WO2025193777A1 - Pharmaceutical compositions of alpha-1 antitrypsin modulators - Google Patents

Abstract

Novel compositions comprising amorphous (S)-4-(5-(3,4-Difluorophenyl)-8-fluoro-6-(2- hydroxy-1-meth-oxybutan-2-yl)-1,5-dihydropyrrolo[2,3-ƒ]indazol-7-yl)benzoic acid or amorphous (S)-4-(8-fluoro-5-(4-fluoro-3-methoxyphenyl)-6-(2-hydroxy-1-methoxybutan-2- yl)-1.5-dihydropyrrolo[2,3-ƒ|indazol-7-yl)benzoic acid, deuterated derivatives thereof, and pharmaceutically acceptable salts of those compounds and deuterated derivatives useful for treating alpha-1 antitrypsin deficiency (AATD).

Description

Attorney Docket No.10275.0231-00304 VPI/24-005 WO PHARMACEUTICAL COMPOSITIONS OF ALPHA-1 ANTITRYPSIN MODULATORS [0001] This application claims the benefit of U.S. Provisional Application No.63/564,775, filed on March 13, 2024, the contents of which are incorporated by reference in its entirety. [0002] The disclosure provides solid forms of compounds that are capable of modulating alpha-1 antitrypsin (AAT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) by administering one or more such compounds. [0003] AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments for AATD exist, there is currently no cure. AAT is produced primarily in liver cells and secreted into the blood, but it is also made by other cell types including lung epithelial cells and certain white blood cells. AAT inhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase (NE) proteinase 3, and cathepsin G) and thus protects organs such as the lung from protease-induced damage, especially during periods of inflammation. [0004] The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene that encodes the AAT protein. This mutation, known as the Z mutation or the Z allele, leads to misfolding of the translated protein, which is therefore not secreted into the bloodstream and can polymerize within the producing cell. Consequently, circulating AAT levels in individuals homozygous for the Z allele (PiZZ) are markedly reduced; only approximately 15% of mutant Z-AAT protein folds correctly and is secreted by the cell. An additional consequence of the Z mutation is that the secreted Z-AAT has reduced activity compared to wild-type protein, with 40% to 80% of normal antiprotease activity (American Thoracic Society/European Respiratory Society, Am J Respir Crit Care Med.2003;168(7):818-900; and Ogushi et al. J Clin Invest. 1987;80(5):1366-74). [0005] The accumulation of polymerized Z-AAT protein within hepatocytes results in a gain-of-function cytotoxicity that can result in cirrhosis or liver cancer later in life and neonatal liver disease in 12% of patients. This accumulation may spontaneously remit but can be fatal in a small number of children. The deficiency of circulating AAT results in unregulated protease activity that degrades lung tissue over time, resulting in emphysema, a form of chronic obstructive pulmonary disease (COPD). This effect is severe in PiZZ individuals and typically manifests in middle age, resulting in a decline in quality of life and shortened lifespan (mean 68 years of age) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016;11:1663-9). The effect is more pronounced in PiZZ individuals who smoke, resulting in an even further shortened lifespan (58 years). (Piitulainen and Tanash, COPD 2015;12(1):36- Attorney Docket No.10275.0231-00304 VPI/24-005 WO 41). PiZZ individuals account for the majority of those with clinically relevant AATD lung disease. Accordingly, there is a need for additional and effective treatments for AATD. [0006] A milder form of AATD is associated with the SZ genotype in which the Z-allele is combined with an S-allele. The S allele is associated with somewhat reduced levels of circulating AAT but causes no cytotoxicity in liver cells. The result is clinically significant lung disease but not liver disease. (Fregonese and Stolk, Orphanet J Rare Dis.2008; 33:16). As with the ZZ genotype, the deficiency of circulating AAT in subjects with the SZ genotype results in unregulated protease activity that degrades lung tissue over time and can result in emphysema, particularly in smokers. [0007] The current standard of care for AAT-deficient individuals who have or show signs of developing significant lung or liver disease is augmentation therapy or protein replacement therapy. Augmentation therapy involves administration of a human AAT protein concentrate purified from pooled donor plasma to augment the missing AAT. Although infusions of the plasma protein have been shown to improve survival or slow the rate of emphysema progression, augmentation therapy is often not sufficient under challenging conditions such as during an active lung infection. Similarly, although protein replacement therapy shows promise in delaying progression of disease, augmentation does not restore the normal physiological regulation of AAT in patients and efficacy has been difficult to demonstrate. In addition, augmentation therapy requires weekly visits for treatment and augmentation therapy cannot address liver disease, which is driven by the toxic gain-of-function of the Z allele. Thus, there is a continuing need for new and more effective treatments for AATD. [0008] A key consideration for the selection of compounds suitable for clinical development is the projection of human dose. Two key parameters that factor into the projection of human dose are the unbound clearance of a compound and the plasma efficacious exposure (also referred to herein as potency). Together, these parameters are known to one skilled in the art as measurements of Compound Quality (as defined herein) and suitability for advancement into clinical development. Thus, in evaluating AAT modulator compounds, it is necessary to consider both potency and unbound clearance parameters. The relationship between these two parameters can be very difficult to predict. [0009] The compounds of the invention exhibit an unanticipated improvement in the compound potency and unbound clearance relative to the closest prior art, WO 2020/247160. The compounds of the invention are characterized by both high potency and low unbound clearance. Thus, the compounds of the invention exhibit improved Compound Quality scores Attorney Docket No.10275.0231-00304 VPI/24-005 WO relative to the prior art. Compounds with high projected human doses (e.g., a compound with a high unbound clearance) may limit the ability to reach efficacious exposures in clinical trials. In contrast, a higher-quality compound may result in a greater potential to test the full range of the predicted efficacious exposure of a compound. Exploration of higher efficacious exposures may lead to greater clinical benefit for a compound. [0010] A separate but related consideration for the selection of AAT-modulator compounds involves exposure multiples, which are an assessment of relative compound exposure in toxicology studies relative to the predicted plasma efficacious exposure. Higher exposure multiples in preclinical toxicology studies can provide the opportunity to explore higher exposures in clinical development. The larger the exposure multiple, the more suitable the compound may be for clinical development. However, exposures that result in an adverse toxicological outcome is unpredictable. [0011] Prior art publication, WO 2020/247160, leaves the relationship between compound potency and unbound clearance, as well as exposure multiples, for compounds of the disclosed scaffold challenging to predict. Experimentation on compounds of WO 2020/247160 shows no identifiable structure activity relationship (SAR) that can be used to predict which compounds might possess the appropriate efficacious exposure/unbound clearance relationship to make them better candidates for clinical development. Nor does WO 2020/247160 suggest any means for improving exposure multiples in disclosed compounds. In fact, SAR from WO 2020/247160 did not support exploration of 8F compounds for any reason. [0012] The compounds and formulations of the invention unexpectedly exhibit a significantly superior Compound Quality compared to compounds disclosed in WO 2020/247160. The compounds of the invention also exhibit unexpectedly enhanced exposure multiples due to the substitution of fluorine for hydrogen at C8 of the core ring structure. [0013] Compound 1 and Compound 2 have unexpectedly and significantly lower anticipated human dose projection (as measured by the Compound Quality score) compared to prior art compounds sharing this same scaffold. [0014] Compound 1 and Compound 2, as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, and deuterated derivatives have an EC50 of 0.04 μM or less when tested in an AAT Function Assay, such as, e.g., the MSD Assay NL20-SI Cell Line described in Example 6. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [0015] Compound 1 and Compound 2, including tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, and deuterated derivatives have an unbound hepatocyte clearance value of 12 µL/min/million cells or less or less when tested a human hepatocyte clearance assay. [0016] In some embodiments, Compound 1 and Compound 2, including tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, and deuterated derivatives have a Compound Quality (potency in an AAT functional assay multiplied by unbound clearance) score of less than or equal to 0.30. [0017] In some embodiments, Compound 1 and Compound 2, including tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, and deuterated derivatives are provided for use in the treatment of AATD. [0018] Solid forms of Compounds of Formula I, (Compound 1 and Compound 2) include solid dispersions, including spray dried dispersions of amorphous Compound 1 and spray dried dispersions of amorphous Compound 2. The solid dispersions comprising Compound 1 or Compound 2 have the advantage of superior solubility and bioavailability in vivo resulting in higher exposure upon administration to a patient in need thereof. [0019] In some embodiments, the invention provides solid dispersions, e.g., spray dried dispersions of (S)-4-(5-(3,4-Difluorophenyl)-8-fluoro-6-(2-hydroxy-1-meth-oxybutan-2-yl)- 1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 1): O OH (Compound 1) as well as tautomers of of Compound 1 and its tautomers, and pharmaceutically acceptable salts of Compound 1, its tautomers, and its deuterated derivatives that can be employed in the treatment of AATD. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [0020] In some embodiments, the invention provides solid dispersions of compounds selected from amorphous (S)-4-(8-fluoro-5-(4-fluoro-3-methoxyphenyl)-6-(2-hydroxy-1- methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 2): (Compound 2) as well as tautomers of of Compound 2 and its tautomers, and pharmaceutically acceptable salts of Compound 2, its tautomers, and its deuterated derivatives that can be employed in the treatment of AATD. [0021] In some embodiments, the disclosure provides a pharmaceutical composition comprising such solid dispersions, e.g., a spray-dried dispersion comprising at least one compound selected from amorphous Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the disclosure provides pharmaceutical compositions comprising solid dispersions, e.g., a spray-dried dispersion comprising at least one compound selected from amorphous Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further include at least one additional active pharmaceutical ingredient and/or at least one carrier. [0022] Another aspect of the invention features Compound 1 wherein at least 85% of the Compound 1 is amorphous (i.e., less than about 15% of the Compound 1 is crystalline). In some embodiments, a solid dispersion of the invention comprises Compound 1, wherein at least 85% of the Compound 1 is amorphous (i.e., less than 15% the Compound 1 is crystalline). [0023] In some embodiments, at least 90% of the Compound 1 is amorphous (i.e., less than about 10% of the Compound 1 is crystalline). In some embodiments, a solid dispersion of the invention comprises Compound 1, wherein at least 90% of the Compound 1 is amorphous (i.e., less than 10% the Compound 1 is crystalline). Attorney Docket No.10275.0231-00304 VPI/24-005 WO [0024] In some embodiments, at least 95% of the Compound 1 is amorphous (i.e., less than about 5% of the Compound 1 is crystalline). In some embodiments, a solid dispersion of the invention comprises Compound 1, wherein at least 95% of the Compound 1 is amorphous (i.e., less than 5% the Compound 1 is crystalline). [0025] In some embodiments, Compound 1 is 100% amorphous. In some embodiments, 100% of the Compound 1 in a solid dispersion is amorphous. [0026] In some embodiments, the invention features Compound 2, wherein at least 85% of the Compound 2 is amorphous (i.e., less than about 15% of Compound 2 is crystalline). In some embodiments, a solid dispersion of the invention comprises Compound 2, wherein at least 85% of the Compound 2 is amorphous (i.e., less than 15% the Compound 2 is crystalline). [0027] In some embodiments, at least 90% of the Compound 2 is amorphous (i.e., less than about 10% of the Compound 2 is crystalline). In some embodiments, a solid dispersion of the invention comprises Compound 2, wherein at least 90% of the Compound 2 is amorphous (i.e., less than 10% the Compound 2 is crystalline). [0028] In some embodiments, at least 95% of the Compound 2 is amorphous (i.e., less than about 5% of the Compound 2 is crystalline). In some embodiments, a solid dispersion of the invention comprises Compound 2, wherein at least 95% of the Compound 2 is amorphous (i.e., less than 5% the Compound 2 is crystalline). [0029] In some embodiments, Compound 2 is 100% amorphous. In some embodiments, 100% of the Compound 2 in a solid dispersion is amorphous. [0030] Another aspect of the disclosure provides methods of treating AATD comprising administering to a subject in need thereof a pharmaceutical composition comprising a solid dispersion such as, e.g., a spray dried dispersion, comprising at least one compound selected from amorphous Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing or a pharmaceutical composition comprising the at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the methods comprise administering a compound selected from amorphous Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing or a pharmaceutical composition comprising the at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. [0031] In some embodiments, the methods of treatment include administration of at least Attorney Docket No.10275.0231-00304 VPI/24-005 WO one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the solid dispersion comprising at least one compound selected from amorphous Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions. In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the solid dispersion comprising at least one compound selected from amorphous Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions. In some embodiments, the subject in need of treatment carries the ZZ mutation. In some embodiments, the subject in need of treatment carries the SZ mutation. [0032] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the solid dispersion comprising at least one compound selected from amorphous Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions, wherein the additional active agent is alpha-1 antitrypsin protein (AAT) from the blood plasma of healthy human donors. In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the solid dispersion comprising at least one compound selected from amorphous Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions, wherein the additional active agent is alpha-1 antitrypsin protein (AAT) from the blood plasma of healthy human donors. [0033] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the solid dispersion comprising at least one compound selected from amorphous Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions, wherein the additional active agent is recombinant AAT. In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the solid dispersion comprising at least one compound selected from amorphous Compound Attorney Docket No.10275.0231-00304 VPI/24-005 WO 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions, wherein the additional active agent is recombinant AAT. [0034] Also provided are methods of modulating AAT, comprising administering to a subject in need thereof, a pharmaceutical composition comprising a solid dispersion, e.g., a spray dried dispersion, comprising at least one compound selected from amorphous Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. Also provided are methods of modulating AAT, comprising administering to a subject in need thereof, a pharmaceutical composition comprising a solid dispersion, e.g., a spray dried dispersion, comprising at least one compound selected from amorphous Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. [0035] Also provided is a solid dispersion, e.g., a spray dried dispersion, (or a pharmaceutical composition comprising such solid dispersion) wherein the solid dispersion comprises amorphous Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy, such as, e.g., treating AATD. In some embodiments, there is provided a solid dispersion, e.g., a spray dried dispersion (or a pharmaceutical composition comprising such solid dispersion) wherein the solid dispersion comprises amorphous Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy, such as, e.g., treating AATD. [0036] In some embodiments, a solid dispersion, e.g., a spray dried dispersion, comprising amorphous Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, is used in the manufacture of a medicament for therapy, such as treating AATD. In some embodiments, there is provided a solid dispersion, e.g., a spray dried dispersion, comprising amorphous Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing, for use in the manufacture of a medicament for therapy, such as treating AATD. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [0037] In some embodiments the solid dispersion comprises one or more of a surfactant and/or a polymer. In some embodiments, the polymer is one or more than one water-soluble or partially water-soluble polymers. In some embodiments, the polymer is hydroxypropyl- methylcellulose (HPMC). In some embodiments, the polymer is hydroxypropylmethyl- cellulose acetate succinate (HPMCAS). In some embodiments, the polymer is vinylpyrrolidone/vinyl acetate copolymer (PVP-VA). In some embodiments, the polymer is present in an amount of from about 10% by weight to about 80% by weight, for example, the polymer is present in an amount of less than about 70% by weight, the polymer is present in an amount of about 50% by weight, or the polymer is present in an amount of about 30% by weight. In some embodiments, the solid dispersion of the invention comprising Compound 1 or Compound 2, further comprises about 0.25-1.0% wt/wt of surfactant. [0038] In some embodiments, the invention comprises methods of preparing amorphous Compound 1 and amorphous Compound 2, as well as solid dispersions comprising amorphous Compound 1 or amorphous Compound 2. In some embodiments, the methods comprise combining Compound 1 and a suitable solvent to form a mixture, and then spray- drying the mixture to obtain the amorphous form of Compound 1. In some embodiments, the methods comprise combining Compound 2 and suitable solvent to form a mixture, and then spray-drying the mixture to obtain the amorphous form of Compound 2. In some embodiments, the mixture comprises Compound 1, a suitable solvent, and a polymer. The mixture is spray dried to provide a solid dispersion comprising Compound 1. In some embodiments, the mixture comprises Compound 1, a suitable solvent, and a polymer. The mixture is spray dried to provide a solid dispersion comprising Compound 1 or Compound 2. Brief Description of the Drawings [0039] FIG.1 is an XRPD diffractogram for SDD 1A. A lack of crystalline diffraction peaks indicates that dispersion is amorphous. [0040] FIG.2 is a plot of heat flow as a function of temperature generated by differential scanning calorimetry (DSC) analysis of SDD 1A, showing a glass transition at 124 °C. [0041] FIG.3 is an XRPD diffractogram for SDD 1B. A lack of crystalline diffraction peaks indicates that dispersion is amorphous. [0042] FIG.4. is a plot of heat flow as a function of temperature generated by differential Attorney Docket No.10275.0231-00304 VPI/24-005 WO scanning calorimetry (DSC) analysis of SDD 1B showing a glass transition at 124 °C. [0043] FIG.5. depicts solid state ¹³C NMR spectra for SDD 1B. [0044] FIG.6 depicts solid state ¹⁹F NMR spectra for SDD 1B. [0045] FIG.7 is an XRPD diffractogram for SDD 1C. Lack of crystalline diffraction peaks indicates that material is amorphous. [0046] FIG.8 is a plot of heat flow as a function of temperature generated by differential scanning calorimetry (DSC) analysis of SDD 1C, showing a glass transition at 124 °C. [0047] FIG.9 depicts an overlay of solid state ¹H NMR (top), ¹³C NMR (middle) and ¹⁹F NMR (bottom) data of SDD 1C as compared to SDD 1B. [0048] FIG.10 is an XRPD diffractogram 1D. A lack of crystalline diffraction peaks indicates that dispersion is amorphous. [0049] FIG.11 is a plot of heat flow as a function of temperature generated by differential scanning calorimetry (DSC) analysis of SDD 1D, showing a glass transition at 137 °C. [0050] FIG.12 is a plot of weight (%) as a function of temperature generated by thermogravimetric analysis of SDD 1D, showing a weight loss of ~2.5% by roughly 180 °C. [0051] FIG.13 is an XRPD diffractogram for SDD 1E. A lack of crystalline diffraction peaks indicates that dispersion is amorphous. [0052] FIG.14 is a plot of heat flow as a function of temperature generated by differential scanning calorimetry (DSC) analysis of SDD 1E, showing a glass transition at 139 °C. [0053] FIG.15 is a plot of weight (%) as a function of temperature generated by thermogravimetric analysis of SDD 1E, showing a weight loss of ~3% by roughly 150 °C. [0054] FIG.16 depicts solid state ¹³C NMR spectra for SDD 1E. [0055] FIG.17 depicts solid state ¹⁹F NMR spectra for SDD 1E. [0056] FIG.18 is an XRPD diffractogram for SDD 2A. A lack of crystalline diffraction peaks indicates that dispersion is amorphous. [0057] FIG.19 is a plot of heat flow as a function of temperature generated by differential scanning calorimetry (DSC) analysis of SDD 2A, showing a glass transition at 124 °C. [0058] FIG.20 depicts solid state ¹³C NMR spectra for SDD 2A. [0059] FIG.21 depicts solid state ¹⁹F NMR spectra for SDD 2A. [0060] FIG.22 is an XRPD diffractogram for SDD 2B. A lack of crystalline diffraction peaks indicates that dispersion is amorphous. [0061] FIG.23 is a plot of heat flow as a function of temperature generated by differential scanning calorimetry (DSC) analysis of SDD 2B, showing a glass transition at 124 °C. