one aspect, the application pertains to treating prostate cancer with a solid form of Compound A of the disclosure or a salt form of Compound A of the disclosure in combination with another anti-cancer agent. In some embodiments, the prostate cancer treated with the combination of a solid form of Compound A of the disclosure or a salt form of Compound A of the disclosure and another anti-cancer agent is metastatic prostate cancer, castrate-resistant prostate cancer, metastatic castrate-resistant prostate cancer (mCRPC), castrate-sensitive prostate cancer, metastatic castrate-sensitive prostate cancer, prostate cancer naïve to novel hormonal agents (NHA), metastatic prostate cancer naïve to novel hormonal agents (NHA), castrate-resistant prostate cancer naïve to novel hormonal agents (NHA), castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA), metastatic castrate-resistant prostate cancer naïve to novel hormonal agents (NHA), or metastatic castrate-sensitive prostate cancer naïve to novel hormonal agents (NHA).
In some embodiments, the prostate cancer treated with the combination of a solid form of Compound A of the disclosure or a salt form of Compound A of the disclosure and another anti-cancer agent is not prostate cancer naïve to novel hormonal agents (NHA). In some embodiments, the prostate cancer that is not prostate cancer naïve to novel hormonal agents (NHA) is also metastatic prostate cancer, castrate-resistant prostate cancer, metastatic castrate-resistant prostate cancer, castrate-sensitive prostate cancer, or metastatic castrate-sensitive prostate cancer.
In some embodiments, the other anti-cancer agent is abiraterone, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, zolendronate, or a pharmaceutically acceptable salt thereof.
In some embodiments, treating cancer results in a reduction in size of a tumor. A reduction in size of a tumor may also be referred to as “tumor regression”. Preferably, after treatment, tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Size of a tumor may be measured by any reproducible means of measurement. In a preferred aspect, size of a tumor may be measured as a diameter of the tumor.
In some embodiments, treating cancer results in a reduction in tumor volume. Preferably, after treatment, tumor volume is reduced by 5% or greater relative to its volume prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Tumor volume may be measured by any reproducible means of measurement.
In some embodiments, treating cancer results in a decrease in number of tumors. Preferably, after treatment, tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. Number of tumors may be measured by any reproducible means of measurement. In a preferred aspect, number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. In some embodiments, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.
In some embodiments, treating cancer results in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. In some embodiments, the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In some embodiments, the specified magnification is 2×, 3×, 4×, 5×, 10×, or 50×.
In some embodiments, treating cancer results in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. In some embodiments, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active agent or compound of the disclosure. In some embodiments, an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active agent or compound of the disclosure.
In some embodiments, treating cancer results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. In some embodiments, an increase in average survival time of a population may be measured by calculating for a population the average length of survival following initiation of treatment with an active agent or compound of the disclosure. In some embodiments, an increase in average survival time of a population may be measured by calculating for a population the average length of survival following completion of a first round of treatment with a compound of the disclosure.
In some embodiments, treating cancer results in a decrease in tumor growth rate. Preferably, after treatment, tumor growth rate is reduced by at least 5% relative to growth rate prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Tumor growth rate may be measured by any reproducible means of measurement. In some embodiments, tumor growth rate is measured according to a change in tumor diameter per unit time.
In some embodiments, treating cancer results in a decrease in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%; more preferably, tumor regrowth is 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 may be measured by any reproducible means of measurement. In some embodiments, tumor regrowth is measured by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. In some embodiments, a decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
The dosages of the solid forms of Compound A of the disclosure or salt forms of Compound A of the disclosure for any of the methods and uses described herein vary depending on the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
The therapeutically effective amount of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure may be administered one or more times over a day for up to 30 or more days, followed by 1 or more days of non-administration of the compound. This type of treatment schedule, i.e., administration of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure on consecutive days followed by non-administration of solid/salt forms on consecutive days may be referred to as a treatment cycle. A treatment cycle may be repeated as many times as necessary to achieve the intended affect.
In some embodiments, the therapeutically effective amount of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure is 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, 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, 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, 970, 975, 980, 985, 990, 995, or 1,000 mg administered once, twice, three times, four times, or more daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty, twenty-five, thirty consecutive days, or, once, twice, three times, four times, or more daily, in single or divided doses, for 2 months, 3 months, 4 months, 5 months, 6 months, or longer.
In some embodiments, the therapeutically effective amount of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to about 180 mg, about 160 to about 190 mg, about 170 to about 200 mg, about 180 to about 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 to about 320 mg, about 300 to about 330 mg, about 310 to about 340 mg, about 320 to about 350 mg, about 330 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 550 to about 580 mg, about 560 to about 590 mg, about 570 to about 600 mg, about 580 to about 610 mg, about 590 to about 620 mg, about 600 to about 630 mg, about 610 to about 640 mg, about 620 to about 650 mg, about 630 to about 660 mg, about 640 to about 670 mg, about 650 to about 680 mg, about 660 to about 690 mg, about 670 to about 700 mg, about 680 to about 710 mg, about 690 to about 720 mg, about 700 to about 730 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 administered once, twice, three times, four times, or more daily in single or divided doses (which dose may be adjusted for the patient's weight in kg, body surface area in m2, and/or age in years).
