EP-4735437-A1 - CRYSTALLINE FORMS OF 6-(6-(((1R,2R,3S,5S)-2-FLUORO-9-AZABICYCLO[3.3.1]NONAN-3-YL)(METHYL)AMINO)PYRIDAZIN-3-YL)-2-METHYLBENZO[D]OXAZOL-5-OL, A SPLICING MODULATOR FOR THE TREATMENT OF HUNTINGTON'S DISEASE

Abstract

Described herein are crystalline forms of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (compound A), a small molecule splicing modulator (SMSM) of mRNA, such as pre-mRNA, encoded by genes, for the treatment of Huntington's disease.

Inventors

• DE POEL, Wester
• LUZZIO, MICHAEL
• LUCAS, BRIAN

Assignees

• Skyhawk Therapeutics, Inc.

Dates

Publication Date

20260506

Application Date

20240628

Claims (1)

1. Docket No.51503-768.601 CLAIMS WHAT IS CLAIMED IS: 1. A solid state form of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Compound A) or a stereoisomer thereof. 2. A solid state form of Compound A, having a structure of 3. The solid state form of claim 1 or 2, wherein the solid state form is a crystalline form. 4. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form A of Compound A. 5. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form B of Compound A. 6. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form C of Compound A. 7. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form D of Compound A. 8. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form E of Compound A. 9. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form F of Compound A. 10. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form G of Compound A. 11. The solid state form of claim 1 or 2, wherein the solid state form is crystalline form H of Compound A. 12. A crystalline form of 6-(6-(((1R,2R,3S,5S)-2-fluoro-9-azabicyclo[3.3.1]nonan-3- yl)(methyl)amino)pyridazin-3-yl)-2-methylbenzo[d]oxazol-5-ol (Compound A), wherein the crystalline form is characterized as exhibiting: (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1A, FIG.1B, or FIG.1C as measured using Cu Kα radiation; (b) an XRPD pattern with peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation; Docket No.51503-768.601 (c) an XRPD pattern with one or more peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, and 17.5 ±0.2 º2-Theta as measured using Cu Kα radiation; (d) an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.1 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation; (e) an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2- Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta and 27.1 ±0.2 º2- Theta as measured using Cu Kα radiation; (f) a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.10; (g) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 178 °C; (h) a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 192 °C; (i) a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.15; or (j) a Thermogravimetric Thermal Analysis (TGA) thermogram exhibiting a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C. 13. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in FIG.1A, FIG.1B, FIG. 1C, or FIG.1D, as measured using Cu Kα radiation. 14. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting an XRPD pattern with peaks at 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2- Theta, and 17.5 ±0.2 º2-Theta as measured using Cu Kα radiation. 15. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting an XRPD pattern with at least three, at least four, at least five, or all of the peaks at 7.1 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2-Theta, 14.8 ±0.2 º2- Theta, 17.5 ±0.2 º2-Theta, and 26.1 ±0.2 º2-Theta as measured using Cu Kα radiation. 16. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting an XRPD pattern with at least three, at least six, at least nine, or all of the peaks at 7.1 ±0.2 º2-Theta, 7.6 ±0.2 º2-Theta, 11.1 ±0.2 º2-Theta, 12.4 ±0.2 º2- Theta, 14.8 ±0.2 º2-Theta, 15.2 ±0.2 º2-Theta, 16.0 ±0.2 º2-Theta, 16.3 ±0.2 º2-Theta, 17.5 ±0.2 º2-Theta, 19.3 ±0.2 º2-Theta, 25.3 ±0.2 º2-Theta, 26.1 ±0.2 º2-Theta, and 27.1 ±0.2 º2- Theta as measured using Cu Kα radiation. Docket No.51503-768.601 17. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram substantially the same as shown in FIG.10. 18. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram substantially the same as shown in FIG.15. 19. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak having an onset temperature at about 178 °C. 20. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Differential Scanning Calorimetry (DSC) thermogram with an endothermic peak at about 192 °C. 21. The crystalline form of Compound A according to claim 12, wherein the crystalline form is characterized as exhibiting a Thermogravimetric Thermal Analysis (TGA) thermogram that shows a mass loss of about 5.7 % from the onset of heating up to approximately 160 °C. 22. The crystalline form of Compound A according to claim 12 , wherein the crystalline form is anhydrous. 23. A pharmaceutical composition comprising the crystalline form of Compound A or the solid state form of Compound A of any one of claims 1-22 and at least one pharmaceutically acceptable excipient. 24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is formulated in the form of a solid form pharmaceutical composition for oral administration to a mammal. 25. A method of treating a condition or a disorder in a subject in need thereof, the method comprising administering to the subject the crystalline form of Compound A or the solid state form of Compound A according to any one of claims 1-22, or the pharmaceutical composition of claim 23 or 24. 26. The method of claim 25, wherein the condition or disorder comprises Huntington's disease. 27. A method of treating Huntington's disease in a subject in need thereof, comprising administering to the subject the crystalline form of Compound A or the solid state form of Compound A according to any one of claims 1-22 or the pharmaceutical composition of claim 23 or 24. 28. A method of modulating splicing comprising administering to cells the crystalline form of Compound A or the solid state form of Compound A according to any one of claims 1-22, or a pharmaceutical composition of claim 23 or 24, wherein the the crystalline form of Compound A or the solid state form of Compound A modulates splicing at a splice site Docket No.51503-768.601 sequence of a pre-mRNA that encodes an mRNA, and wherein the mRNA encodes a target protein or a functional RNA. 29. Use of the crystalline form of Compound A or the solid state form of Compound A according to any one of claims 1-22, or the pharmaceutical composition of claim 23 or 24, in the manufacture of a medicament for the treatment of a condition or disease.