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [0062] FIG.24 shows an XRPD diffractogram of Compound 1 Monohydrate Form A. [0063] FIG.25 shows a TGA thermogram of Compound 1 Monohydrate Form A. [0064] FIG.26 shows DSC thermogram of Compound 1 Monohydrate Form A. [0065] FIG.27 shows a solid state ¹³C NMR spectrum of Compound 1 Monohydrate Form A. [0066] FIG.28 shows solid state ¹⁹F NMR spectrum of Compound 1 Monohydrate Form A. [0067] FIG.29 shows an XRPD diffractogram of Compound 1 free form Form A. [0068] FIG.30 shows a TGA thermogram of Compound 1 free form Form A. [0069] FIG.31 shows a DSC thermogram of Compound 1 free form Form A. [0070] FIG.32 shows a solid state ¹³C NMR spectrum of Compound 1 free form Form A. [0071] FIG.33 shows solid state ¹⁹F NMR spectrum of Compound 1 free form Form A. [0072] FIG.34 shows an XRPD diffractogram of Compound 1 EtOH Solvate Form A. [0073] FIG.35 shows a TGA thermogram of Compound 1 EtOH Solvate Form A. [0074] FIG.36 shows a DSC thermogram of Compound 1 EtOH Solvate Form A. [0075] FIG.37 shows a solid state ¹³C NMR spectrum of Compound 1 EtOH Solvate Form A. [0076] FIG.38 shows solid state ¹⁹F NMR spectrum of Compound 1 EtOH Solvate Form A. [0077] FIG.39 shows an XRPD diffractogram of Compound 2 free form Form A. [0078] FIG.40 shows a TGA thermogram of Compound 2 free form Form A. [0079] FIG.41 shows a DSC thermogram of Compound 2 free form Form A. [0080] FIG.42 shows a solid state ¹³C NMR spectrum of Compound 2 free form Form A. [0081] FIG.43 shows a solid state ¹⁹F NMR spectrum of Compound 2 free form Form A. [0082] FIG.44 shows an XRPD diffractogram of Compound 1 free form Form B. [0083] FIG.45 shows a TGA thermogram of Compound 1 free form Form B. [0084] FIG.46 shows a DSC thermogram of Compound 1 free form Form B. I. Definitions [0085] The term “AAT” as used herein means alpha-1 antitrypsin or a mutation thereof, including, but not limited to, the AAT gene mutations such as Z mutations. As used herein, “Z-AAT” means AAT mutants which have the Z mutation. [0086] As used herein, “mutations” can refer to mutations in the SERPINA1 gene (the gene Attorney Docket No.10275.0231-00304 VPI/24-005 WO encoding AAT) or the effect of alterations in the gene sequence on the AAT protein. A “SERPINA1 gene mutation” refers to a mutation in the SERPINA1 gene, and an “AAT protein mutation” refers to a mutation that results in an alteration in the amino acid sequence of the AAT protein. A genetic defect or mutation, or a change in the nucleotides in a gene in general, results in a mutation in the AAT protein translated from that gene. [0087] As used herein, a patient who is “homozygous” for a particular gene mutation has the same mutation on each allele. [0088] As used herein, a patient who has the PiZZ genotype is a patient who is homozygous for the Z mutation in the AAT protein. [0089] The term “AATD” as used herein means alpha-1 antitrypsin deficiency, which is a genetic disorder characterized by low circulating levels of AAT. [0090] The term “compound,” when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis/trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound. [0091] The term “isotopologue” refers to a species in which the chemical structure differs from a specific compound of this disclosure only in the isotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by Attorney Docket No.10275.0231-00304 VPI/24-005 WO deuterium or tritium, or the replacement of a carbon by a ¹³C or ¹⁴C are within the scope of this disclosure. [0092] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis/trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. [0093] “Stereoisomer” refers to both enantiomers and diastereomers. [0094] The term “tautomer,” as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule. [0095] Certain compounds disclosed herein may exist as tautomers and both tautomeric forms are intended, even though only a single tautomeric structure is depicted. For example, a description of Compound A is understood to include its tautomer Compound B and vice versa, as well as mixtures thereof: Compound A Compound B Unless disclosure are within the scope of the disclosure. [0096] Unless otherwise stated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., geometric (or conformational), such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the compounds of the disclosure are within the scope of the disclosure. [0097] As used herein, “deuterated derivative” refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom, depicted as “H²” or “D”. For example, a deuterated methyl group may Attorney Docket No.10275.0231-00304 VPI/24-005 WO H² H² be depicted as -CD_{3, . It will be recognized that some variation of} natural isotopic compound depending on the origin of chemical materials The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivatives described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated derivative” of a compound of the disclosure, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%). In some embodiments, the deuterated derivatives of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5% deuterium incorporation at each designated deuterium) at least 4500, (67.5 % deuterium incorporation), at least 5000 (75% deuterium incorporation) at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at lease 6333.3 (95% deuterium incorporation, at least 6466.7 (97% deuterium incorporation, or at least 6600 (99% deuterium incorporation). [0098] The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. [0099] Examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc) benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods of adding (a process generally referred to as "protecting") and removing (process generally referred to as "deprotecting") such amine protecting groups are well-known in the art and available, for example, in P. J. Kocienski, Protecting Groups, Thieme, 1994, which is hereby incorporated by reference in its entirety and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999). [00100] Examples of suitable solvents for use in spray dried dispersions that may be used in this disclosure include, but not limited to water, acetone, dichloromethane (methylene chloride, DCM, CH2Cl2), methanol (MeOH), ethanol (EtOH), methyl acetate (MeOAc), ethyl acetate (EtOAc), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), and combinations thereof. [00101] Examples of suitable bases that may be used in this disclosure include, but not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), Attorney Docket No.10275.0231-00304 VPI/24-005 WO potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropyl-ethyl amine (i-Pr₂EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH3). [00102] The disclosure includes pharmaceutically acceptable salts of the disclosed compounds. A salt of a compound of the disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. [00103] The term “pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. [00104] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with Attorney Docket No.10275.0231-00304 VPI/24-005 WO mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid. [00105] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(C_1-4alkyl)₄ salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts. [00106] As used herein, the term “pharmaceutically acceptable solid form” refers to a solid form of the referenced compound of this disclosure wherein the solid form (e.g., crystalline free form, crystalline salt, crystalline salt solvate, crystalline salt hydrate, and amorphous form) of the referenced compound of the disclosure is nontoxic and suitable for use in pharmaceutical compositions. [00107] As used herein, a "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g., colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase), or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments an amorphous solid dispersion includes the polymer constituting the dispersed phase, and the drug constitute the continuous phase. In some embodiments, the dispersion includes amorphous Compound 1 or substantially amorphous Compound 1. In some embodiments, the dispersion includes amorphous Compound 2 or substantially amorphous Compound 2. [00108] The term "solid amorphous dispersion" generally refers to a solid dispersion of two or more components, usually a drug and polymer, but possibly containing other components such as surfactants or other pharmaceutical excipients, where e.g., Compound 1 (or Compound 2) is amorphous (e.g., contains less than 15% crystalline Compound 1 (or Attorney Docket No.10275.0231-00304 VPI/24-005 WO Compound 2)), and the physical stability and/or dissolution and/or solubility of the amorphous drug is enhanced by the other components. [00109] A solid dispersion as provided herein is a particularly favourable embodiment of this invention. Solid dispersions typically include a compound dispersed in an appropriate carrier medium, such as a solid-state carrier. In one embodiment, a carrier according to this invention comprises a polymer, preferably, a water-soluble polymer or a partially water- soluble polymer. It would be understood that one or more than one water-soluble or partially water-soluble polymer could be used in a solid dispersion of this invention. [00110] The term “SDD” as used herein refers to a spray dried dispersion, i.e., a solid dispersion prepared by spray drying the contents of the solid dispersion. [00111] An exemplary solid dispersion is a co-precipitate or a co-melt of Compound 1 or Compound 2 with at least one polymer. A "co-precipitate" is a product after dissolving a drug and a polymer in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the polymer can be suspended in the solvent or solvent mixture. The solvent or solvent mixture includes organic solvents and supercritical fluids. A "co-melt" is a product after heating a drug and a polymer to melt, optionally in the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent if applicable, and cooling to room temperature at a selected rate. In some cases, the solid dispersions are prepared by adding a solution of a drug and a solid polymer followed by mixing and removal of the solvent. To remove the solvent, vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures may be applied. Applying any of these methods using appropriate processing parameters, according to this invention, would provide Compound 1 or Compound 2 in an amorphous state in the final solid dispersion product. [00112] As noted above, in some embodiments, a solid material may comprise a mixture of crystalline solids and amorphous solids. A solid material comprising an amorphous compound may also, for example, contain up to 15% of a crystalline solid. In some embodiments, a solid material prepared to comprise an amorphous compound may also, for example, contain up to 10%, 5%, or 2% of a crystalline solid. In other embodiments, an amorphous material may be 100% amorphous, i.e., it contains 100% amorphous compound. [00113] In embodiments wherein the solid material contains a mixture of crystalline solids and amorphous solids, the characterizing data, such as XRPD, may contain indicators of both Attorney Docket No.10275.0231-00304 VPI/24-005 WO crystalline and amorphous solids. In some embodiments, a crystalline form of this disclosure may contain up to 15% amorphous compound. In some embodiments, a crystalline preparation of a referenced compound of the disclosure may contain up to 10%, 5%, or 2% of an amorphous solid. In other embodiments, a crystalline material may be 100% crystalline, i.e., it contains 100% crystalline compound. [00114] As used herein, the term “amorphous” refers to a solid material having no long- range order in the position of its molecules. For example, amorphous materials have less than 15% crystallinity (e.g., less than 10% crystallinity, less than 5% crystallinity, or less than 2% crystallinity). It is also noted that the term “amorphous” includes materials having no (0%) crystallinity. Amorphous solids are generally glasses or supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are generally rather isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. Instead, they typically exhibit a glass transition temperature which marks a transition from glassy amorphous state to supercooled liquid amorphous state upon heating. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. See US 2004/0006237 for a comparison of XRPDs of an amorphous material and crystalline material. In some embodiments, a solid material may comprise an amorphous compound, and the material may, for example, be characterized by a lack of sharp characteristic crystalline peak(s) in its XRPD spectrum (i.e., the material is not crystalline, but is amorphous, as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may appear in the XRPD pattern of the material. See US 2004/0006237 for a representative comparison of XRPDs of an amorphous material and crystalline material. A solid material, comprising an amorphous compound, may be characterized by, for example, a wider temperature range for the melting of the solid material, as compared to the range for the melting of a pure crystalline solid. Other techniques, such as, for example, solid state NMR may also be used to characterize crystalline or amorphous forms. [00115] As used herein, the terms “crystal form,” “crystalline,” and “crystalline form” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and Attorney Docket No.10275.0231-00304 VPI/24-005 WO distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, and solid state nuclear magnetic resonance (e.g., ¹³C, ¹⁹F, ¹⁵N, and ³¹P ssNMR). Accordingly, as used herein, the terms “Compound 1 free form Form A” and “Compound 1 Monohydrate Form A” refer to unique crystalline forms that can be identified and distinguished from each other by one or more characterization techniques including, for example, XRPD, single crystal X-ray diffraction, and ¹³C ssNMR. In some embodiments, the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more specified degree two-theta (°2θ) values. [00116] As used herein, the term “ambient conditions” means room temperature, open air condition and uncontrolled humidity condition. As used herein, the terms “room temperature” and “ambient temperature” mean 15 °C to 30 °C. [00117] As used herein, the terms “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” “XRPD pattern,” “XRPD spectrum” interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate). [00118] A “signal” or “peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. An XRPD peak is identified by its angular value as measured in degrees 2θ (° 2θ), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed, for example, as “a signal at … degrees two-theta,” “a signal at [a] two-theta value(s)of …” and/or “a signal at at least … two-theta value(s) selected from ….” [00119] The repeatability of the measured angular values is in the range of ±0.2° 2θ, i.e., the angular value can be at the recited angular value +0.2 degrees two-theta, the angular value -0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta). [00120] One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00121] The terms “signal intensities” and “peak intensities” interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly). [00122] As used herein, an X-ray powder diffractogram is “substantially similar to that in a [specified] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99% of the signals in the two diffractograms overlap. In determining “substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form. Thus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta) generally mean that value is identified as ±0.2 degrees two-theta of the reported value, an art-recognized variance. [00123] As used herein, the term “TGA” refers to thermogravimetric analysis and “TGA/DSC” refers to thermogravimetric analysis and differential scanning calorimetry. [00124] As used herein, the term “DSC” refers to the analytical method of differential scanning calorimetry. [00125] As used herein, the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of product >1 g/L). [00126] As used herein, the term “glass transition temperature” or “Tg” refers to the temperature above which a hard and brittle “glassy” amorphous solid becomes viscous or rubbery. [00127] As used herein, the terms “melting temperature”, “melting point”, and “Tm” refer to a temperature at which the solid and liquid state are at equilibrium. [00128] As used herein, the term “Compound Quality” refers to the potency of a compound multiplied (x) by the compound’s unbound clearance as measured using the assays described in Example 6. [00129] The term “unbound clearance” refers to unbound intrinsic clearance (unbound CLint) in hepatocytes - the intrinsic clearance a drug would have in the absence of protein binding. Unbound CLint = CLint,hep/fu,hep, where CLint,hep is intrinsic clearance in hepatocytes and fu,hep is unbound fraction in hepatocytes. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00130] “Exposure multiple” as used herein, refers to an assessment of relative compound exposure in toxicology studies. The calculation of an exposure multiple is accomplished by comparing the exposure (AUC) achieved in a toxicology species relative to the target efficacious exposure at steady state (AUCss). The larger exposure multiple provides the opportunity to explore higher doses relative to efficacious concentration in clinical development. However, the exposure that results in an adverse toxicological outcome is unpredictable. [00131] The terms “patient” and “subject” are used interchangeably and refer to an animal including a human. [00132] The terms “effective dose,” “effective amount,” “therapeutically effective dose,” and “therapeutically effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in AATD or a symptom of AATD, lessening the severity of AATD or a symptom of AATD, and/or reducing the rate of onset or incidence of AATD or a symptom of AATD). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). [00133] As used herein, the term “treatment” and its cognates (e.g., “treat,” “treating”) refer to improving AATD or its symptoms in a subject, delaying the onset of AATD or its symptoms in a subject, or lessening the severity of AATD or its symptoms in a subject. “Treatment” and its cognates as used herein, include, but are not limited to the following: improved liver and/or spleen function, lessened jaundice, improved lung function, lessened lung diseases and/or pulmonary exacerbations (e.g., emphysema), lessened skin disease (e.g., necrotizing panniculitis), increased growth in children, improved appetite, and reduced fatigue. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed. [00134] The terms “about” and “approximately,” when used in connection with temperatures, peaks, signals, doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified temperature, peak, signal, dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified temperature, peak, signal, dose, amount, or weight Attorney Docket No.10275.0231-00304 VPI/24-005 WO percent. Typically, the term “about” refers to a variation of up to 10%, up to 5%, or up to 2% of a stated value. [00135] In some embodiments, Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing may be administered once daily, twice daily, or three times daily for the treatment of AATD. In some embodiments, at least one compound chosen from Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one compound selected from compounds of Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing is administered twice daily. In some embodiments, a compound selected from Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing is administered three times daily. [00136] In some embodiments, Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing may be administered once daily, twice daily, or three times daily for the treatment of AATD. In some embodiments, at least one compound chosen from Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one compound selected from compounds of Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing is administered twice daily. In some embodiments, a compound selected from Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing is administered three times daily. [00137] Any one or more of Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing may be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. In some embodiments, any one or more of Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing may be administered Attorney Docket No.10275.0231-00304 VPI/24-005 WO in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. [00138] As used herein, “AAT augmentation therapy” refers to the use of alpha-1 antitrypsin protein (AAT) from the blood plasma of healthy human donors to augment (increase) the alpha-1 antitrypsin levels circulating in the blood. “AAT replacement therapy” refers to administration of recombinant AAT. [00139] In some embodiments, 5 mg to 1,000 mg, 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, 400 mg to 2,500 mg or 400 mg to 600 mg of Compound 1, a tautomer of Compound 1, deuterated derivatives of Compound 1 and tautomer, and pharmaceutically acceptable salts of any of the foregoing is administered once daily, twice daily, or three times daily. [00140] In some embodiments, 5 mg to 1,000 mg, 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2000 mg, or 400 mg to 600 mg of a compound selected from Compound 2, a tautomer of Compound 2, deuterated derivatives of Compound 2 and tautomer, and pharmaceutically acceptable salts of any of the foregoing is administered once daily, twice daily, or three times daily. [00141] One of ordinary skill in the art would recognize that, when an amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. It is noted that the disclosed amounts of the compounds, tautomers, deuterated derivatives, and pharmaceutically acceptable salts are based upon the free base form of the reference compound. For example, “10 mg of at least one compound chosen from Compound 1 and pharmaceutically acceptable salts thereof” includes 10 mg of a compound of Compound 1 and a concentration of a pharmaceutically acceptable salt of compounds of Compound 1 equivalent to 10 mg of Compound 1. [00142] It should be understood that references herein to methods of treatment (e.g., methods of treating AATD) using one or more of Compound 1, Compound 2, tautomers of Compound 1 and Compound 2, deuterated derivatives of Compound 1, Compound 2 and tautomers thereof, and pharmaceutically acceptable salts of any of the foregoing should also be interpreted as references to: - one or more compounds (e.g., Compound 1, Compound 2, tautomers of Compound 1 and Compound 2, deuterated derivatives of Compound 1, Compound 2 and tautomers thereof, and pharmaceutically acceptable salts of any of the foregoing) for use in methods of Attorney Docket No.10275.0231-00304 VPI/24-005 WO treating, e.g., AATD; and/or - the use of one or more compounds (e.g., Compound 2, tautomers of Compound 1 and Compound 2, deuterated derivatives of Compound 1, Compound 2 and tautomers thereof, and pharmaceutically acceptable salts of any of the foregoing) in the manufacture of a medicament for treating, e.g., AATD. II. Polymers [00143] Solid dispersions including amorphous Compound 1 or amorphous Compound 2 and a polymer (or solid-state carrier) also are included herein. For example, Compound 1 or Compound 2 is present as an amorphous compound as a component of a solid amorphous dispersion. The solid amorphous dispersion generally includes Compound 1 or Compound 2 and a polymer. Exemplary polymers include cellulosic polymers such as HPMC or HPMCAS and pyrrolidone-containing polymers such as PVP/VA. In some embodiments, the solid amorphous dispersion includes one or more additional excipients, such as a surfactant. [00144] In one embodiment, a polymer is able to dissolve in aqueous media. The solubility of the polymers may be pH-independent or pH-dependent. The latter include one or more enteric polymers. The term "enteric polymer" refers to a polymer that is preferentially soluble in the less acidic environment of the intestine relative to the more acid environment of the stomach, for example, a polymer that is insoluble in acidic aqueous media but soluble when the pH is above 5-6. An appropriate polymer should be chemically and biologically inert. In order to improve the physical stability of the solid dispersions, the glass transition temperature (Tg) of the polymer should be as high as possible. For example, preferred polymers have a glass transition temperature at least equal to or greater than the glass transition temperature of the drug (e.g., Compound 1). Other preferred polymers have a glass transition temperature that is within about 10 to about 15 °C of the drug (e.g., Compound 1 or Compound 2). Examples of suitable glass transition temperatures of the polymers include at least about 90 °C, at least about 95 °C, at least about 100 °C, at least about 105 °C, at least about 110 °C, at least about 115 °C, at least about 120 °C, at least about 125 °C, at least about 130 °C, at least about 135 °C, at least about 140 °C, at least about 145 °C, at least about 150 °C, at lea t about 155 °C, at least about 160 °C, at least about 165 °C, at least about 170 °C, or at least about 175 °C (as measured under dry conditions). Without wishing to be bound by theory, it is believed that the underlying mechanism is that a polymer with a higher Tg Attorney Docket No.10275.0231-00304 VPI/24-005 WO generally has lower molecular mobility at room temperature, which can be a crucial factor in stabilizing the physical stability of the amorphous solid dispersion. [00145] Additionally, the hygroscopicity of the polymers should be as low, e.g., less than about 10%. For the purposes of comparison in this application, the hygroscopicity of a polymer or composition is characterized at about 60% relative humidity. In some preferred embodiments, the polymer has less than about 10% water absorption, for example less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% water absorption. The hygroscopicity can also affect the physical stability of the solid dispersions. Generally, moisture adsorbed in the polymers can greatly reduce the Tg of the polymers as well as the resulting solid dispersions, which will further reduce the physical stability of the solid dispersions as described above. [00146] In one embodiment, the polymer is one or more water-soluble polymer(s) or partially water-soluble polymer(s). Water-soluble or partially water-soluble polymers include but are not limited to, cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as polymethacrylate (e.g., Eudragit® E); cyclodextrins (e.g., β-cyclodextrin) and copolymers and derivatives thereof, including for example PVP-VA (polyvinylpyrrolidone-vinyl acetate). [00147] In some embodiments, the polymer is hydroxypropylmethylcellulose (HPMC), such as HPMC E50, HPMCE15, or HPMC60SH50). [00148] As discussed herein, the polymer can be a pH-dependent enteric polymer. Such pH- dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methyl cellulose phthalates (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or a salt thereof (e.g., a sodium salt such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), or polymethacrylates (e.g., Eudragit® S). In some embodiments, the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS). [00149] In yet another embodiment, the polymer is a polyvinylpyrrolidone co-polymer, for example, a vinylpyrrolidone/vinyl acetate co-polymer (PVP/VA). Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00150] In embodiments where Compound 1 forms a solid dispersion with a polymer, for example with an HPMC, HPMCAS or PVP/VA polymer, the amount of polymer relative to the total weight of the solid dispersion ranges from about 0.1% to 99% by weight. Unless otherwise specified, percentages of drug, polymer and other excipients as described within a dispersion are given in weight percentages. The amount of polymer is typically at least about 20%, and preferably at least about 30%, for example, at least about 35%, at least about 40%, at least about 45%, or about 50% (e.g., 49.5%). The amount is typically about 99% or less, and preferably about 80% or less, for example about 75% or less, about 70% or less, about 65% or less, about 60% or less, or about 55% or less. In one embodiment, the polymer is in an amount of up to about 50% of the total weight of the dispersion (and even more specifically, between about 40% and 50%, such as about 49%, about 49.5%, or about 50%). HPMC and HPMCAS are available in a variety of grades (e.g., H, L, and M) from AquaSolve and ShinEtsu, for example. HPMCAS is also available in a number of varieties, including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, AS-HG. Each of these grades/varieties vary with the percent substitution of acetate and succinate. [00151] In some embodiments, Compound 1 or Compound 2 and polymer are present in roughly equal amounts, for example each of the polymer and the drug make up about half of the percentage weight of the dispersion. For example, the polymer is present in about 50% and the drug is present in about 50%. In other embodiments, the polymer is present in about 20% and Compound 1 or Compound 2 is present in about 80%. [00152] In some preferred embodiments, the dispersion further includes other minor ingredients, such as a surfactant (e.g., SLS). In some preferred embodiments, the surfactant is present in less than about 10% of the dispersion, for example less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, about 1%, or about 0.5%. [00153] In embodiments including a polymer, the polymer should be present in an amount effective for stabilizing the solid dispersion. Stabilizing includes inhibiting or preventing, the crystallization of Compound 1. Such stabilizing would inhibit the conversion Compound 1 or Compound 2 from amorphous to crystalline form. For example, the polymer would prevent at least a portion (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or greater) of Compound 1 from converting from an amorphous to a crystalline form. Stabilization can be measured, for example, by measuring the glass Attorney Docket No.10275.0231-00304 VPI/24-005 WO transition temperature of the solid dispersion, measuring the rate of relaxation of the amorphous material, or by measuring the solubility or bioavailability of Compound 1 or Compound 2. [00154] Suitable polymers for use in combination with Compound 1 or Compound 2, for example to form a solid dispersion such as an amorphous solid dispersion, should have one or more of the following properties. [00155] The glass transition temperature of the polymer should have a temperature of no less than about 10-15 °C lower than the glass transition temperature of Compound 1 or Compound 2. Preferably, the glass transition temperature of the polymer is greater than the glass transition temperature of Compound 1, and in general at least 50 °C higher than the desired storage temperature of the drug product. For example, at least about 100 °C, at least about 105 °C, at least about 105 °C, at least about 110 °C, at least about 120 °C, at least about 130 °C, at least about 140 °C, at least about 150 °C, at least about 160 °C, at least about 160 °C, or greater. [00156] The polymer should be relatively non-hygroscopic. For example, the polymer should, when stored under standard conditions, absorb less than about 10% water, for example, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%, less than about 4%, or less than about 3% water. Preferably the polymer will, when stored under standard conditions, be substantially free of absorbed water. [00157] The polymer should have similar or better solubility in solvents suitable for spray drying processes relative to that of Compound 1 or Compound 2. In preferred embodiments, the polymer will dissolve in one or more of the same solvents or solvent systems as Compound 1 or Compound 2. It is preferred that the polymer is soluble in at least one non- hydroxy containing solvent such as methylene chloride, acetone, or a combination thereof. [00158] The polymer, when combined with Compound 1 or Compound 2, for example in a solid dispersion or in a liquid suspension, should increase the solubility of Compound 1 in aqueous and physiologically relative media either relative to the solubility of Compound 1 or Compound 2 in the absence of polymer or relative to the solubility of Compound 1 when combined with a reference polymer. For example, the polymer could increase the solubility of amorphous Compound 1 by reducing the amount of amorphous Compound 1 or Compound 2 that converts to crystalline Compound 1 or Compound 2, either from a solid amorphous dispersion or from a liquid suspension. [00159] The polymer should decrease the relaxation rate of the amorphous substance. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00160] The polymer should increase the physical and/or chemical stability of Compound 1 or Compound 2. [00161] The polymer should improve the manufacturability of Compound 1 or Compound 2. [00162] The polymer should improve one or more of the handling, administration or storage properties of Compound 1 or Compound 2. [00163] The polymer should not interact unfavorably with other pharmaceutical components, for example excipients. [00164] The suitability of a candidate polymer (or other component) can be tested using the spray drying methods (or other methods) described herein to form an amorphous composition. The candidate composition can be compared in terms of stability, resistance to the formation of crystals, or other properties, and compared to a reference preparation, e.g., a preparation of neat amorphous Compound 1 or Compound 2, or crystalline Compound 1 or Compound 2. For example, a candidate composition could be tested to determine whether it inhibits the time to onset of solvent mediated crystallization, or the percent conversion at a given time under controlled conditions, by at least 50%, 75%, 100%, or 110% as well as the reference preparation, or a candidate composition could be tested to determine if it has improved bioavailability or solubility relative to crystalline Compound 1 or Compound 2. III. Surfactants [00165] A solid dispersion or other composition may include a surfactant. A surfactant or surfactant mixture would generally decrease the interfacial tension between the solid dispersion and an aqueous medium. An appropriate surfactant or surfactant mixture may also enhance aqueous solubility and bioavailability of Compound 1 from a solid dispersion. The surfactants for use in connection with the present invention include, but are not limited to, sorbitan fatty acid esters (e.g., Spans®), polyoxyethylene sorbitan fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS) dioctyl sodium sulfosuccinate (Docusate), dioxycholic acid sodium salt (DOSS), Sorbitan Monostearate, Sorbitan Tristearate, hexadecyltrimethyl ammonium bromide (HTAB), Sodium N-lauroylsarcosine, Sodium Oleate, Sodium Myristate, Sodium Stearate, Sodium Palmitate, Gelucire 44/14, ethylenediamine tetraacetic acid (EDTA), Vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), Lecithin, MW 677-692, Glutamic acid monosodium monohydrate, Labrasol, PEG 8 caprylic/capric glycerides, Transcutol, Attorney Docket No.10275.0231-00304 VPI/24-005 WO diethylene glycol monoethyl ether, Solutol HS-15, polyethylene glycol/hydroxystearate, Taurocholic Acid, Pluronic F68, Pluronic F108, and Pluronic Fl27 (or any other polyoxyethylene-5 polyoxypropylene co-polymers (Pluronics®) or saturated polyglycolized glycerides (Gelucirs®)). Specific example of such surfactants that may be used in connection with this invention include, but are not limited to, Span 65, Span 25, Tween 20, Capryol 90, Pluronic Fl 08, sodium lauryl sulfate (SLS), Vitamin E TPGS, pluronics and copolymers. SLS is generally preferred. [00166] The amount of the surfactant (e.g., SLS) relative to the total weight of the solid dispersion may be between 0.1-15%. Preferably, it is from about 0.5% to about 10%, more preferably from about 0.5 to about 5%, e.g., about 1%, about 2%, about 3%, about 4%, or about 5%. [00167] In certain embodiments, the amount of the surfactant relative to the total weight of the solid dispersion is at least about 0.1%, preferably about 0.5%. In these embodiments, the surfactant would be present in an amount of no more than about 15%, and preferably no more than about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1%. An embodiment wherein the surfactant is in an amount of about 0.5% by weight is preferred. [00168] Candidate surfactants (or other components) can be tested for suitability for use in the invention in a manner similar to that described for testing polymers. IV. Pharmaceutical Compositions [00169] Another aspect of the disclosure provides a pharmaceutical composition comprising a solid dispersion comprising Compound 1, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the pharmaceutical composition comprises a solid dispersion comprising Compound 2, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the pharmaceutical composition comprising a solid dispersion comprising Compound 1, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, is administered to a patient in need thereof. In some embodiments, the pharmaceutical composition comprising a solid dispersion comprising Compound 4, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a Attorney Docket No.10275.0231-00304 VPI/24-005 WO pharmaceutically acceptable salt of any of the foregoing, is administered to a patient in need thereof. [00170] In some embodiments, the pharmaceutical composition of the invention comprises a solid dispersion comprising Compound 1, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing and one or more of a surfactant and a polymer. In some embodiments, the pharmaceutical composition of the invention comprises a solid dispersion comprising Compound 2, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing and one or more of a surfactant and a polymer. [00171] In some embodiments, the pharmaceutical composition of the invention comprises a solid dispersion comprising Compound 1, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing and one or polymers selected from water-soluble or partially water-soluble polymers. In some embodiments, the pharmaceutical composition of the invention comprises a solid dispersion comprising Compound 2, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing and one or polymers selected from water-soluble or partially water-soluble polymers. [00172] A pharmaceutical composition of the invention may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants. [00173] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988- 1999, Marcel Dekker, New York discloses various carriers used in formulating Attorney Docket No.10275.0231-00304 VPI/24-005 WO pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants). [00174] In another aspect of the disclosure, the solid dispersions of the invention and the pharmaceutical compositions comprising those solid dispersions as described herein, are used to treat AATD. In some embodiments, the subject in need of treatment with the compounds and compositions of the disclosure carries the ZZ mutation. In some embodiments, the subject in need of treatment with the compounds and compositions of the disclosure carries the SZ mutation. [00175] In some embodiments, said patient in need thereof has a Z mutation in the alpha-1 antitrypsin gene. In some embodiments said patient in need thereof is homozygous for the Z- mutation in the alpha-1 antitrypsin gene. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00176] In some embodiments, the methods of modulating alpha-1 antitrypsin activity take place in vivo. In some embodiments, the methods of modulating alpha-1 antitrypsin activity take place ex vivo and said alpha-1-antitrypsin is from a biological sample obtained from a human subject. In some embodiments, the methods of modulating AAT take place in vitro and said alpha-1-antitrypsin is from a biological sample obtained from a human subject. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is a sample taken from a liver biopsy. [00177] An exemplary 25 mg tablet comprising Compound 1 or Compound 2 comprises the following components: Component Component Amount per Content Function Tablet (mg) (% w/w) Compound 1 SDD or Active 50.00 50.00 Compound 2 SDD * Microcrystalline Diluent 16.25 16.25 Cellulose Lactose Monohydrate Diluent 16.25 16.25 Intragranular Blend Croscarmellose Sodium Disintegrant 3.00 3.00 Sodium Stearyl Lubricant 1.00 1.00 Fumarate Microcrystalline Diluent 10.00 10.00 Cellulose Croscarmellose Sodium Disintegrant 1.50 1.50 Extragranular Blend Sodium Stearyl Lubricant 2.00 2.00 Fumarate Total --- 100.0 100.0 *The SDD contains 50% w/w drug substance (Compound 1 or Compound 2) and 50% w/w polymer (e.g., HPMCAS). [00178] An exemplary process for preparing a pharmaceutical composition comprising Compound 1 or Compound 2 comprises the following steps: 1. Weighing and sieving a spray dried dispersion of Compound 1 or Compound 2, Microcrystalline Cellulose, Lactose Monohydrate, and Croscarmellose Sodium. Adding the components to a bin blender and blending to form the intragranular (IG) blend; Attorney Docket No.10275.0231-00304 VPI/24-005 WO 2. Weighing and sieving Sodium Stearyl Fumarate. Adding this component to powder mixture generated in Step 1 and blending to form the lubricated IG blend; 3. Dry granulating the lubricated IG blend using a roller compactor and in-line mill; 4. Adding the milled granules to a bin blender along with sieved Microcrystalline Cellulose and Croscarmellose Sodium and blending to form the extragranular (EG) blend; 5. Weighing and sieving Sodium Stearyl Fumarate, adding this component to the powder mixture generated in Step 4, and blending to form the lubricated EG blend; and 6. Compressing the lubricated EG blend into tablets containing the equivalent of 25mg Compound 1 or Compound 2 using a tablet press. [00179] An exemplary process for preparing a tablet formulation comprising Compound 1 or Compound 2 comprises the following steps: 1. The solid dispersion comprising substantially amorphous Compound 1 or Compound 2 (e.g., amorphous Compound 1 comprising less than 15% crystalline Compound 1), and excipients may be screened prior to or after weigh out. Appropriate screen sizes are mesh 30, or mesh 60; 2. The solid dispersion comprising substantially amorphous Compound 1 or Compound 2, and excipients may be added to the blender in any order. Additional lubing steps may be included. The blending and lubing may be performed in a Turbula blender or a bin blender. The components may be blended for 4.5 minutes and lubed for 2 minutes; 3. The blend may be granulated using a Gerteis roller compactor equipped with paddle agitator, smooth/knurled rolls and an integrated 1.00 mm mesh milling screen with pocketed rotor. The gerteis roller compactor may be operated with a roll gap of 2 mm, roll pressure of 5.0 kN/cm, roll speed of 2 rpm, agitator speed of 40 rpm, granulation speed clockwise/counterclockwise of 80/80 rpm, and oscillation clockwise/counterclockwise of 330/360 degrees. The ribbons produced may be milled with integrated mill equipped with 1.00 mm mesh screen; 4. The roller compacted granules may be blended with extra-granular excipients such as a diluent, disintegrant and, if needed lubricant using a turbula blender or a bin blender. The blending time may be 8 minutes or may be lubed for 3 minutes; and 5. The compression blend may be compressed into tablets using a single station or rotary tablet press such as the Riva Piccola press, using TSM D 6.35 mm round tooling. The weight Attorney Docket No.10275.0231-00304 VPI/24-005 WO of a tablet for a dose of 25 mg of substantially amorphous Compound 1 or Compound 2 may be approximately 100 mg. V. Preparation of Solid Dispersions of Compound 1 or Compound 2 [00180] Any method of preparing a solid dispersion may be used to make the solid dispersions of the invention. An exemplary solid dispersion is a co-precipitate or a co-melt of Compound 1 or Compound 2 with at least one polymer. A "co-precipitate" is a product after dissolving a drug and a polymer in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the polymer can be suspended in the solvent or solvent mixture. The solvent or solvent mixture includes organic solvents and supercritical fluids. A "co-melt" is a product after heating a drug and a polymer to melt, optionally in the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent if applicable, and cooling to room temperature at a selected rate. In some cases, the solid dispersions are prepared by adding a solution of a drug and a solid polymer followed by mixing and removal of the solvent. To remove the solvent, vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures may be applied. Applying any of these methods using appropriate processing parameters, according to this invention, would provide Compound 1 or Compound 2 in an amorphous state in the final solid dispersion product. [00181] In some embodiments, the solid dispersion is made using amorphous compound 1 or Compound 2. In some embodiments, amorphous Compound 1 or Compound 2 can be made using a variety of techniques, including, for example spray drying a solution of Compound 1 or Compound 2 to provide amorphous Compound 1 or Compound 2, e.g., as a neat solid or as a component of a solid dispersion, said method utilizing spray-drying means to effect said conversion. For example, amorphous Compound 1 can be made by converting a form of Compound 1, e.g., a crystalline form of Compound 1, such as free form Form A or Monohydrate Form A to an amorphous form of Compound 1 by dissolving the crystalline compound into a solution and spray drying the solution, thereby converting crystalline Compound 1, into amorphous Compound 1. Exemplary processes for making amorphous Compound 1 by converting crystalline Compound 1 into a substantially amorphous form of Compound 1 are recited in the examples. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00182] Any method for obtaining amorphous forms of Compound 1 or Compound 2, including neat amorphous Compound 1 or Compound 2 and solid amorphous dispersions of Compound 1 or Compound 2, can be used including, for example, those described in US 2003/0186952 and US 2003/0185891. In general, methods that could be used include those that involve rapid removal of solvent from a mixture or cooling a molten sample. Such methods include, but are not limited to, rotational evaporation, freeze-drying (i.e., lyophilization), vacuum drying, melt congealing, and melt extrusion. However, a preferred embodiment includes amorphous Compound 1 or Compound 2, such as a neat preparation or a solid dispersion obtained by spray-drying. Accordingly, in some embodiments, the amorphous product obtained by spray-drying is further dried, for example, to remove residual solvent. [00183] Preparations disclosed herein, e.g., a pharmaceutical composition, can be obtained by spray-drying a mixture comprising Compound 1 or Compound 2, a suitable polymer, and an appropriate solvent. Spray drying is a method that involves atomization of a liquid mixture containing, e.g., a solid and a solvent, and removal of the solvent. Atomization can be done, for example, through a nozzle or on a rotating disk. [00184] Spray drying is a process that converts a liquid feed to a dried particulate form. Optionally, a secondary drying process such as fluidized bed drying or vacuum drying, may be used to reduce residual solvents to pharmaceutically acceptable levels. Typically, spray- drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. The preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray-drying apparatus. In a standard procedure, the preparation is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector (e.g., a cyclone). The spent air is then exhausted with the solvent, or alternatively the spent air is sent to a condenser to capture and potentially recycle the solvent. Commercially available types of apparatus may be used to conduct the spray-drying. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g., the PSD line of spray driers manufactured by Niro) (see, US 2004/0105820; US 2003/0144257). [00185] Spray-drying typically employs solids loads of material from about 3% to about 30% by weight, (i.e., drug plus and excipients), for example about 4% to about 20% by Attorney Docket No.10275.0231-00304 VPI/24-005 WO weight, preferably at least about 10%. In general, the upper limit of solids loads is governed by the viscosity of (e.g., the ability to pump) the resulting solution and the solubility of the components in the solution. Generally, the viscosity of the solution can determine the size of the particle in the resulting powder product. [00186] Techniques and methods for spray-drying may be found in Perry's Chemical Engineering Handbook, 6th Ed., R.H. Perry, D.W. Green & J.O. Maloney, eds.), McGraw- Hill Book Co. (1984); and Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). In general, the spray-drying is conducted with an inlet temperature of from about 60 °C to about 200 °C, for example, from about 95 °C to about 185 °C, from about 110 °C to about 182 °C, from about 96 °C to about 108 °C, e.g., about 175 °C. The spray-drying is generally conducted with an outlet temperature of from about 30 °C to about 80 °C, for example from about 31 °C to about 72 °C, about 37 °C to about 41 °C e.g., about 60 °C. The atomization flow rate is generally from about 4 kg/h to about 12 kg/h, for example, from about 4.3 kg/h to about 10.5 kg/h, e.g., about 6 kg/h or about 10.5 kg/h. The feed flow rate is generally from about 3 kg/h to about 10 kg/h, for example, from about 3.5 kg/h to about 9.0 kg/h, e.g., about 8 kg/h or about 7.1 kg/h. The atomization ratio is generally from about 0.3 to 1.7, e.g., from about 0.5 to 1.5, e.g., about 0.8 or about 1.5. [00187] Removal of the solvent may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100 °C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200 °C). [00188] In one embodiment, the solid dispersion is fluid-bed dried. [00189] In some embodiments, the solvent includes a volatile solvent, for example a solvent having a boiling point of less than about 100 °C. In some embodiments, the solvent includes a mixture of solvents, for example a mixture of volatile solvents or a mixture of volatile and non-volatile solvents. Where mixtures of solvents are used, the mixture can include one or more non-volatile solvents, for example, where the non-volatile solvent is present in the mixture at less than about 15%, e.g., less than about 12%, less than about 10%, less than about 8%, less than about 5%, less than about 3%, or less than about 2%. [00190] In particular embodiments, solvents are selected from those in which Compound 1 or Compound 2 has a solubility of at least about 10 mg/mL (e.g., at least about 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, or Attorney Docket No.10275.0231-00304 VPI/24-005 WO greater). More preferred solvents include those where Compound 1 has a solubility of at least about 50 mg/mL. [00191] Exemplary solvents that could be used in the processes of preparing solid dispersions of the invention include water, acetone, dichloromethane (methylene chloride, DCM, CH₂Cl₂), methanol (MeOH), ethanol (EtOH), methyl acetate (MeOAc), ethyl acetate (EtOAc), acetonitrile, t-butanol, tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), and combinations thereof. Exemplary co-solvents include acetone/water, MEK/water, THF/water, and DCM/MeOH/water. In a two-solvent system, the solvents can be present in of from about 0.1% to about 99.9%. In some embodiments, water is a co-solvent with acetone where water is present from about 0.1% to about 15%, for example about 9% to about 11%, e.g., about 10%. In some preferred embodiments, water is a co-solvent with MEK where water is present from about 0.1% to about 15%, for example about 9% to about 11%, e.g., about 10%. In some embodiments the solvent solution includes three solvents. For example, acetone and water can be mixed with a third solvent. In some embodiments, the three solvents include DCM, MeOH, and water. In instances where amorphous Compound 1 or Compound 2 is a component of a solid amorphous dispersion, preferred solvents dissolve both Compound 1 (or Compound 2) and the polymer. In some embodiments, suitable solvents include those described above, for example, DCM, MeOH, MEK, acetone, water, and mixtures thereof. [00192] In general, the process for preparing a spray dried dispersion according to the invention involves the following steps: 1. Weighing the selected solvent or solvents, such as, e.g., dichloromethane and methanol, into a preparation vessel and mixing; 2. Weighing the drug substance (Compound 1 or Compound 2) and adding it to the solvent system from Step 1. Allowing the drug substance to completely dissolve. Visually confirming that the drug substance is dissolved; 3. Weighing the polymer, e.g., HPMCAS, and adding it to the drug substance/solvent solution from Step 2. Allowing the polymer to completely dissolve; 4. Spray-drying the drug/polymer solution from Step 3 and collecting the spray-dried dispersion; and Attorney Docket No.10275.0231-00304 VPI/24-005 WO 5. Transferring the spray-dried dispersion to a secondary drying chamber for further drying. [00193] In some embodiments, a spray drier, e.g., an Anhydro-MS-75, fitted with a two- fluid nozzle (e.g., 0.8 mm) is used to prepare the spray dried dispersions disclosed herein according to the following exemplary parameters: Parameter Value Outlet temperature (C) 48.0 Process gas flow (kg/hr) 75.0 Nozzle gas flow (kg/hr) 8.5 Solution feed rate (g/min) 75.0 Tray drier temperature (C) 40.0 A cyclone can be used to separate the wet product from the spray gas and solvent vapors. The wet product can be transferred to a secondary drier to reduce residual solvents, e.g., to a level of less than about 600 ppm for dichloromethane and less than about 3000 ppm for methanol. [00194] In some embodiments, the solid dispersion comprises solid particles. The particle size and the temperature drying range may be modified to prepare an optimal solid dispersion. As would be appreciated by skilled practitioners, a small particle size would lead to improved solvent removal. Smaller particles can lead to fluffy particles that, under some circumstances do not provide optimal solid dispersions for downstream processing such as tableting. At higher temperatures, crystallization or chemical degradation of Compound 1 or Compound 2 may occur. At lower temperatures, a sufficient amount of the solvent may not be removed. [00195] Compound 1 and Compound 2 of the disclosure may be made according to standard chemical practices or as described herein. Throughout the following synthetic schemes and in the descriptions for preparing Compound 1, Compound 2, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, solid dispersions comprising Compound 1 or Compound 2, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing and pharmaceutical compositions comprising those solid dispersions, tautomers of those compounds, deuterated Attorney Docket No.10275.0231-00304 VPI/24-005 WO derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used: A. Abbreviations [00196] Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: NMR Nuclear magnetic resonance ESI-MS Electrospray mass spectrometry LC/MS Liquid chromatography-mass spectrometry SFC Supercritical fluid chromatography ESI Electrospray ionization cm Centimeters g Grams mg Milligrams L Liter(s) mL Milliliters μL Microliters mmol Millimoles h Hours min Minutes mm Millimeters μm Micrometers nm Nanometer MHz Megahertz Hz Hertz N Normal (concentration) M Molar (concentration) mM Millimolar (concentration) μM Micromolar (concentration) ppm Parts per million % w/w Weight-weight concentration rac-BINAP (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene tbuOK Potassium tert-butoxide Cbz-Cl Benzyl chloroformate Cy2NMe N,N-dicyclohexylmethylamine DCM Dichloromethane DIBAL Diisobutylaluminum hydride DIPA Diisopropylamino DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide Et2O Diethyl ether EtOH Ethanol EtOAc Ethyl acetate LDA Lithium diisopropylamide LED Light Emitting Diode LiHMDS Lithium bis(trimethylsilyl)amide Attorney Docket No.10275.0231-00304 VPI/24-005 WO LiOH Lithium Hydroxide MC Methyl cellulose MeOH Methanol MeCN Acetonitrile (Me2SiH)2O 1,1,3,3-Tetramethyldisiloxane 2-MeTHF 2-Methyltetrahydrofuran MP-TMT Macroporous polystyrene-bound 2,4,6-trimercaptotriazine MTBE Methyl tert-butyl ether NaO^tBu Sodium tert-butoxide N2H4.H2O Hydrazine monohydrate NIS N-Iodosuccinimide PTSA para-Toluenesulfonic acid RT Ambient temperature rt Retention time THF Tetrahydrofuran TMSCI Trimethylchlorosilane TPGS Vitamin E tocopheryl polyethylene glycol succinate HPMCAS Hydroxypropylmethylcellulose acetate succinate PVP Polyvinylpyrrolidone (E.g., PVP K30) MC Methyl Cellulose SLS Sodium lauryl sulfate PEG + 15% Polyethylene glycol 400, 5%TPGS, 1%HPMCAS, 0.25% PVP WH Wistar Han B. Starting Materials 6-Bromo-7-fluoro-N-(4-fluoro-3-methoxyphenyl)-1H-indazol-5-amine (S1) and benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methoxyphenyl)amino)-1H-indazole-1- carboxylate (S2) [00197] 4-Fluoro-3-methoxyaniline (18 g, 126.25 mmol) was added to a stirred and degassed suspension of 6-bromo-7-fluoro-5-iodo-1H-indazole (33 g, 90.989 mmol), NaO^tBu (26.5 g, 267.47 mmol) and XantPhos Pd G3 (4.5 g, 4.513 mmol) in anhydrous 1,4-dioxane Attorney Docket No.10275.0231-00304 VPI/24-005 WO (300 mL) at ambient temperature under a nitrogen atmosphere. The synthesis of 6-bromo-7- fluoro-5-iodo-1H-indazole is described in International Patent Publication WO 2020/247160 A1 (C245). The mixture was stirred at 85 °C for 1.5 h, then cooled down to ambient temperature. A saturated aqueous NH₄Cl solution (10 vol), an aqueous KHCO₃ solution (20 % w/w, 10 vol) and 2-MeTHF (10 vol) were added to the mixture. The organic layer was separated, dried (Na₂SO₄), filtered through a pad of Celite and concentrated in vacuo. The crude residue was taken up in DCM (10 vol) and the suspension was stirred for 3 days at ambient temperature. The suspension was filtered and the solids were dried under reduced pressure at 40 °C for 1 h to give 6-bromo-7-fluoro-N-(4-fluoro-3-methoxyphenyl)-1H- indazol-5-amine (S1, 30.094 g, 92%) as a beige solid.¹H NMR (400 MHz, DMSO-d6, 80 °C) δ 13.45 (s, 1H), 8.07 (s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 6.99 (dd, J = 11.5, 8.8 Hz, 1H), 6.74 (dd, J = 7.6, 2.7 Hz, 1H), 6.41 (dt, J = 8.6, 3.1 Hz, 1H), 3.78 (s, 3H) ppm.¹⁹F NMR (376 MHz, DMSO-d6, 80 °C) δ -119.43 (s, 1F), -145.92 (s, 1F) ppm. ESI-MS m/z calc.352.998, found 354.0 (M+1)⁺. Step 2: [00198] In a 5 L 3-necked round bottom flask fitted with a magnetic stirrer, a J-Kem temperature probe, and a nitrogen inlet/outlet, ^tBuOK (40 g, 356.5 mmol) was added to a stirred solution of 6-bromo-7-fluoro-N-(4-fluoro-3-methoxyphenyl)-1H-indazol-5-amine (115 g, 324.7 mmol) in THF (1.2 L) cooled to -5 °C at such a rate to keep the temperature below 0 °C. Cbz-Cl (50 mL, 350.2 mmol) was added dropwise via an addition funnel to the reaction mixture at such a rate to keep the temperature below 0 °C. The reaction mixture was stirred at this temperature for 30 min. The reaction was quenched by addition of a saturated aqueous NH₄Cl solution (50 mL) and warmed up to ambient temperature over 30 min. The mixture was partitioned between a saturated aqueous NH4Cl solution (600 mL), water (200 mL) and ethyl acetate (1.4 L) and stirred for 20 min. The organic phase was separated, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was triturated from MTBE (1 L) by stirring the suspension for 12 h at ambient temperature. The solid was filtered, rinsed with MTBE (500 mL), dried with air suction for 1 h at ambient temperature and further dried in a vacuum oven at 80 °C for 2 h to give benzyl 6-bromo-7-fluoro-5-((4-fluoro-3- methoxyphenyl)amino)-1H-indazole-1-carboxylate (S2, 130 g, 82%) as a tan solid, which contained small amounts of MTBE and ethyl acetate.¹H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.57 - 7.49 (m, 2H), 7.49 - 7.34 (m, 4H), 7.13 (dd, J = 11.4, Attorney Docket No.10275.0231-00304 VPI/24-005 WO 8.7 Hz, 1H), 6.97 (dd, J = 7.8, 2.6 Hz, 1H), 6.68 (ddd, J = 8.7, 3.7, 2.6 Hz, 1H), 5.50 (s, 2H), 3.79 (s, 3H) ppm.¹⁹F NMR (282 MHz, DMSO-d₆) δ -103.16, -143.49 ppm. [00199] The following starting materials were made using the method described in Starting Material 1, except that, in Step 1, different anilines were used as the Buchwald coupling partner in place of 4-fluoro-3-methoxyaniline. In the case of S3, the reaction was carried out at 90 °C: Starting Material Structure Name LC/MS NMR (shifts in ppm) d, 4 , 5, . Intermediate 1 Methyl (rac)-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate (Peak A, N1), methyl (rac)-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate (Peak B, N2), methyl (rel)-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate (Peak AA, N3) and methyl (rel)-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate (Peak AB, N4)