In some embodiments, the therapeutically effective amount of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure is about 70 mg to about 1000 mg administered once, twice, three times, four times, or more daily in single or divided doses (which dose may be adjusted for the patient's weight in kg, body surface area in m2, and/or age in years).
In some embodiments, the therapeutically effective amount of the solid form of Compound A of the disclosure or the salt form of Compound A of the 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 administered once, twice, three times, four times, or more daily in single or divided doses (which dose may be adjusted for the patient's weight in kg, body surface area in m2, and/or age in years).
In some embodiments, the therapeutically effective amount of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure is administered to the subject once daily. In some embodiments, this daily dose of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure may be administered to the subject all at once. In some embodiments, this daily dose of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure may be administered to the subject in two portions (i.e., a divided dose). In some embodiments, this daily dose of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure may be administered to the subject in three divided doses. In some embodiments, this daily dose of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure may be administered to the subject in four divided doses. In some embodiments, this daily dose of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure may be administered to the subject in five or more divided doses. In some embodiments, these portions or divided doses are administered to the subject at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.
The therapeutically effective amount of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure can be estimated initially either in cell culture assays or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
Dosage and administration are adjusted to provide sufficient levels of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, once every two weeks, or monthly depending on half-life and clearance rate of the particular formulation.
In some embodiments, for the methods of treating prostate cancer with the combination of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure and another anti-cancer agent, the therapeutically effective amount of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure is described herein, and the therapeutically effective amount of the other anti-cancer agent is 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, 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, 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, 970, 975, 980, 985, 990, 995, or 1,000 mg administered once, twice, three times, four times, or more daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or thirty consecutive days, or, once, twice, three times, four times, or more daily, in single or divided doses, for 2 months, 3 months, 4 months, 5 months, 6 months, or longer.
In some embodiments, the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure and the other anti-cancer agent 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 the other anti-cancer agent are administered to the subject sequentially.
In some embodiments, the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure and the other anti-cancer agent are administered to the subject in temporal proximity.
In some embodiments, “temporal proximity” means that administration of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure occurs within a time period before or after the administration of additional anti-cancer 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 the additional anti-cancer 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 the additional anti-cancer agent. In some embodiments, “temporal proximity” means that administration of the solid form of Compound A of the disclosure or the salt form of Compound A of the disclosure occurs within a time period before or after the administration of additional anti-cancer 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 anti-cancer agent.
“Temporal proximity” may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered. In some embodiments, “temporal proximity” means within 15 minutes, within 30 minutes, within an hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within a week, within 2 weeks, within 3 weeks, within 4 weeks, with 6 weeks, or within 8 weeks. In some embodiments, multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may change during a treatment cycle or within a dosing regimen.
XRPD analysis was carried out on a PANalytical X'pert pro with PIXcel detector (128 channels), scanning the samples between 3 and 35 °2θ. The material was gently ground to release any agglomerates and loaded onto a multi-well plate with Kapton or Mylar polymer film to support the sample. The multi-well plate was then placed into the diffractometer and analyzed using Cu K radiation (α1γ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5) running in transmission mode (step size 0.0130 °2θ, step time 18.87 s) using 40 kV/40 mA generator settings. Data were visualized and images generated using the HighScore Plus 4.7 desktop application (PANalytical, 2θ17).
XRPD analysis of the second set of competitive slurry experiments was carried out on a Philips X'Pert Pro Multipurpose diffractometer equipped with a spinning stage autosampler. The samples were scanned between 5 and 34.997 °2θ using Cu K radiation (α1γ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5) running in Bragg-Brentano geometry (step size 0.008 °2θ, step time 10.160 s, rotation period 2 s) using 40 kV/40 mA generator settings. Data were visualized and images generated using the HighScore Plus 4.7 desktop application (PANalytical, 2θ17).
The presence of crystallinity (birefringence) was determined using an Olympus BX50 microscope, equipped with cross-polarising lenses and a Motic camera. Images were captured using Motic Images Plus 2.0. All images were recorded using the 20× objective, unless otherwise stated.
Approximately 5 mg of material was weighed into an open aluminium pan and loaded into a simultaneous thermogravimetric/differential thermal analyser (TG/DTA) and held at room temperature. The sample was then heated at a rate of 10° C./min from 20° C. to 300° C. during which time the change in sample weight was recorded along with any differential thermal events (DTA). Nitrogen was used as the purge gas, at a flow rate of 300 cm3/min.