Description

WSGR Docket No.51503-768.601 COMPOSITIONS FOR MODULATING SPLICING CROSS REFERENCE [0001] This application claims the benefit of priority to U.S. Provisional Application No.63/511,325, filed June 30, 2023, which is incorporated herein by reference in its entirety. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted in electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 17, 2024, is named 51503-768_601_SL.xml and is 1,885 bytes in size. FIELD OF THE INVENTION [0003] Described herein are solid state forms of splicing modulator Compound A, as well as pharmaceutical compositions thereof, and methods of use thereof in the treatment of diseases or conditions that would benefit from treatment with Compound A. BACKGROUND [0004] The majority of protein-coding genes in the human genome are composed of multiple exons (coding regions) that are separated by introns (non-coding regions). Gene expression results in a single precursor messenger RNA (pre-mRNA). The intron sequences are subsequently removed from the pre-mRNA by a process called splicing, which results in the mature messenger RNA (mRNA). By including different combinations of exons, alternative splicing gives rise to multiple mRNAs encoding distinct protein isoforms. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, catalyzes splicing. [0005] Small molecule splicing modulators (SMSMs) overcome many of the problems associated with therapies such as oligonucleotide technologies (antisense, RNA interference, etc.), including lack of oral bioavailability, and lack of blood-brain-barrier penetration, with the latter precluding delivery to the brain or spinal cord after parenteral drug administration for the treatment of diseases (e.g., neurological diseases, brain cancers, etc.). [0006] Many compounds can exist in different crystal forms, or polymorphs, which exhibit different physical, chemical, and spectroscopic properties. For example, certain polymorphs of a compound may be more readily soluble in particular solvents, may flow more readily, or may compress more easily than others. In the case of drugs, certain solid forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory standpoint, since drugs are approved by agencies such as the U.S. Food and Drug Administration only if they meet exacting purity and characterization standards. Indeed, the regulatory approval of one polymorph of a compound, which exhibits certain Docket No.51503-768.601 solubility and physico-chemical (including spectroscopic) properties, typically does not imply the ready approval of other polymorphs of that same compound. [0007] Polymorphic forms of a compound are known in the pharmaceutical arts to affect, for example, the solubility, stability, flowability, fractability, and compressibility of the compound, as well as the safety and efficacy of drug products comprising it. Therefore, the discovery of new polymorphs of a drug can provide a variety of advantages. [0008] WO2020/163541 discloses 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8-azabicyclo[3.2.1]octan-3- yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol, which is useful in treating and preventing a wide range of diseases and conditions through modulating splicing of pre-mRNA, including, but not limited to, neurodegenerative diseases, such as Huntington’s Disease. SMSMs, however, can also have challenges, such as metabolic profiles in patients, clearance rates, the amount of compound available to exert an effect (e.g., fraction unbound in plasma, half-life of the compound in circulation, etc.). [0009] Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. It is caused by an increase in the number of trinucleotide CAG repeats (36 repeats or more) on the short arm of chromosome 4p16.3. Huntington's disease can have a wide impact on the patient’s functional abilities and can cause movement, cognitive, and psychiatric disorders. The prevalence of Huntington's disease is estimated to be about 1/10,000 to about 1/20,000. Current treatments can alleviate certain symptoms but cannot slow or reverse the progression of Huntington’s disease. SUMMARY [0010] The present disclosure relates to various solid state forms of the small molecule splicing modulator Compound A. Such forms of Compound A are useful for modulating the activity of splicing in mammals that would benefit from such activity. [0011] As mentioned above, WO2020/163541 discloses 6-(6-{[(1R,2R,3S,5S)-2-fluoro-8- azabicyclo[3.2.1]octan-3-yl](methyl)amino}pyridazin-3-yl)-2-methyl-1,3-benzoxazol-5-ol, which is useful in treating and preventing a wide range of diseases and conditions through modulating splicing of pre-mRNAs, including, but not limited to, neurodegenerative diseases,