Attorney Docket No.10275.0231-00304 VPI/24-005 WO Step 1: [00200] In a 100 mL round-bottom flask, LiHMDS (15 mL, 1 M solution in THF, 15.0 mmol) was added dropwise to a solution of methyl 4-ethynylbenzoate (2 g, 12.24 mmol) in THF (40 mL) at -78 °C under a nitrogen atmosphere and the reaction mixture was stirred at - 78 °C for 30 min. (rac)-2-Methoxycyclohexan-1-one (1.9 mL, 15.12 mmol) was added dropwise to the solution via syringe. Upon complete addition, the cold bath was removed and the solution was stirred for 2 h at ambient temperature. The reaction was quenched by addition of an aqueous saturated NH4Cl solution (20 mL of 1:1 solution) and stirred for 30 min. The mixture was extracted with EtOAc (3 x). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (80 g SiO₂, 0 to 50 % EtOAc in heptane) gave the syn and anti diastereoisomers of methyl 4-((1- hydroxy-2-methoxycyclohexyl)ethynyl)benzoate: [00201] Peak A: methyl (rac)-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate (N1, 4.2 g, 90%) as a yellow oil.¹H NMR (400 MHz, Chloroform-d) δ 8.03 - 7.89 (m, 2H), 7.53 - 7.43 (m, 2H), 3.91 (s, 3H), 3.51 (s, 3H), 3.46 - 3.37 (m, 1H), 2.93 (s, 1H), 2.12 - 1.96 (m, 1H), 1.90 - 1.69 (m, 3H), 1.69 - 1.59 (m, 2H), 1.57 - 1.47 (m, 1H), 1.43 - 1.30 (m, 1H) ppm. [00202] Peak B: methyl (rac)-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate (N2, 482 mg, 12%) as a yellow oil.¹H NMR (400 MHz, Chloroform-d) δ 8.03 - 7.86 (m, 2H), 7.67 - 7.42 (m, 2H), 3.91 (s, 3H), 3.47 (s, 3H), 3.25 (s, 1H), 3.11 (dd, J = 11.3, 4.0 Hz, 1H), 2.22 - 2.03 (m, 2H), 1.88 - 1.77 (m, 1H), 1.77 - 1.58 (m, 3H), 1.56 - 1.44 (m, 1H), 1.35 - 1.23 (m, 1H) ppm. Step 2: [00203] The enantiomers of methyl (rac)-4-((1-hydroxy-2- methoxycyclohexyl)ethynyl)benzoate (Peak A) (N1, 3.33 g, 8.777 mmol) were separated by chiral SFC using a Chiralpak IC column, 5 μm particle size, 15 cm x 30 mm from Daicel Corporation (Mobile phase: 40% methanol (supplemented with 5mM ammonia), 60% CO2; Flow rate 100 mL/min): [00204] Peak AA (rt = 1.70 min): methyl rel-4-((1-hydroxy-2- methoxycyclohexyl)ethynyl)benzoate (N3, 1.211 g, 47%) as a yellow oil.¹H NMR (400 MHz, Chloroform-d) δ 8.09 - 7.89 (m, 2H), 7.62 - 7.39 (m, 2H), 3.91 (s, 3H), 3.51 (s, 3H), 3.42 (dd, J = 7.4, 3.7 Hz, 1H), 2.94 (s, 1H), 2.15 - 1.95 (m, 1H), 1.90 - 1.71 (m, 3H), 1.69 - 1.58 (m, 2H), 1.56 - 1.47 (m, 1H), 1.40 - 1.26 (m, 1H) ppm. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00205] Peak AB (rt = 2.61 min): methyl rel-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl) benzoate (N4, 1.122 g, 43%) as a yellow oil.¹H NMR (400 MHz, Chloroform-d) δ 8.04 - 7.92 (m, 2H), 7.54 - 7.42 (m, 2H), 3.91 (s, 3H), 3.51 (s, 3H), 3.47 - 3.37 (m, 1H), 2.93 (s, 1H), 2.12 - 1.94 (m, 1H), 1.89 - 1.69 (m, 3H), 1.68 - 1.58 (m, 2H), 1.55 - 1.46 (m, 1H), 1.40 - 1.27 (m, 1H) ppm. [00206] The following reagents were made using the methods described in Intermediate 1 except that, in Step 1, different ketones were used as starting materials in place of (rac)-2- methoxycyclohexan-1-one: Structure Name SFC conditions LC/MS NMR (shifts in ppm) 6) , , , , 6) , , , , Attorney Docket No.10275.0231-00304 VPI/24-005 WO Example 1 (S)-4-(5-(3,4-Difluorophenyl)-8-fluoro-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5- dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 1) [00207] Pd(^tBu3P)2 (10 g, 19.57 mmol) was added to a nitrogen flushed solution of benzyl 6-bromo-5-((3,4-difluorophenyl)amino)-7-fluoro-1H-indazole-1-carboxylate (S3, 137 g, 287.7 mmol), methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate (Peak B, N6, 77.3 g, 294.7 mmol) and N,N-dicyclohexylmethylamine (160 mL, 747.0 mmol) in 1,4- dioxane (1.4 L) and the reaction mixture was heated to 100 °C for 2.5 h. The mixture was cooled to ambient temperature overnight and partitioned between EtOAc (1.4 L) and a 1 M aqueous HCl solution (1 L). The organic layer was separated, washed with a 1 M aqueous HCl solution (1 L) and with a mixture of water and a saturated brine solution (2:1, 1.5 L), dried (MgSO4) filtered and concentrated in vacuo. Purification by flash chromatography (3 Kg SiO₂, 0 to 60 % EtOAc in heptane) gave benzyl (S)-5-(3,4-difluorophenyl)-8-fluoro-6-(2- hydroxy-1-methoxybutan-2-yl)-7-(4-(methoxycarbonyl)phenyl)pyrrolo[2,3-f]indazole-1(5H)- carboxylate (132 g, 70%) as a yellow glassy oil. ESI-MS m/z calc.657.209, found 658.3 (M+1)⁺. Step 2: [00208] Pd/C (27 g, 5 % w/w, 12.69 mmol) and ammonium formate (135 g, 2.141 mol) were successively added to a stirred solution of benzyl (S)-5-(3,4-difluorophenyl)-8-fluoro-6- (2-hydroxy-1-methoxybutan-2-yl)-7-(4-(methoxycarbonyl)phenyl)pyrrolo[2,3-f]indazole- 1(5H)-carboxylate (140 g, 212.9 mmol) in EtOH (1.6 L) and the reaction mixture was heated at reflux for 90 min. The mixture was cooled slowly while standing at ambient temperature overnight. The mixture was diluted with EtOAc (1L) and heated to ~ 85°C. The mixture was filtered hot through a pad of Celite, washing with hot EtOAc (3 x 500 mL). The reaction was concentrated in vacuo to a volume of approximately 300 mL. The mixture was cooled and Attorney Docket No.10275.0231-00304 VPI/24-005 WO filtered to give a first crop of methyl (S)-4-(5-(3,4-difluorophenyl)-8-fluoro-6-(2-hydroxy-1- methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate. The mother liquors were concentrated in vacuo to give a gold solid (75g). The solid was recrystallised from EtOAc (~ 150mL, 2 vol) and heptane (3 vol) to give a second crop of methyl (S)-4-(5-(3,4- difluorophenyl)-8-fluoro-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3- f]indazol-7-yl)benzoate. The crops were combined to give methyl (S)-4-(5-(3,4- difluorophenyl)-8-fluoro-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3- f]indazol-7-yl)benzoate (114g, 97%) as a beige solid. ESI-MS m/z calc.523.172, found 524.2 (M+1)⁺. Step 3: [00209] 2 M NaOH (70 mL of, 140.0 mmol) was added to a stirred solution of methyl (S)-4- (5-(3,4-difluorophenyl)-8-fluoro-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5- dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (7.4 g, 14.14 mmol) in a mixture of MeOH (70 mL) and THF (140 mL) and the reaction mixture was heated to 50 °C for 30 min. Alternatively, LiOH may be used in the final hydrolysis step. The mixture was concentrated in vacuo. Water was added and the pH of the solution was adjusted to 3 by addition of 1 M HCl. The formed solid was filtered, washed with water and dried overnight to give (S)-4-(5- (3,4-difluorophenyl)-8-fluoro-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo-[2,3- f]indazol-7-yl)benzoic acid (Compound 1, 6.705 g, 93%) as an off-white solid.¹H NMR (400 MHz, DMSO-d6) δ 12.97 (m, 2H), 8.11 - 7.93 (m, 3H), 7.73 - 7.43 (m, 4H), 7.48 - 7.13 (m, 1H), 6.78 (d, J = 1.6 Hz, 1H), 4.69 (d, J = 23.5 Hz, 1H), 3.27 - 3.16 (m, 2H), 3.12 (d, J = 9.4 Hz, 3H), 1.52 - 1.37 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H) ppm. ESI-MS m/z calc.509.156, found 510.1 (M+1)⁺. Example 2

Attorney Docket No.10275.0231-00304 VPI/24-005 WO Step 1: [00210] Pd(^tBu₃P)₂ (10 g, 19.57 mmol) was added to a nitrogen flushed solution of 6- bromo-7-fluoro-N-(4-fluoro-3-methoxyphenyl)-1H-indazol-5-amine (S1, 102 g, 287.7 mmol), methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate (Peak B, N6, 77.3 g, 294.7 mmol) and N,N-dicyclohexylmethylamine (160 mL, 747.0 mmol) in 1,4- dioxane (1.4 L) and the reaction mixture was heated to 100 °C for 2.5 h. The mixture was cooled to ambient temperature overnight and partitioned between EtOAc (1.4 L) and a 1 M aqueous HCl solution (1 L). The organic layer was separated, washed with a 1 M aqueous HCl solution (1 L) and with a mixture of water and a saturated brine solution (2:1, 1.5 L), dried (MgSO4) filtered and concentrated in vacuo. Purification by flash chromatography (3 Kg SiO₂, 0 to 60 % EtOAc in heptane) gave methyl (S)-4-(8-fluoro-5-(4-fluoro-3- methoxyphenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7- yl)benzoate (89 g, 58%) as a yellow glassy oil. ESI-MS m/z calc.657.209, found 658.3 (M+1)⁺. Step 2: [00211] An aqueous solution of lithium hydroxide hydrate (69 mL of 2.5 M, 172.5 mmol) was added to a solution of methyl (S)-4-(8-fluoro-5-(4-fluoro-3-methoxyphenyl)-6-(2- hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (9.37 g, 17.24 mmol) in THF (77 mL) and methanol (77 mL). The reaction was stirred at 55 °C for 1 hour. The mixture was concentrated in vacuo to remove most of the organics. Diluted with 70 ml of water and washed with 500 ml of ethyl acetate. large emulsion. acidified to ~pH 1 with HCl (190 mL of 1 M, 190.0 mmol). Washed the water layer with ethyl acetate 300 ml. Combined organics were dried with sodium sulfate, filtered and concentrated to dryness to give a light pink solid. Diluted with 13 vol of ACN and 10 volumes of water. Stirred overnight at room temperature. Filtered and washed the filter cake with (1:1, 150 ml) ACN:water. All color went into the mother liquor. The filter cake was transferred to a crystallization dish and dried over 72 hours at 65 °C to give a white solid, (S)-4-(8-fluoro-5- (4-fluoro-3-methoxyphenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3- f]indazol-7-yl)benzoic acid (Compound 2, 7.2462 g, 80%) ¹H NMR (300 MHz, DMSO-d6) δ 12.93 (s, 2H), 8.04 (d, J = 3.4 Hz, 1H), 8.03 - 7.92 (m, 2H), 7.63 - 7.50 (m, 2H), 7.46 - 7.35 (m, 1H), 7.35 - 7.18 (m, 1H), 7.11 - 6.94 (m, 1H), 6.76 (d, J = 5.4 Hz, 1H), 4.55 (d, J = 33.2 Hz, 1H), 3.85 (d, J = 1.9 Hz, 3H), 3.30 - 3.16 (m, 2H), 3.12 (d, J = 13.7 Hz, 3H), 1.56 - 1.41 Attorney Docket No.10275.0231-00304 VPI/24-005 WO (m, 2H), 0.79 - 0.68 (m, 3H). ESI-MS m/z calc.521.1762, found 522.11(M+1); Retention time: 0.79 minutes. Example 3 Alternate Synthesis of Compound 1 and Compound 2 A. Synthesis of (S)-4-(5-(3,4-Difluorophenyl)-8-fluoro-6-(2-hydroxy-1-meth- oxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 1) Step 1 – Reductive coupling Procedure A hexamethylphosphetane-1-oxide (0.3 equiv) and 6-bromo-7-fluoro-5-nitro-1(H)-indazole (0.1 equiv) in dioxane were added concomitantly, a solution of nitroindazole 6-bromo-7-fluoro-5- nitro-1(H)-indazole (0.9 equiv) in dioxane as well as neat TMDS (6 equiv). The mixture was stirred at 100 ºC until the reaction was deemed complete. The reaction was quenched with aqueous NaOH.2-MeTHF was added and the phases were separated. The organic phase was washed with aqueous HCl. The organic phase was concentrated, and the residue taken up in toluene. The product S14 was isolated by crystallization, filtration and drying. Procedure B , difluorophenylboronic acid (2 equiv), 1,2,2,3,4,4-hexamethylphosphetane-1-oxide (0.3 equiv) Attorney Docket No.10275.0231-00304 VPI/24-005 WO was added neat PMHS (6 equiv). The mixture was stirred at 100 ºC until the reaction was deemed complete. The reaction mixture was quenched with aqueous NaOH and the phases were separated. The dioxane is distilled off and 2-MeTHF is added. The mixture was stirred with aqueous sorbitol and then the aqueous phase was separated. The solvent was distilled off, and the product S14 was isolated by crystallization from toluene and acetonitrile, filtration and drying. Step 2 – Larock Annulation [00214] Procedure A: N,N-Dicyclohexylmethylamine (2.5 equiv) was added to a heated mixture of S14 (1 equiv), Peak B N6 (1.25 equiv) and Pd(^tBu₃P)₂ (0.03 equiv) in DMAc. The reaction mixture was stirred at 120 ºC until complete. The mixture was cooled and diluted with 2-MeTHF, and then washed with aqueous HCl. The mixture was concentrated and the residue was taken up in methanol. Water was added and the product methyl (S)-4-(5-(3,4- difluorophenyl)-8-fluoro-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3- f]indazol-7-yl)benzoate was isolated by crystallization, filtration and drying. [00215] Procedure B: This procedure can be carried out with a catalyst mixture consisting of AmPhos and (MeCN)₂PdCl₂ instead of Pd(^tBu₃P)₂.

Attorney Docket No.10275.0231-00304 VPI/24-005 WO Step 3 – Ester Hydrolysis [00216] To a solution of methyl (S)-4-(5-(3,4-difluorophenyl)-8-fluoro-6-(2-hydroxy-1- methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (1 equiv) in THF and MeOH was added aqueous LiOH (4 equiv). The mixture was stirred at 20 ºC until the reaction was complete. The mixture concentrated and the product was extracted into MTBE. After layer separation, the organic phase was washed with aqueous citric acid followed by aqueous NaCl. The organic phase was concentrated and then redissolved in EtOAc. After heating and adding heptane, the product Compound 1 was isolated as the EtOAc Heptane Solvate Form A by crystallization, filtration and drying. Step 4 – Form Conversion to Monohydrate [00217] A solution of Compound 1 EtOAc Heptane Solvate propanol was heated to 55 ºC and then diluted with water. The mixture was seeded at 47 ºC with Compound 1 Monohydrate Form A and then diluted with more water. The mixture was Attorney Docket No.10275.0231-00304 VPI/24-005 WO cooled to 18 ºC and then the product Compound 1 Monohydrate Form A was isolated by filtration and drying. B. Synthesis of (S)-4-(8-fluoro-5-(4-fluoro-3-methoxyphenyl)-6-(2-hydroxy-1- methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 2) Step 1 – Buchwald coupling [00218] 6-bromo-7-fluoro-5-iodo-1H-indazole and 4-fluoro-3-methoxyaniline suspended in degassed 1,4-dioxane. XantPhos-Pd-G3 and sodium tert-butoxide were added and the mixture was heated until deemed complete. Once complete, the reaction was cooled and quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate and concentrated. The product S1 was isolated by trituration with toluene, filtration and drying. Step 2 – Larock Annulation

Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00219] N,N-Dicyclohexylmethylamine (2.5 equiv) was added to a heated mixture of S1, Peak B, N6 and Pd(t-Bu₃P)₂ in DMAc. The reaction mixture was stirred at 120 ºC until complete. The mixture was cooled and diluted with ethyl acetate, and then washed with aqueous HCl. The organic layer can be treated with a palladium scavenging resin such as Silia-MetS-thiol or Silia-MetS-DMT to remove residual palladium catalyst. The mixture was filtered, concentrated and the residue was taken up in methanol. Water was added and the product (methyl (S)-4-(8-fluoro-5-(4-fluoro-3-methoxyphenyl)-6-(2-hydroxy-1- methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate was isolated by filtration and drying. Step 3 – Ester Hydrolysis [00220] To a solution of (methyl (S)-4-(8-fluoro-5-(4-fluoro-3-methoxyphenyl)-6-(2- hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (1 equiv) in THF and MeOH was added aqueous LiOH (4 equiv). The mixture was stirred at 20 ºC until the reaction was complete. The mixture concentrated and the product was extracted into 2- methyl tetrahydrofuran. After layer separation, the organic phase was washed with aqueous citric acid followed by water. The organic phase was treated with SiliaMetS-thiol and SiliaMetS-DMT resins and filtered. The filtrate was concentrated to a foam and crystallized from acetonitrile and water. The solids were isolated by filtration and drying to provide Compound 2. Attorney Docket No.10275.0231-00304 VPI/24-005 WO Step 4 – Reslurry dissolved in acetonitrile at the mixture was brought back up to reflux. The mixture was over Compound 2 was isolated by filtration, a wash with 1:1 acetonitrile:water, and drying. Example 4 Crystalline Forms of Compound 1 A. Compound 1 Monohydrate Form A 1. Synthetic Procedures [00222] 5 g of Compound 1 free form Form A and 25 mL of 1-propanol were added to a reactor. The slurry was stirred and heated to 50 °C to obtain a clear solution. To the clear solution, 25 mL of water was added over 2 hours and during this addition, a slurry was formed. The slurry was then cooled to 20 °C over 5 hours, agitated for another 8 hours, and filtered. Filtered solids were washed with a 15 ml mixture of 1:1 (v/v) 1-propanol:water and then dried at 50 °C in a vacuum oven with a nitrogen bleed. Final solids were confirmed to be Compound 1 Monohydrate Form A via XRPD and ssNMR. [00223] Alternatively, 5 g of Compound 1 EtOAc-heptane solvate and 20 mL of 1-propanol were added to a reactor. The slurry was stirred and heated to 50 °C to obtain a clear solution. To the clear solution, 5 mL of water was added over 1 hour. The clear solution was then seeded with 1 wt% Monohydrate Form A seeds and agitated for 1 hour. To the slurry, 25 mL of water was added over 5 hours, then cooled to 20 °C over 5 hours, agitated for another 8 hours, and filtered. Filtered solids were washed with a 15 ml mixture of 2:3 (v/v) 1-propanol: water and then dried at 50 °C in a vacuum oven with a nitrogen bleed to provide Compound 1 Monohydrate Form A. 2. X-Ray Powder Diffraction [00224] The XRPD results are shown in FIG.24 and the table below: Attorney Docket No.10275.0231-00304 VPI/24-005 WO XRPD Signals for Compound 1 Monohydrate Form A No. Pos. [±0.2,°2θ] Rel. Int. [%] 1 19.8 100.0 3. [00225] Thermogravimetric analysis of Compound 1 Monohydrate Form A was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately 1-10 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Series^TM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.25) showed 3.3% weight loss from ambient temperature up to 160 °C. 4. Differential Scanning Calorimetry Analysis [00226] DSC of Compound 1 Monohydrate Form A was measured using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10 °C/min to a temperature of 250 °C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.26) showed endothermic peaks around 141 °C and 163 °C. 5. Solid state NMR [00227] All carbon and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence. The ¹³C CPMAS and ¹⁹F MAS on Compound 1 Attorney Docket No.10275.0231-00304 VPI/24-005 WO Monohydrate Form A results are shown in FIG.27 and FIG.28, respectively and in the tables below: 1³C CPMAS on Compound 1 Monohydrate Form A Chem Shift Intensity Chem Shift Intensity Peak # [± 0.2 ppm] [rel] Peak # [ppm] [rel] Chem Shift Peak # [± 0.2 ppm] Intensity [rel] 6. S [00228] Single crystals having the Compound 1 Monohydrate Form A structure were grown from a mixture of 1-propanol and water. X-ray diffraction data were acquired at 100K on a Bruker diffractometer equipped with Cu Kα radiation (λ=1.54178 Å) and a CMOS detector. The structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122) and results are summarized in the table below.