Approximately 5 mg of material was weighed into an aluminium DSC pan and sealed non-hermetically with a pierced aluminium lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with a RC90 cooler. The sample and reference were heated to 270° C. at a scan rate of 10° C./min and the resulting heat flow response monitored. The sample was re-cooled to 20° C. and then reheated again to 270° C. all at 10° C./min. Nitrogen was used as the purge gas, at a flow rate of 50 cm3/min.
Infrared spectroscopy was carried out on a Bruker ALPHA P spectrometer. Sufficient material was placed onto the centre of the plate of the spectrometer and the spectra were obtained using the following parameters:
NMR experiments were performed on a Bruker A VIIIHD spectrometer operating at 400 MHZ for protons. Experiments were performed in deuterated DMSO and each sample was prepared to ca. 10 mM concentration.
10-20 mg of sample was placed into a mesh vapour sorption balance pan and loaded into a DVS-1 dynamic vapour sorption balance by Surface Measurement Systems. The sample was subjected to a ramping profile from 40-90% relative humidity (RH) at 10% increments, maintaining the sample at each step until a stable weight had been achieved (dm/dt 0.004%, minimum step length 30 minutes, maximum step length 500 minutes) at 25° C. After completion of the sorption cycle, the sample was dried using the same procedure to 0% RH and then a second sorption cycle back to 40% RH. Two cycles were performed. The weight change during the sorption/desorption cycles were plotted, allowing for the hygroscopic nature of the sample to be determined. XRPD analysis was then carried out on any solid retained.
VT-XRPD analysis was carried out on a Philips X'Pert Pro Multipurpose diffractometer equipped with a temperature chamber. The samples were scanned between 4 and 35.99 °2θ using Cu K radiation (α1γ=1.54060 Å; α2=1.54443 Å; β=1.39225 Å; α1:α2 ratio=0.5) running in Bragg-Brentano geometry (step size 0.008 °2θ) using 40 kV/40 mA generator settings. The sample was heated at a 10° C./min heating rate and held at each temperature for 3 minutes 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.
Compound A was characterized by the following techniques: XRPD, PLM, Multinuclear NMR, TG/DSC, VT-XRPD, DSC, DSV, and HPLC.
A known volume aliquot (typically 5 volumes) of solvent was added to approximately 5 mg of Compound A. See Table 14 for the selected solvents for the solvent solubility screen.
Between each addition, the mixture was checked for dissolution and where no dissolution was apparent, the mixture was heated to ca. 40° C. and checked again. This procedure was continued until dissolution was observed or until 100 volumes of solvent had been added.
Where dissolution was not observed, solids were isolated centrifugally and analyzed by XRPD. The saturated solutions were analyzed by HPLC to obtain the solubility.
Where dissolution was noted, the clear solutions were left to evaporate at ambient conditions and the solids that were obtained were analyzed by XRPD.
See Table 15 for a summary table of the solvent solubility screen.
The solution/slurry of counterion was added to the solution/slurry of the free base material.
This was mixed using a vortex mixer and observations were noted, see Table 18.
Any samples that were clear solutions after temperature cycling were left to evaporate at ambient conditions. See Table 20 for observations made after evaporation. Solids obtained through evaporation were analyzed by XRPD.
Pattern 4 from malonic acid and benzoic acid.
See Tables 21-23 for a summary of the XRPD results of the primary salt screen.
Potential chloride salt Pattern 2, tosylate Pattern 1, besylate Pattern 1, and phosphate Pattern 1 were characterized by the following techniques:
1H NMR
Unfortunately, the solubility of all three samples were below the LOQ and thus could not be quantified.
Three additional chloride salt formation experiments were conducted to further investigate the possibility of stable chloride salt formation which appeared elusive, despite the large pKa difference between Compound A and hydrochloric acid. (Table 26)
Free base forms were characterized by PLM, TG/DSC, and 1H NMR.
See Table 30 for a summary of the XRPD Patterns obtained during the primary crystallization screen.
1H
See Table 32 for the experimental details and observations made during the first attempt at scaling up at free base Patterns 1, 2, and 6.
XRPD Analysis of the Dried Free Base Forms Determined the Forms were Retained
See Table 33 for experimental details and observations.
1H NMR
1H NMR
1H NMR
See Table 42 for details and observations made during the second attempt.
1H NMR
The following procedure was used to determine the solubility of Compound A free base Pattern 1, Compound A tosylate, Compound A besylate and Compound A phosphate.
See Table 44 for a full summary of the thermodynamic solubility determination results.
See below for a summary of the results and for the impurity peak tables.
While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.
The aspects of the present disclosure are further described with reference to the following embodiments:
This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/493,245, filed Mar. 30, 2023, which is incorporated by reference in its entirety for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 63493245 | Mar 2023 | US |