Attorney Docket No.10275.0231-00304 VPI/24-005 WO Single Crystal Elucidation of Compound 1 Monohydrate Form A Crystal System Monoclinic Space Group P21 wn from a mixture of 1-propanol and water. X-ray diffraction data were acquired at 293K on a Bruker diffractometer equipped with Cu K_α radiation (λ=1.54178 Å) and a CMOS detector. The structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122) and results are summarized in the table below. Single Crystal Elucidation of Compound 1 Monohydrate Form A Crystal System Monoclinic Space Group P2₁ B. Compound 1 free form Form A 1. Synthetic Procedure [00230] Compound 1 EtOH solvate Form A was dissolved in 4:1 DCM:MeOH (500 mL), evaporated to dryness. Residue was dissolved in 4:1 DCM:MeOH (500 mL), evaporated to dryness. Residue was dissolved in DCM (500 mL), evaporated to dryness. Residue was dissolved/suspended in DCM (250 mL), refluxed for 2 h to give a uniform suspension. Slowly allowed to cool to room temp, stood at room temp overnight. After 16 h, suspension was filtered, washing with DCM (100 mL). Collected solid was dried under suction for 1 h, Attorney Docket No.10275.0231-00304 VPI/24-005 WO then on rotovap (2 mbar), followed by vacuum oven dried at 75 - 90 °C for days until DCM level was below International Conference on Harmonization (ICH) limit. 2. X-Ray Powder Diffraction [00231] The XRPD results are shown in FIG.29 and the table below. XRPD Signals for Compound 1 free form Form A No. Pos. [±0.2, °2θ] Rel. Int. [%] No. Pos. [±0.2, °2θ] Rel. Int. [%] . e og a e c a a ys s [00232] Thermogravimetric analysis of Compound 1 free form Form A was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately 1-10 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Series^TM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.30) showed 0.2 % weight loss from ambient temperature up to 180 °C. 4. Differential Scanning Calorimetry Analysis [00233] DSC of Compound 1 free form Form A was measured using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10 °C/min to a temperature of 220 °C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.31) showed endothermic peaks around 193 °C. 5. Solid state NMR Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00234] All carbon, phosphorus and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence. The ¹³C CPMAS and ¹⁹F MAS on Compound 1 free form Form A results are shown in FIG.32 and FIG.33, respectively and in the tables below: 1³C CPMAS on Compound 1 free form Form A Chem Shift Chem [ppm] Intensity Shift Intensity Peak # Chem Shift [ppm] Intensity [rel] Peak # Chem Shift Intensity [ppm] [rel] . [00235] Single crystals having the Compound 1 free form Form A structure were grown from a mixture of acetonitrile and water. X-ray diffraction data were acquired at 100K on a Bruker diffractometer equipped with Cu Kα radiation (λ=1.54178 Å) and a CMOS detector. The structure was solved and refined using SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122) and results are summarized in the table below. Attorney Docket No.10275.0231-00304 VPI/24-005 WO Single Crystal Elucidation of Compound 1 free form Form A Crystal System Triclinic Space Group P1 Å C. 1. Synthetic Procedure [00236] 150 mg of Compound 1 free form Form A was placed in a glass vial along with a stir bar, 0.9 mL of octanol was added to this vial and let the sample stir at 80 °C for 3 days while protected from exposure to light. After 3 days stirring, solids were collected by centrifuge filtration (0.22 um, 14k rpm) providing Compound 1 free form Form B for XRPD analysis. 2. X-Ray Powder Diffraction [00237] The XRPD results are shown in FIG.44 and the table below: XRPD Signals for Compound 1 free form Form B No. Pos. [±0.2, °2θ] Rel. Int. [%] No. Pos. [±0.2, °2θ] Rel. Int. [%] 1 184 1000 8 249 199 3. Thermogravimetric analysis [00238] Thermogravimetric analysis of Compound 1 free form Form B was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately 1-10 mg was scanned from 25 °C to 400 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Series^TM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.45) showed 1.0% weight loss from ambient temperature up to 200 °C. Attorney Docket No.10275.0231-00304 VPI/24-005 WO 4. Differential Scanning Calorimetry Analysis [00239] DSC of Compound 1 free form Form B was measured using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed, and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10 °C/min to a temperature of 300 °C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.46) showed an endothermic peak around 240 °C. D. Compound 1 EtOH Solvate Form A 1. Synthetic Procedure [00240] Raw Compound 1 (80 g, 157.0 mmol) was diluted in EtOAc (500 mL) and treated with activated charcoal (10 g, 832.6 mmol). Refluxed for 30 min, then cooled to room temp, then filtered through Celite (65 mm dia x 30 mm h), washing with EtOAc (250 mL). Combined filtrate was concentrated to give a yellow foam. [00241] In a 3 L RBF, foam was treated with EtOH (310 mL, 70% histology grade); heated to reflux in a metal heating bath. Refluxed for 45 min to give a uniform suspension. Power to heating bath was switched off, slowly allowed to cool to rt, stirred overnight. After 16 h, suspension was filtered, collected solid was washed with EtOH (50 mL, 70% histology grade), dried under suction for 30 min then on rotovap (2 mbar, 75 °C) for 1 h.63.5 g pale yellow crystals, Compound 1 EtOH Solvate Form A, was obtained. 2. X-Ray Powder Diffraction [00242] X-ray powder diffraction (XRPD) spectra results are shown in FIG.34 and the table below: XRPD Signals for Compound 1 EtOH Solvate Form A No. Pos. [±0.2, °2θ] Rel. Int. [%] No. Pos. [±0.2, °2θ] Rel. Int. [%] Attorney Docket No.10275.0231-00304 VPI/24-005 WO 10 22.0 29.3 20 21.0 10.1 [00243] Thermogravimetric analysis of Compound 1 EtOH Solvate Form A was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately 1-10 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Series^TM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.35) showed 7.0% weight loss from ambient temperature up to 180 °C. 4. Differential Scanning Calorimetry Analysis [00244] DSC of Compound 1 EtOH Solvate Form A was measured using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10 °C/min to a temperature of 250 °C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.36) showed an endothermic peak around 163 °C. 5. Solid state NMR [00245] All carbon, phosphorus and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence. The ¹³C CPMAS and ¹⁹F MAS of Compound 1 EtOH Solvate Form A results are shown in FIG.37 and FIG.38, respectively and in the tables below: 1³C CPMAS on Compound 1 EtOH Solvate Form A Peak # Chem Shift [ppm] Intensity [rel] Peak # Chem Shift [ppm] Intensity [rel] Attorney Docket No.10275.0231-00304 VPI/24-005 WO 11 126.7 6.1 25 18.8 2.6 12 123.6 6.7 26 8.2 5.3 Peak # Chem Shift [ppm] Intensity [rel] 1 -130.0 1.1 6. Single C [00246] Single crystals having the Compound 1 EtOH Solvate Form A structure were grown from a mixture of ethanol and water. X-ray diffraction data were acquired at 100K on a Bruker diffractometer equipped with Cu Kα radiation (λ=1.54178 Å) and a CMOS detector. The structure was solved and refined SHELX programs (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122) and results are summarized in the table below. Single Crystal Elucidation of Compound 1 EtOH Solvate Form A Crystal System Triclinic Space Group P1 Example 5 Solid Forms of Compound 2 A. Compound 2 free form Form A 1. Synthetic Procedure [00247] Reaction mixture was concentrated in vacuo to remove THF and methanol. Raw Compound 2 was treated with water (800 mL) acidified with aqueous 2 N HCl to pH = 3, and cooled to 0 °C with ice/water bath. Reaction mixture was further treated with EtOAc (1 L), stirred for 10 minutes, and extracted with EtOAc (500 mL). Combined organic phase was washed with water (400 mL), brine (600 mL), dried over MgSO₄, filtered, and concentrated Attorney Docket No.10275.0231-00304 VPI/24-005 WO in vacuo to afford Compound 2 (80 g) as a peach-colored crispy foam. Foam was further treated with acetonitrile (800 mL), refluxed for 30 minutes, treated with water (1 L), refluxed for additional 1 h, and allowed to cool down to room temperature over 12 h. Suspension was filtered. Collected solid was washed with acetonitrile:water (1:1, 1L), dried under air suction for 2 h, and further dried in vacuum oven at 90 °C for 2 days. The resulting solid was collected to provide Compound 2 free form Form A. 2. X-Ray Powder Diffraction [00248] X-ray powder diffraction (XRPD) spectra results are shown in FIG.39 and the table below. XRPD Signals for Compound 2 free form Form A No. Pos. [±0.2, °2θ] Rel. Int. No. Pos. [±0.2, °2θ] Rel. Int. [%] [%] 3. Thermogravimetric Analysis [00249] Thermogravimetric analysis of Compound 2 free form Form A was measured using TA Discovery 550 TGA from TA Instrument. A sample with weight of approximately 1-10 mg was scanned from 25 °C to 300 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Series^TM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.40) showed 0.4 % weight loss from ambient temperature up to about 230 °C. 4. Differential Scanning Calorimetry Analysis [00250] DSC of Compound 2 free form Form A was measured using the TA Discovery 550 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An Attorney Docket No.10275.0231-00304 VPI/24-005 WO empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. The heating program was set to heat the sample at a heating rate of 10 °C/min to a temperature of 300° C. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The thermogram (FIG.41) showed an endothermic peak at about 244 ⁰C. 5. Solid state NMR [00251] All carbon and fluorine spectra were recorded with proton decoupling using SPINAL64 decoupling sequence. The ¹³C CPMAS and ¹⁹F MAS on Compound 2 free form Form A results are shown in FIG.42 and FIG.43, respectively, and in the tables below: 13C CPMAS on Compound 2 free form Form A Peak # Chem Shift [ppm] Intensity [rel] Peak # Chem Shift [ppm] Intensity [rel] 1 170.6 7.7 16 116.8 7.9 19 F MAS on Compound 2 free form Form A Peak # Chem Shift [ppm] Intensity [rel] 1 1328 100 Example 6 Assays for Detecting and Measuring AAT Modulator Properties of Compounds A. AAT Function Assay (MSD Assay NL20-SI Cell Line) [00252] Alpha-1 antitrypsin (AAT) is a SERPIN (serine protease inhibitor) that inactivates enzymes by binding to them covalently. This assay measured the amount of functionally Attorney Docket No.10275.0231-00304 VPI/24-005 WO active AAT in a sample in the presence of the disclosed compounds 1-210 by determining the ability of AAT to form an irreversible complex with human neutrophil Elastase (hNE). In practice, the sample (cell supernatant, blood sample, or other) was incubated with excess hNE to allow AAT-Elastase complex to be formed with all functional AAT in the sample. This complex was then captured to a microplate coated with an anti-AAT antibody. The complex captured to the plate was detected with a labeled anti-Elastase antibody and quantitated using a set of AAT standards spanning the concentration range present in the sample. Meso Scale Discovery (MSD) plate reader, Sulfo-tag labeling, and microplates were used to provide high sensitivity and wide dynamic range. MATERIALS: Reagents/Plates Concentration Goat anti-human Alpha-1-Antitrypsin 1 mL @ 1 mg/mL Polyclonal Antibody Use at 5 μg/mL in phosphate buffered saline (PBS) Human Neutrophil Elastase 100 μg lyophilized Stock at 3.4 μM (0.1 mg + 1 mL PBS) Working at 1μg/mL (34nm) in MSD Assay buffer (1% bovine serum albumin (BSA)) Mouse anti-human Neutrophil Elastase Monoclonal Antibody 900 μg/mL Sulfo-tagged @ 12:1 using MSD Gold Sulfo-tag N- hydroxysuccinimide (NHS) ester; use at 0.45 μg/mL in MSD Assay buffer (1% BSA) M-AAT (Alpha-1-Antitrypsin) 5 mg lyophilized MSD Blocker A (BSA) 250 mL 5% solution in PBS for blocking 1% solution in PBS for assay buffer MSD Read Buffer T (4X) with Surfactant 1 L or 250 mL MSD 384 high bind plates Polypropylene for dilution 384 well plate Tissue culture treated black well 384 well plate INSTRUMENT(S): Meso Sector S600 Bravo Attorney Docket No.10275.0231-00304 VPI/24-005 WO Washer dispenser Multidrop Combi ASSAY PROTOCOL Day 1 Cell Culture 1. Harvest NL20 human bronchial epithelial cells expressing human Z-AAT in OptiMEM™ containing Pen/Strep (P/S). 2. Seed at 16,000 cells/well in 30 µL (384 well plate). 3. Centrifuge plates briefly up to speed (1200 rpm) and place into 37 °C incubator overnight. Day 2: Compound Addition and Coating Plates with Capture Antibody Compound Addition: 1. Dispense 40 µL of OptiMEM™ (P/S) with doxycycline (1:1000 stock = 0.1 µM final) to each well of the compound plate using a multidrop Combi in hood. 2. Remove cell plate from incubator, flip/blot and take immediately to Bravo to transfer compounds. 3. Return plates to incubator overnight. Coat MSD Plates 1. Dilute capture antibody (Polyclonal Goat anti-AAT) to 5 μg/mL (1:200) in PBS (no BSA). 2. Dispense 25 μL of diluted capture antibody into all wells of MSD 384-well High Bind plate using the Multidrop equipped with a standard cassette. 3. Incubate overnight at 4 °C. Prepare Blocker A (BSA) Solutions 1. Prepare solution of 5% MSD Blocker A (BSA) following the manufacturer’s instructions. 2. Further dilute the 5% MSD Blocker A in PBS to 1% (Blocker A) as needed. Day 3: Run MSD Assay Block Plates 1. Wash plate 1x with 50 µL Wash buffer (PBS + 0.5% Tween 20), and add 35 µL 5% Block A buffer to block non-specific binding on washer dispenser. 2. Rotate plates on shaker for 1 hour at 600 rpm. Attorney Docket No.10275.0231-00304 VPI/24-005 WO Prepare M-AAT Standards 1. Dilute M-AAT stock to 1.6 µg/mL in 1% BSA Blocker A (Stock in -70 °C); then prepare 12 x 1:2 serial dilutions in 1% Blocker A. 2. The top starting final concentration on MSD plate is 320 ng/mL. These dilutions correspond to a final concentration of 320, 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.312, 0.156 ng/mL. Dilution plate 1. Add 80 µL of 1% Assay buffer to all wells except columns 1/24 (standards) with Multidrop Combi. 2. Add diluted standards to columns 1 and 24. 3. Centrifuge dilution plates 1200 rpm briefly. Cell plate 1. Aspirate columns which will have the standards from the cell plates in the hood using 16-pin aspirator. Prepare human Neutrophil Elastase (hNE) 1. Prepare 1 μg/mL Human Neutrophil Elastase by diluting in 1% Blocker A. a. Small 100 µg vial – add 1 mL PBS (100 µg/mL). i. This can then be diluted 1:100 in 1% Assay Buffer for a final 1 µg/mL concentration. MSD – add hNE (20 µL/well) 1. After the MSD plate has blocked for at least 1 hour, wash plate 1x with 50 µL. Wash buffer (PBS + 0.5% Tween 20) and then add 20 µL hNE to each well. Bravo – Cell Plate – Dilution Plate – MSD Plate Using the Bravo aspirate 10 µL from the cell plate, transfer to the dilution plate (9-fold dilution) 1. Mix 25 µL 3x, then aspirate 5 µL, transfer to MSD plate (5-fold dilution). 2. Mix 10 µL 3x. Total dilution is 45-fold. 3. Shake plates at 600 rpm for 1.5 hours Add Functional detection hNE antibody 1. Wash plate 1X with wash buffer. 2. Add 25 μL Sulfo-tagged anti-Elastase Monoclonal Mouse anti-Elastase) diluted to 0.45 μg/mL (1:2000) in 1% Blocker A into all wells of the functional activity MSD plates using the washer/dispenser. Attorney Docket No.10275.0231-00304 VPI/24-005 WO Note: The dilution required for sufficient signal must be determined for each new lot of labeled antibody. 3. Incubate at room temperature shaking at 600 rpm for 1 hour. Final wash and MSD imager read 1. Wash the plate 1x, and add 25 µL of Wash Buffer to the plate. 2. Make 2 x Read buffer. 3. Remove wash buffer from MSD plate. 4. Transfer 35 µL 2x Read Buffer to MSD plate using Bravo and take to MSD to read immediately. Data analysis in MSD Discovery Workbench 4.0 software and EC50 values were determined using Genedata. B. Human Hepatocyte Clearance Assay 1. Determination of Human Hepatocyte CLint [00253] Test compound was prepared to 10 mM in 100% DMSO and further diluted to 100 μM in 50% acetonitrile:50% water (v/v). The cryopreserved human hepatocytes were prepared in CHRM (cryopreserved hepatocyte recovery medium). After cell viability was determined using a Nexcelom cell counter, hepatocytes were suspended and incubated in Williams’ E media (pH 7.4) containing 0.5 million hepatocytes/mL and a final compound concentration of 1 µM. The compound/cell suspension (500 µL) was incubated for 2 hours at 37 °C in a humidified incubator with 5% CO2 and 85% humidity and shaken at 900 rpm on an Eppendorf Thermomixer Comfort plate shaker. Samples (50 µL) were taken at 5, 30, 60, and 120 minutes and quenched with 100 μL of 100% acetonitrile with internal standard. Samples were vortexed for 5 minutes and centrifuged at 3700 rpm for 20 minutes to pellet precipitated protein. The supernatant fraction was diluted 1:1 with deionized water before LCMS analysis. 2. Determination of Protein Binding to Hepatocytes (fu hep) [00254] Rat hepatocyte binding assay was completed using a 96-well rapid equilibrium dialysis (RED) plate. Test compound was diluted to 100 μM in 48% acetonitrile:48% water:4% DMSO (v/v/v) from 2.5 mM working stock solution in 100% DMSO, and further diluted in 300 μL of 0.6X106 heat inactivated cell suspension in 150 mM phosphate buffer pH 7.4 to achieve a final compound concentration of 1 μM in the incubation. Immediately, 50 μL of the spiked cell suspension was aliquoted as a control T=0 sample. The T=0 sample was matrix matched with 50 μL of blank phosphate buffered solution (pH 7.4) and quenched with Attorney Docket No.10275.0231-00304 VPI/24-005 WO 300 μL of 100% acetonitrile with internal standard. Phosphate buffered solution (pH 7.4; 500 μL) was added to the receiver chamber of the dialysis block and spiked rat hepatocyte suspension (300 μL) was added to the donor chamber. The plate was covered with a gas- permeable lid and incubated for 18 hours at 37 °C in a humidified incubator (no CO₂) on an Ohaus shaker at 300 rpm. At the end of incubation, 50 μL of post-dialysis sample from the donor and receiver wells were matrix-matched with 50 μL of phosphate buffered solution (pH 7.4) or blank rat hepatocyte suspension, respectively. The samples were subsequently quenched separately in 300 μL of 100% acetonitrile with internal standard. Quenched samples were shaken using a plate mixer for 10 minutes and centrifuged for 10 minutes at 4000 rpm to pellet precipitated protein. The supernatant fraction was further diluted 1:1 with deionized water for analysis by LCMS. Compound recovery and stability in the matrix were determined using the T=0 and T=18 samples. 3. LC-MS/MS Analysis [00255] Compounds were analyzed by LC/ hybrid Quadrupole-Orbitrap™ mass spectrometry using electrospray ionization on a QExactive (ThermoFisher Scientific, Waltham, MA). Aliquots of extracts (5 mL) were injected on an Acquity UPLC BEH C181.7 µm column, (2.1x50 mm) (Waters Corporation, Milford, MA) using a Vanquish auto-sampler and Vanquish binary pumps (ThermoFisher Scientific, Waltham, MA). A gradient of 15% to 99% B over 0.85 minutes was used with a flow rate of 0.8 mL/min. Mobile phases are A: 0.1% formic acid in water and B: 0.1% formic acid in acetonitrile. Compounds was monitored using their exact masses. The peak area ratio in each sample was determined by comparison of its peak area to the peak area of internal standard in the sample. 4. Data Analysis The t1/2 and, subsequently, the CLint of the compounds incubated in human hepatocytes were calculated according to equations 1 and 2: ^_{^1/2 ൌ ^୬^ଶ^} (1) divided by the number of cells (X10⁶) in the incubation. The unbound fraction (fu) of the compounds in rat hepatocyte was calculated according to equation 3: ^_{^^^, ℎ^^^^ ൌ ୮^ୟ୩ ୟ୰^ୟ ୧୬ ୠ^^^^୰ ୡ୦ୟ୫ୠ^୰} ୮^ୟ୩ ୟ୰^ୟ ୧୬ ୡ^୪୪ ^^^୮^୬^^୧୭୬ ୡ୦ୟ୫ୠ^୰ (3) Attorney Docket No.10275.0231-00304 VPI/24-005 WO Compound recovery in the relevant matrix were determined according to equation 4: ^ୟ^^୰ୟ^^ ୟ୰^ୟ ୠ^^^^୰ ୡ୦ୟ୫ୠ^୰∗^ఱబబ^ାୟ^^୰ୟ^^ ୟ୰^ ^^^^^^^^^^^ ൌ _యబ ୟ ୡ^୪୪ ୡ୦ୟ୫ୠ^୰^ ^ ^^^ % ^^^^^ _బ ^^ୟ୬^ୟ୰^ ୟ୰^ୟ ୟ^ ^^ (4) exposure for AAT compounds. The target plasma efficacious exposure at steady state in human for each compound is set to target free average concentration (Cavg) equivalent to the AAT NL20 EC₅₀. The daily target free efficacious exposure (AUC_0-24h) is estimated as target Cavg*24 and the target total AUC0-24h is estimated as target free AUC0-24h,ss/fup (fraction unbound in human plasma). The anticipated therapeutic dose in human (Dose) is estimated based on Equation 1: Dose = CL * AUC0-24h,ss / F Equation 1 and that, AUC0-24h,ss = Cavg * 24/fup = EC50 * 24/fup Equation 2 where CL is total clearance, AUC0-24h,ss is daily exposure at steady state, and F is bioavailability. Thus, to calculate the dose required to achieve daily Cavg, Dose = CL * EC50 * 24/fup / F Equation 3 Adam J. Lucas, Joanne L. Sproston, Patrick Barton & Robert J. Riley (2019): Estimating human ADME properties, pharmacokinetic parameters and likely clinical dose in drug discovery, Expert Opinion on Drug Discovery, DOI: 10.1080/17460441.2019.1660642. [00257] A key consideration for the selection of compounds suitable for clinical development is the projection of human dose as described in Equations 1-3. Two key parameters that comprise the dose equation are the unbound clearance of a compound and the plasma efficacious exposure (also referred to herein as compound potency). Together these parameters are known to one skilled in the art as a measurement of Compound Quality and suitability for advancement into clinical development. Thus, when evaluating AAT modulator compounds, one needs to consider both the potency and unbound clearance parameters (i.e., Compound Quality). The relationship between these two parameters can be challenging to predict. Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00258] The compounds disclosed within exhibit an unanticipated improvement in the compound potency and unbound clearance relative to compounds previously disclosed which resulted in lower human projected doses. For example, comparing compound 33 from WO 2020/247160 (which has a hydrogen substituent at C8) with compound 45 from WO 2020/247160 (identical to compound 33 except that it has a fluorine substituent at C8) as shown in the table in Example 6 below, established that the H to F substitution at C8 was not anticipated to improve subsequent molecules from the series with respect to projected human dose. [00259] Evaluating Compound Quality, this disclosure identifies select compounds that exhibit superiority over compounds disclosed in WO 2020/247160. For example, the compounds claimed herein have a significantly superior Compound Quality (i.e., lower Compound Quality score) relative to compounds of the prior art. Example 7 A. Identification of Compounds with Superior Compound Quality Score [00260] The closest prior art compounds can be found in WO 2020/247160, which discloses compounds of the general formula: genus). [00261] As (WO 2020/247160 compound 33). Attorney Docket No.10275.0231-00304 VPI/24-005 WO has a Compound Quality score of 1.73. After synthesis of many compounds structurally similar to WO 2020/247160 compound 33, it became clear that the Compound Quality scores of compounds having the same structural core as the compounds of WO 2020/247160 are not predictable. [00262] For example, preparation of many structurally similar compounds and analogs of WO 2020/247160 compound 33 (some of which were specifically exemplified in WO 2020/247160), demonstrated the tremendous variability in Compound Quality score as shown in the table below: WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound d N * Ring at N5 at C6 at C7 at C8 Quality Attorney Docket No.10275.0231-00304 VPI/24-005 WO WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound Cmpd No.* Ring at N5 at C6 at C7 at C8 Quality Attorney Docket No.10275.0231-00304 VPI/24-005 WO WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound Cmpd No.* Ring at N5 at C6 at C7 at C8 Quality Attorney Docket No.10275.0231-00304 VPI/24-005 WO WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound Cmpd No.* Ring at N5 at C6 at C7 at C8 Quality Attorney Docket No.10275.0231-00304 VPI/24-005 WO WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound Cmpd No.* Ring at N5 at C6 at C7 at C8 Quality Attorney Docket No.10275.0231-00304 VPI/24-005 WO WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound Cmpd No.* Ring at N5 at C6 at C7 at C8 Quality Attorney Docket No.10275.0231-00304 VPI/24-005 WO WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound Cmpd No.* Ring at N5 at C6 at C7 at C8 Quality Attorney Docket No.10275.0231-00304 VPI/24-005 WO WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound Cmpd No.* Ring at N5 at C6 at C7 at C8 Quality Attorney Docket No.10275.0231-00304 VPI/24-005 WO WO 2020/247160 Pyrazole Substituent Substituent Substituent Substituent Compound Cmpd No.* Ring at N5 at C6 at C7 at C8 Quality compounds with Compound Quality score ≤ 0.30, rendering the search for compounds with low projected human dose very challenging. B. Compound Quality Data for Compounds of the Invention [00264] The compounds of Formulae I and II are useful as modulators of AAT activity and are unexpectedly superior to prior art compounds. The values provided in the table below are calculated by multiplying the EC50 of each of the compounds by the result from the clearance assay procedures described above and described in PCT/US2023/032282 and rounded to two significant figures. In the table below, the following meanings apply for Compound Quality (i.e., compound potency x unbound clearance) values: “++++” means ≤ 0.2; “+++” means > 0.20 and ≤ 0.30; “++” means > 0.30 and ≤ 0.40; “+” means > 0.40 and ≤ 0.50. Compound No. Compound Qualit Example 8 Enhancement of Exposure Multiple [00265] Irrespective of a superior Compound Quality score, it has been unexpectedly discovered that substitution of hydrogen with fluorine at C8 of the core rings of the disclosed Formulae results in enhancement of drug exposure multiple. The calculation of an exposure multiple is accomplished by comparing the plasma exposure (AUC) achieved in a toxicology Attorney Docket No.10275.0231-00304 VPI/24-005 WO species relative to the target efficacious exposure at steady state (AUCss). The larger this exposure multiple, the superior the molecule because it provides the potential opportunity to explore higher exposures in clinical development if a larger window is established in toxicology studies. In addition, this exposure multiple can allow for further exploration of the desired pharmacology due to the opportunity for a larger window established in toxicology studies. However, the exposure that results in a toxicological outcome in preclinical toxicology studies is unpredictable. [00266] As previously noted, SAR based on compounds disclosed in WO 2020/247160 did not support exploration of 8F analogs. WO 2020/247160 suggested no superiority in 8F compounds over 8 H compounds, and in fact, disclosed only two such compounds. When further evaluated, the two 8F compounds disclosed in WO 2020/247160 provided the following data: WO 2020/247160 compound 45 WO 2020/247160 compound 341 , , from WO 2020/247160 also showed no reason to further explore 8F compounds: WO 2020/247160 compound 45 WO 2020/247160 compound 33 [002 l enh le resul the . as compared to the same compound having a hydrogen at that position. Human exposure Attorney Docket No.10275.0231-00304 VPI/24-005 WO multiple (EM) values shown relate to the fold increase in exposure achieved in rat 5-day toxicology studies for a given dose relative to the predicted efficacious exposure anticipated in human (based on cellular NL20 EC50 in vitro efficacy). The exposure multiple score is based on the maximum exposure multiple achieved in the given study. This allows relative comparison across compounds when also considering the administered dose. The 8F compounds surprisingly demonstrated enhanced exposure multiples when compared to their 8H counterparts. In the tables below, the following meanings apply for exposure multiple scores: “-” means <1; “+” means 1-10; “++” means 10-20; “+++” means 20-30; “++++” means 30-50; and “+++++” means >50. Cmpd No. Structure Rat Bid Exposure EM Score Attorney Docket No.10275.0231-00304 VPI/24-005 WO [00268] Once this side-by-side result was observed, the trend continued to show that the 8F compounds demonstrated enhanced exposure multiples compared to similar 8H compounds, and thus, superior profiles relative to the prior art. Example 9 Procedures for Solid Dispersions of Compound 1 and Compound 2 [00269] Unless otherwise stated, the following procedures were employed for the analysis of all solid dispersions. X-Ray Powder Diffraction [00270] X-ray powder diffraction (XRPD) spectra were recorded at room temperature in transmission mode using a PANalytical Empyrean system equipped with a sealed tube source and a PIXcel 1D Medipix-3 detector (Malvern PANalytical Inc, Westborough, Massachusetts). The X-Ray generator operated at a voltage of 45 kV and a current of 40 mA with copper radiation (1.54060 Å). The powder sample was placed on a 96 well sample holder with mylar film and loaded into the instrument. The sample was scanned over the range of about 3° to about 40°2θ with a step size of 0.0131303° and 49s per step. Solid State NMR [00271] Bruker-Biospin 400 MHz wide-bore spectrometer equipped with Bruker-Biospin 4mm HFX probe was used. Samples were packed into 4mm ZrO₂ rotors and spun under Magic Angle Spinning (MAS) condition with spinning speed typically set to 12.5 kHz. The proton relaxation time was measured using ¹H MAS T₁ saturation recovery relaxation experiment in order to set up proper recycle delay of the ¹³C and ³¹P cross-polarization (CP) MAS experiments. The fluorine relaxation time was measured using ¹⁹F MAS T₁ saturation recovery relaxation experiment in order to set up proper recycle delay of the ¹⁹F MAS experiment. The CP contact time of carbon as well as phosphorus CPMAS experiments was set to 2 ms. A CP proton pulse with linear ramp (from 50% to 100%) was employed. The carbon Hartmann-Hahn match was optimized on external reference sample (glycine), while phosphorus Hartmann-Hahn match was optimized on the actual samples. All carbon, phosphorus and fluorine spectra were recorded with proton decoupling using TPPM15 decoupling sequence with the field strength of approximately 100 kHz. Differential Scanning Calorimetry [00272] Modulated Differential Scanning Calorimetry Analysis of Compound 1 SDD was carried out using the TA Instruments Q2000 or Discovery 2500 DSC. A sample with a weight Attorney Docket No.10275.0231-00304 VPI/24-005 WO between roughly 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed, and a flow of nitrogen was passed through the cell. The sample was heated from 25 to 200 °C at a rate of 1-3 °C/min (modulation amplitude 0.32-1 °C, modulation period 30-60 sec). When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The glass transition was taken from the Reversing Heat Flow. Residual Solvent Analysis: [00273] Analytical method (all samples): Residual solvents were determined by head-space gas chromatography using an Agilent system (GC 6890N with Headspace unit 7967A, or equivalent). Sample material (50 or 100 mg ± 10%) was dissolved in 1.0 mL of dimethyl acetamide inside of a 10 mL headspace vial; vial was then capped. The column used in analysis was DB-624, 30 m x 0.32 mm i.d., 1.8 µm film thickness (manufacturer J & W). Residual solvents were detected by Flame Ionization Detection (FID). 1. Compound 1 A. SDD 1A: 50% Amorphous Compound 1 and 50% Polymer Solvent: DCM/MeOH/H₂O (47.3/47.3/5.5 w/w/w) Polymer: HPMCAS-H (1) Synthetic Procedure [00274] 3.2 g of amorphous Compound 1 prepared according to Example 1 above was weighed into a bottle.100.2 g of 50/50 DCM/MeOH was added. The bottle was capped and contents were stirred for ~30 mins. Solution still had small and large particles remaining, and therefore an additional 28.7 g of 50/50 DCM/MeOH as well as 7.5 g of water was added. After 10 mins of sonication and 10 mins of additional stirring the solution was clear and orange in color.3.2 g of HPMCAS-H was added. The bottle was capped and the contents were stirred for ~1.5 hrs at room temperature. This solution was then spray dried to make SDD 1A comprising amorphous Compound 1 and polymer in a ratio of 1:1. Buchi B-290 Parameters Pump Set Point (%) 40 A i t (%) 100 s Attorney Docket No.10275.0231-00304 VPI/24-005 WO (2) X-Ray Powder Diffraction [00275] X-ray powder diffraction (XRPD) spectra (FIG.1) were recorded at room temperature in transmission mode using a PANalytical Empyrean system. XRPD of this spray dried dispersion was done prior to secondary drying. Lack of crystalline diffraction peaks indicates that material is amorphous (with likely contamination from sodium chloride as evidenced by peak at ~31 °2Th). (3) Differential Scanning Calorimetry [00276] Analysis of spray dried dispersion 1A was also carried out using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The modulated DSC ramping temperature was 1 °C/min up to 200 °C. The thermogram at Time 0 using an open pan shows a glass transition at 124 °C in the Reversing Heat Flow as shown in FIG.2. B. SDD 1B: 50% Amorphous Compound 1 and 50% Polymer Solvent: DCM/MeOH/H₂O (48/48/4 w/w/w) Polymer: HPMCAS-H (1) Synthetic Procedure [00277] 72.1 g of Compound 1 free form Form A was weighed into a container.1298 g of 48/48/4 DCM/MeOH/H2O was added. The bottle was capped and contents were stirred for ~2 hrs resulting in a clear orange solution.72.1 g of HPMCAS-H was added. The bottle was capped and the contents were stirred overnight at room temperature. This solution was then spray dried to make SDD 1B comprising amorphous Compound 1 and polymer in a ratio of 1:1. Buchi B-290 Parameters Pump Set Point (%) 30 A ir t r (%) 100 Attorney Docket No.10275.0231-00304 VPI/24-005 WO (2) X-Ray Powder Diffraction: [00278] X-ray powder diffraction (XRPD) spectra (FIG.3) were recorded at room temperature in transmission mode using a PANalytical Empyrean system. The XRPD was carried out on this spray dried dispersion prior to secondary drying. Lack of crystalline diffraction peaks indicates that material is amorphous. (3) Differential Scanning Calorimetry [00279] Analysis of spray dried dispersion 1B was carried out using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). The glass transition temperature was calculated from the reversing heat flow. Modulated DSC ramping temperature at 1 °C/min up to 200 °C. The thermogram at Time 0 using an open pan shows a glass transition at 124 °C in the Reversing Heat Flow as shown in FIG.4. (4) Solid State NMR (a) ¹³C NMR (CPMAS) (FIG.5): Peak # Chem Shift [± 0.2 ppm] Intensity [rel] 1 173.2 1.56 Attorney Docket No.10275.0231-00304 VPI/24-005 WO (b) ¹⁹F NMR (FMAS) (FIG.6) Peak # Chem Shift [± 0.2 ppm] Intensity [rel] 1 -138.0 10 [00280] Sample Results (ppm) of residual solvents detected in SDD 1B samples just after manufacture (T0), after one day (T1) or 5 days (T5) of secondary drying at 40 ºC, vacuum: Sample: T0 ppm (prior to T1 ppm (day 1 of T5 ppm (day 5 of secondary drying) secondary drying secondary drying M H 4 ND ND C. SDD 1C: 50% Amorphous Compound 1 and 50% Polymer Solvent: DCM/MeOH (50/50 w/w) Polymer: HPMCAS-H (1) Synthetic Procedure [00281] 13.6 g of Compound 1 free form Form A was weighed into a container.244.8 g of 50/50 DCM/MeOH was added. The container was capped and contents were stirred for ~1 min resulting in a clear orange solution.13.6 g of HPMCAS-H was added and the contents were stirred for 2.5 hrs at room temperature. This solution was then spray dried to provide SDD 1C comprising amorphous Compound 1 and polymer in a ratio of 1:1. Buchi B-290 Parameters Pump Set Point (%) 30 A i t (%) 100 s Attorney Docket No.10275.0231-00304 VPI/24-005 WO (2) X-Ray Powder Diffraction: [00282] X-ray powder diffraction (XRPD) spectra (FIG.7) were recorded at room temperature in transmission mode using a PANalytical Empyrean system. The XRPD was carried out on SDD 1C prior to secondary drying. Lack of crystalline diffraction peaks indicates that material is amorphous. (3) Differential Scanning Calorimetry [00283] Analysis of SDD 1C was carried out using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). Modulated DSC ramping temperature at 1 °C/min up to 200 °C. The glass transition temperature was calculated from the reversing heat flow. The thermogram at Time 0 using an open pan shows a glass transition at 124 °C in the Reversing Heat Flow as shown in FIG.8. (4) Solid State NMR [00284] ¹H, ¹³C, and ¹⁹F ssNMR were run on SDD 1C. The results are shown in FIG.9 as compared to the data from SDD 1B. (5) Residual Solvents [00285] Sample Results (ppm) of residual solvents detected in SDD 1C samples after manufacture 5 days (T5) of secondary drying at 40 ºC, vacuum: Sample: T5 ppm (day 5 of secondary drying Attorney Docket No.10275.0231-00304 VPI/24-005 WO D. SDD 1D: 80% Amorphous Compound 1 and 20% Polymer Solvent: DCM/MeOH (50/50 w/w) Polymer: HPMCAS-H (1) Synthetic Procedure [00286] 31.4 g of 50/50 DCM/MeOH was weighed into a container.1.006 g of amorphous Compound 1 solid dispersion with HPMCAS-H (SDD 1C) and 1.508 g Compound 1 Free Form A was added (resulting composition 4:1 amorphous Compound 1:HPMCAS-H). The container was capped and contents were stirred for overnight resulting in a clear yellow solution. This solution was then spray dried to make SDD 1D comprising amorphous Compound 1 and polymer in a ratio of 4:1. Buchi B-290 Parameters Pump Set Point (%) 30 Aspirator (%) 100 4 (2) [00287] X-ray powder diffraction (XRPD) spectra (FIG.10) were recorded at room temperature in transmission mode using a PANalytical Empyrean system. The XRPD was carried out on SDD 1D prior to secondary drying. Lack of crystalline diffraction peaks indicates that material is amorphous. (3) Differential Scanning Calorimetry [00288] Analysis of SDD 1D was carried out using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). Modulated DSC ramping temperature at 1 °C/min up to 200 °C. The glass transition temperature was calculated from the reversing heat flow. The thermogram at Time 0 using an open pan shows a glass transition at 137 °C in the Reversing Heat Flow as shown in FIG.11. Attorney Docket No.10275.0231-00304 VPI/24-005 WO (4) Thermal Gravimetric Analysis [00289] Thermal Gravimetric Analysis of SDD 1D was carried out using the TA Instruments Discovery 5500 TGA. A sample with weight of approximately 1-10 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Series^TM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). Thermogravimetric analysis on SDD 1D prior to any secondary drying. The thermogram at T0 (FIG.12) shows a weight loss of ~2.5% by about 180 °C. E. SDD 1E: 80% Amorphous Compound 1 and 20% Polymer Solvent: Acetone Polymer: HPMCAS-H (1) Synthetic Procedure [00290] 247.17 g of Acetone was weighed into a container.15.996 g of Compound 1 Monohydrate Form A and 4.015 g of HPMCAS-H was added to the same container which was then capped and contents were stirred overnight resulting in a clear yellow solution. This solution was then spray dried to provide SDD 1E comprising amorphous Compound 1 and polymer in a ratio of 4:1. Buchi B-290 Parameters Pump Set Point (%) 30 Aspirator (%) 100 (2) X-Ray Powder Diffraction: [00291] X-ray powder diffraction (XRPD) spectra (FIG.13) were recorded at room temperature in transmission mode using a PANalytical Empyrean system. The XRPD was carried out on SDD 1E prior to secondary drying. Lack of crystalline diffraction peaks indicates that material is amorphous. Attorney Docket No.10275.0231-00304 VPI/24-005 WO (3) Differential Scanning Calorimetry [00292] Analysis of SDD 1E was carried out using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). Modulated DSC ramping temperature at 1 °C/min up to 200 °C. The glass transition temperature was calculated from the reversing heat flow. The thermogram at Time 0 using an open pan shows a glass transition at 139 °C in the Reversing Heat Flow as shown in FIG.14. (4) Thermal Gravimetric Analysis [00293] Thermal Gravimetric Analysis of SDD 1E was carried out using the TA Instruments Discovery 5500 TGA. A sample with weight of approximately 1-10 mg was scanned from 25 °C to 350 °C at a heating rate of 10 °C/min with nitrogen purge. Data were collected by Thermal Advantage Q Series^TM software and analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). Thermogravimetric analysis on SDD 1E prior to any secondary drying. The thermogram at T0 (FIG.15) shows a weight loss of ~3.1% by about 150 °C.

Attorney Docket No.10275.0231-00304 VPI/24-005 WO (5) Solid State NMR (1) ¹³C NMR (CPMAS) (FIG.16): Peak # Chem Shift [± 0.2 ppm] Intensity [rel] 1 173.1 1.16 2 1695 174 (2) F NMR (FMAS) (FIG.17) Peak # Chem Shift [± 0.2 ppm] Intensity [rel] 1 -138.0 10 (6) Residual Solvents [00294] Sample Results (ppm) of residual solvents detected in SDD 1E samples just after manufacture (T0), after two day (T2) or nine days (T9) of secondary drying at 40 ºC, vacuum: Attorney Docket No.10275.0231-00304 VPI/24-005 WO Sample: T0 ppm (prior to T2 ppm (day 2 of T9 ppm (day 9 of secondary drying) secondary drying secondary drying MeOH ND ND ND F. SDD 1F: 80% Amorphous Compound 1 and 20% Polymer Solvent: Acetone Polymer: HPMCAS-L [00295] 61.64 g of Acetone is weighed into a container.4.18 g of Compound 1 Monohydrate Form A and 1.00 g of HPMCAS-L are added to the same container which is then capped and contents are stirred overnight. This solution is then spray dried to provide SDD 1F comprising amorphous Compound 1 and polymer in a ratio of 4:1. G. SDD 1G: 80% Amorphous Compound 1 and 20% Polymer Solvent: DCM:MeOH (50:50 w/w) Polymer: HPMC E15 [00296] 61.62 g of 50/50 w/w DCM/MeOH is weighed into a container.4.18 g of Compound 1 Monohydrate Form A and 1.01 g of HPMC E15 are added to the same container which is then capped and contents are stirred overnight. This solution is then spray dried to provide SDD 1G comprising amorphous Compound 1 and polymer in a ratio of 4:1. H. SDD 1H: 80% Amorphous Compound 1 and 20% Polymer Solvent: DCM:MeOH (50:50 w/w) Polymer: PVP VA64 [00297] 61.64 g of 50/50 w/w DCM/MeOH is weighed into a container.4.18 g of Compound 1 Monohydrate Form A and 1.00 g of PVP VA64 are added to the same container Attorney Docket No.10275.0231-00304 VPI/24-005 WO which is then capped and contents are stirred overnight. This solution is then spray dried to provide SDD 1H comprising amorphous Compound 1 and polymer in a ratio of 4:1. 2. Compound 2 A. SDD 2A: 50% Amorphous Compound 1 and 50% Polymer Solvent: Acetone/H₂O (95/5 w/w) Polymer: HPMCAS-H (1) Synthetic Procedure [00298] 4.4 g of Compound 2 free form Form A was weighed into a container.79.2 g of 95/5 Acetone/H2O was added. The bottle was capped and contents were stirred for ~10 mins resulting in a clear and colorless solution.4.4 g of HPMCAS-H was added. The container was capped and the contents were stirred overnight at room temperature. This solution was then spray dried to provide SDD 2A comprising amorphous Compound and polymer in a ratio of 1:1. Buchi B-290 Parameters Pump Set Point (%) 30 Aspirator (%) 100 2. - ay owder rac on X-ray powder diffraction (XRPD) spectra were recorded at room temperature in transmission mode using a PANalytical Empyrean system on SDD 2A prior to secondary drying. Lack of crystalline diffraction peaks indicates that material is amorphous (FIG.18). (3) Differential Scanning Calorimetry [00299] Analysis of SDD 2A was carried out using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). Modulated DSC Attorney Docket No.10275.0231-00304 VPI/24-005 WO ramping temperature at 1 °C/min up to 200 °C. The glass transition temperature was calculated from the reversing heat flow. The thermogram at Time 0 using an open pan shows a glass transition at 124 °C in the Reversing Heat Flow as shown in FIG.19. (4) Solid State NMR (1) ¹³C NMR (CPMAS) for SDD 2A (FIG.20): Peak # Chem Shift [± 0.2 ppm] Intensity [rel] 1 173.3 1.8 2 1701 315 (2) ¹⁹F NMR (FMAS) (FIG.21) Peak # Chem Shift [± 0.2 ppm] Intensity [rel] 1 1349 1000 (5) Residual Solvents [00300] Sample Results (ppm) of residual solvents detected in SDD 2A samples after manufacture 6 days (T6) of secondary drying at 40 ºC, vacuum: Attorney Docket No.10275.0231-00304 VPI/24-005 WO Sample: T6 ppm (day 6 of secondary drying MeOH ND B. SDD 2B Polymer Solvent: DCM/MeOH (75/25 w/w) Polymer: HPMCAS-H (1) Synthetic Procedure [00301] 10.0 g of Compound 2 free form Form A was weighed into a container.180 g of 75/25 DCM/MeOH was added. The bottle was capped and contents were stirred for ~10 mins resulting in a clear and colorless solution.10.0 g of HPMCAS-H was added. The container was capped and the contents were stirred for 1 hr at room temperature. This solution was then spray dried to provide SDD 2B comprising amorphous Compound 1 and polymer in a ratio of 1:1. Buchi B-290 Parameters Pump Set Point (%) 30 Aspirator (%) 100 s 2. X-Ray Powder Diffraction [00302] X-ray powder diffraction (XRPD) spectra were recorded at room temperature in transmission mode using a PANalytical Empyrean system on SDD 2B prior to secondary drying. Lack of crystalline diffraction peaks indicates that material is amorphous (FIG.22). Attorney Docket No.10275.0231-00304 VPI/24-005 WO (3) Differential Scanning Calorimetry [00303] Analysis of SDD 2B was carried out using the TA Instruments Q2000 DSC. A sample with a weight between 1-10 mg was weighed into an aluminum crimp sealed pan with a pinhole. This pan was placed in the sample position in the calorimeter cell. An empty pan was placed in the reference position. The calorimeter cell was closed and a flow of nitrogen was passed through the cell. When the run was completed, the data were analyzed by Trios and/or Universal Analysis software (TA Instruments, New Castle, DE). Modulated DSC ramping temperature at 1 °C/min up to 200 °C. The glass transition temperature was calculated from the reversing heat flow. The thermogram at Time 0 using an open pan shows a glass transition at 124 °C in the Reversing Heat Flow as shown in FIG.23. (4) Residual Solvents [00304] Sample Results (ppm) of residual solvents detected in SDD 2B samples after manufacture 7 days (T7) of secondary drying at 40 ºC, vacuum: Sample: T2 ppm (day 2 of T7 ppm (day 7 of secondary drying secondary drying

Attorney Docket No.10275.0231-00304 VPI/24-005 WO Example 10 Advantages of Solid Dispersions of Compound 1 and Compound 2 over Crystalline Forms of Compound 1 and Compound 2 A. Compound 1 [00305] Solubility analysis of a number of crystalline forms of Compound 1 (see PCT application PCT/US2023/032282 for a list of solid forms prepared for Compound 5) and a solid dispersion comprising amorphous Compound 1 was carried out. Of the crystalline forms of Compound 1 disclosed in PCT/US2023/032282, Compound 1 free form Form A, Compound 1 Monohydrate Form A, and Compound 1 free form Form B were found to be the most soluble in biorelevant media, and thus, expected to be the most bioavailable forms of crystalline Compound 1. Solubility in Biorelevant Media Solid Form PBS (mg/mL, FeSSIF FaSSIF room temperature) (mg/mL, 37 °C) (mg/mL, 37 °C) [00306] Compound 1 free form Form A was significantly more soluble than Compound 1 Monohydrate Form A, and Compound 1 free form Form B and was selected for further studies. However, Compound 1 free form Form A was discovered to lack phase purity. This may be due in part to the crystal structure of Compound 1 free form Form A having large voids that can fit a variety of solvent molecules. As a result, crystalline Compound 1 free form Form A lacks stability over time. [00307] The stable Compound 1 Monohydrate Form A was not considered a viable alternative for clinical study due to its significantly (several fold) lower solubility as compared to Compound 1 free form Form A. Compound 1 free form Form B was also not considered a viable alternative to Compound 1 free form Form A due to significant stability Attorney Docket No.10275.0231-00304 VPI/24-005 WO issues. Because of the need to dose high in preclinical species to demonstrate exposure multiples, a solid dispersion comprising Compound 1 was used in toxicity studies. Formulation Performance in Rodent [00308] Compound 1 was administered to female Wistar Han rats (group size N = 3) as a precipitation resistant solution (eliminating solubility barriers), as a suspension of crystalline Compound 1 Monohydrate Form A, as a suspension of Compound 1 free form Form B, and as a suspension of SDD 1B (described above). At 25 and 150 mg/kg, the solution and SDD 1B suspension provided similar exposure, indicating that absorption of the solid dispersion of Compound 1 is not limited by solubility. [00309] At 25 mg/kg crystalline suspensions of Compound 1 Monohydrate Form A afforded roughly 2.5-fold lower exposure than the solution formulation. Use of a solubilizing vehicle including Vitamin E TPGS did not improve the exposure from the monohydrate. Free form Form B showed improvement relative to the crystalline monohydrate suspension, but the exposure achieved was inferior to the SDD suspension. When the dose in rats was increased to 150 mg/kg, the crystalline forms of Compound 1 again performed worse than the solution and Compound 1 SDD suspension. The higher dose is more discriminating of formulation performance due to solubility limits of the crystalline forms; a suspension of Compound 1 SDD provides roughly 3-fold improvement in exposure over free form Form B and 7-fold over monohydrate form A. In view of the inferior performance of crystalline suspensions at clinically relevant doses, the solid dispersion of Compound 1 was selected for progression into first-in-human studies. Dose Tmax C AUC AUC /kg) Fo max last inf (mg rm Vehicle Gender/Strain (h) ( /mL) (h* /mL) (h* /mL) .42 1.9 .60 .05 .88 09 0.7 9.3 Attorney Docket No.10275.0231-00304 VPI/24-005 WO Dose T Form Vehicle Gend max Cmax AUClast AUCinf (mg/kg) er/Strain (h) (µg/mL) (h*µg/mL) (h*µg/mL) 2%TPGS .35 8.2 [ assessment of the crystalline monohydrate versus the SDD 1C was conducted. Fasted dogs, pretreated with pentagastrin, were given 10 mg/kg of Compound 1 by oral gavage. [00311] A suspension of crystalline Compound 1 Monohydrate Form A was found to provide approximately 6-fold lower exposure than the solid dispersion of Compound 1 in dogs at 10 mg/kg. In view of the inferior performance of the crystalline Compound 1 Monohydrate Form A relative to the Compound 1 solid dispersion suspension, the solid dispersion was deemed most suitable for clinical development. T_max C_max AUC atment (h) [Observed] (µg/mL) _i (h*µg/mL) Tre _nf [Observed] B. Comparison of Compound 2 Free Form A vs SDD 2A Solubility in Biorelevant Media PBS (mg/mL, Solid Form room FeSSIF FaSSIF [00312] Approximately an order of magnitude improvement for solubility in biorelevant fluid was observed with the spray dried dispersion of Compound 2 versus crystalline Compound 2 Free Form A. Because of the need to dose high in preclinical species to demonstrate exposure multiples, the solid dispersion of Compound 2 SDD progressed to toxicity studies. Attorney Docket No.10275.0231-00304 VPI/24-005 WO Formulation Performance in Dog [00313] Fasted dogs were given 50 mg/kg of Compound 2 Free Form A or SDD 2A by oral gavage. The crystalline Compound 2 Free Form A was suspended in a solubilizing vehicle of 2%TPGS, 1%HPMCAS, 0.25%PVP in 50 mM phosphate pH 7.8. The SDD 2A was suspended in pH 3 buffered 0.5%MC, 0.02% SLS. The SDD 2A suspension provided roughly 10-fold higher exposure than the crystalline Compound 2 Free Form A. The safety profile of the SDD 2A suspension and need for high exposure in clinical ascending dose studies, make the solid dispersion of Compound 2 an excellent clinical candidate. T_max C_max AUC Treatment (h) [Observed] (µg/mL) _inf (h*µg/mL) Other Embodiments [00314] This description provides merely exemplary embodiments of the disclosed subject matter. One skilled in the art will readily recognize from the disclosure and accompanying claims that various changes, modifications and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims.

Claims

Attorney Docket No.10275.0231-00304 VPI/24-005 WO WHAT IS CLAIMED IS: 1. A solid dispersion comprising (a) amorphous Compound 1, 1) wherein the solid Compound 1; or (b) amorphous 2) wherein the solid Compound 2. 2. The solid dispersion according to claim 1, further comprising at least one polymer. 3. The solid dispersion according to claim 2, wherein the at least one polymer is a water- soluble polymer or a partially water-soluble polymer. 4. The solid dispersion according to claim 3, wherein the at least one polymer is selected from cellulose derivatives, polyvinyl pyrrolidones, polyethylene glycols, polyvinyl alcohols, acrylates, cyclodextrins, polymethacrylates, and copolymers and derivatives thereof. 5. The solid dispersion according to claim 2, wherein the at least one polymer is selected Attorney Docket No.10275.0231-00304 VPI/24-005 WO from hydroxypropylcellulose (HPC), hydroxypropyl-methylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate, ethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalates (HPMCP), carboxymethyl cellulose (CMC), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), polyvinylpyrrolidone-vinyl acetate (PVP-VA), and β- cyclodextrin. 6. The solid dispersion according to claim 2, wherein the at least one polymer is selected from hydroxypropyl-methylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone-vinyl acetate (PVP-VA). 7. The solid dispersion according to any one of claims 1 to 6 further comprising a surfactant. 8. The solid dispersion according to claim 7, where the surfactant is sodium lauryl sulfate. 9. The solid dispersion according to any one of claims 1 to 8, wherein the solid dispersion comprises particles. 10. The solid dispersion according to any one of claims 1 to 9, wherein the solid dispersion comprises from about 20% by weight to about 80% by weight of Compound 1 or Compound 2. 11. The solid dispersion according to claim 10, wherein the solid dispersion comprises from about 20% by weight to about 80% by weight of polymer. 12. The solid dispersion according to claim 10, wherein the solid dispersion comprises from about 50% by weight of polymer and about 50% by weight of amorphous Compound 1 or amorphous Compound 2. 13. The solid dispersion according to claim 10, wherein the solid dispersion comprises Attorney Docket No.10275.0231-00304 VPI/24-005 WO from about 20% by weight of polymer and about 80% by weight of amorphous Compound 1 or amorphous Compound 2. 14. The solid dispersion according to any one of claims 1 to 13, wherein the solid dispersion is prepared by spray-drying. 15. A pharmaceutical composition comprising the solid dispersion according to any one of claims 1 to 14. 16. The pharmaceutical composition according to claim 15, wherein the composition is formulated as a tablet for oral administration. 17. A method of treating AATD comprising administering a solid dispersion of comprising Compound 1 or Compound 2 according to any one of claims 1 to 14 or the pharmaceutical composition of claim 15 or claim 16 to a patient in need thereof. 18. A pharmaceutical composition comprising the solid dispersion according to any one of claims 1 to 14 for use in treating AATD. 19. Use of the solid dispersion according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15 or 16, in the manufacture of a medicament for treating AATD. 20. A process for preparing the solid dispersion according to any one of claims 1 to 14 comprising the steps of (a) dissolving amorphous or crystalline Compound 1 or Compound 2 with a solvent; and (b) spray-drying the result of step (a) to provide the solid dispersion. 21. The process according to claim 20, wherein step (a) includes dissolving a polymer with the solvent. 22. The process according to claim 20 or claim 21, wherein the solvent is selected from MeOH, EtOH, Acetone, DCM, water, and combinations thereof.