Alpha-1 antitrypsin modulators

Abstract

Novel compounds, compositions, and methods for using and preparing the same may be useful for treating alpha-1 antitrypsin deficiency (AATD). One aspect of the present invention provides compounds that unexpectedly exhibit significantly superior compound quality compared to the compounds disclosed in International Publication No. 2020 / 247160. The compounds of the present invention also unexpectedly exhibit enhanced exposure due to the substitution of fluorine for hydrogen at C8 of the core ring structure. Thus, one aspect of the present disclosure can be used to treat AATD. JPEG2025532510000251.jpg5050

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 405,080, filed September 9, 2022, and U.S. Provisional Patent Application No. 63 / 489,543, filed March 10, 2023, the contents of which are incorporated herein by reference in their entireties.

[0002] The present disclosure provides compounds capable of modulating alpha-1 antitrypsin (AAT) activity and methods of treating alpha-1 antitrypsin deficiency (AATD) by administering one or more such compounds. [Background technology]

[0003] AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments exist for AATD, there is currently no cure. AAT is primarily produced in hepatocytes and secreted into the blood, but is also produced by other cell types, including lung epithelial cells and certain leukocytes. AAT inhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase (NE), proteinase 3, and cathepsin G), thus protecting organs such as the lungs from protease damage, especially during periods of inflammation.

[0004] The mutation most commonly associated with AATD involves a substitution of glutamic acid (E342K) with lysine in the SERPINA1 gene, which encodes the AAT protein. This mutation, known as the Z mutation or Z allele, leads to misfolding of the translated protein, so that it is not secreted into the bloodstream and can polymerize within the producing cells. As a result, circulating AAT levels in individuals homozygous for the Z allele (PiZZ) are significantly reduced, and only about 15% of the mutant Z-AAT protein is correctly folded and secreted by cells. An additional consequence of the Z mutation is that secreted Z-AAT has reduced activity compared to the wild-type protein, with 40% to 80% of the 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] Accumulation of polymerized Z-AAT protein within hepatocytes results in gain-of-function cytotoxicity, which can lead to cirrhosis or liver cancer later in life and neonatal liver disease in 12% of patients. This accumulation can resolve spontaneously, but can be fatal in a small number of children. Deficiency of circulating AAT leads to unregulated protease activity, which degrades lung tissue over time and leads to emphysema, a form of chronic obstructive pulmonary disease (COPD). This effect is severe in PiZZ individuals, typically manifesting in middle age and resulting in a reduced quality of life and a shortened lifespan (average 68 years) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016;11:1663-9). This effect is more pronounced in PiZZ individuals who smoke, resulting in an even shorter lifespan (58 years) (Piitulainen and Tanash, COPD 2015;12(1):36-41). PiZZ individuals represent a large proportion of people with clinically relevant AATD lung disease. Thus, 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 the S allele. The S allele is associated with slightly reduced levels of circulating AAT, but does not cause cytotoxicity in liver cells. The result is clinically significant lung disease but no liver disease. (Fregonese and Stolk, Orphanet J Rare Dis. 2008;33:16). Similar to the ZZ genotype, the lack of circulating AAT in subjects with the SZ genotype leads to unregulated protease activity, which can degrade lung tissue over time and lead to emphysema, especially in smokers.

[0007] The current standard of care for individuals with AAT deficiency who show signs of or are developing significant lung or liver disease is augmentation therapy or protein replacement therapy. Augmentation therapy involves the administration of human AAT protein concentrate purified from pooled donor plasma to enhance the deficient AAT. While plasma protein infusions have been shown to improve survival or slow the progression of emphysema, augmentation therapy is often insufficient under challenging conditions, such as during active pulmonary infection. Similarly, protein replacement therapy shows promise in slowing disease progression, but augmentation does not restore normal physiological regulation of AAT in patients, and efficacy has been difficult to demonstrate. Additionally, augmentation therapy requires weekly clinic visits for treatment and fails to address liver disease driven by the toxic gain-of-function of the Z allele. Therefore, there is a continuing need for novel and more effective treatments for AATD.

[0008] An important consideration in selecting a compound suitable for clinical development is the prediction of human dose. Two important parameters considered in predicting human dose are the compound's unbound clearance and plasma effective exposure (also referred to herein as efficacy). Both of these parameters are known to those skilled in the art as measurements of compound quality (as defined herein) and suitability for progression to clinical development. Therefore, when evaluating an AAT modulator compound, both efficacy and unbound clearance parameters must be considered. The relationship between these two parameters can be very difficult to predict.

[0009] The compounds of the present invention show unexpected improvements in compound potency and unbound clearance compared to the closest prior art, International Publication No. 2020 / 247160. The compounds of the present invention are characterized by both high potency and low unbound clearance. Therefore, the compounds of the present invention show improved compound quality scores compared to the prior art. Compounds with high predicted human doses (e.g., compounds with high unbound clearance) may limit the ability to reach effective exposure in clinical trials. In contrast, higher quality compounds may provide a greater possibility of testing the full range of the compound's predicted effective exposure. Exploring higher effective exposures may result in greater clinical benefit for the compound. A separate but related consideration for the selection of AAT regulator compounds includes exposure multiplier, which is the relative compound exposure assessment in toxicity test to predicted plasma effective exposure.High exposure multiplier in preclinical toxicity test can provide the opportunity to explore higher exposure in clinical development.The higher exposure multiplier, the more suitable the compound may be for clinical development.However, the exposure that causes adverse toxicity results is unpredictable. Prior art publication WO 2020 / 247160 indicates that for compounds based on the scaffolds of the present disclosure, the relationship between compound potency and unbound clearance, as well as exposure fold, is difficult to predict. Experiments with the compounds in WO 2020 / 247160 do not demonstrate a discernible structure-activity relationship (SAR) that can be used to predict which compounds have an appropriate effective exposure / unbound clearance relationship and will be better candidates for clinical development. WO 2020 / 247160 does not propose any means to improve the exposure fold of the disclosed compounds. In fact, the SARs from WO 2020 / 247160 did not support the exploration of 8F analogs of the compounds in WO 2020 / 247160 for any reason. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2020 / 247160 [Non-patent literature]

[0011] [Non-Patent Document 1] American Thoracic Society / European Respiratory Society, Am J Respir Crit Care Med.2003;168(7):818-900 [Non-patent document 2] Ogushi et al.J Clin Invest.1987;80(5):1366-74 [Non-patent document 3] Tanash et al.Int J Chron Obstruct Pulm Dis.2016;11:1663-9 [Non-patent document 4] Piitulainen and Tanash, COPD 2015;12(1):36-41 Summary of the Invention [Means for solving the problem]

[0012] One aspect of the present invention provides compounds that unexpectedly exhibit significantly superior compound quality compared to the compounds disclosed in WO2020 / 247160.The compounds of the present invention also unexpectedly exhibit enhanced exposure due to the substitution of fluorine for hydrogen at C8 of the core ring structure.Therefore, one aspect of the present disclosure provides compounds of formula I, which can be used for the treatment of AATD: [ka] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, wherein: Ring X is [ka] is selected from Ring Z is [ka] is selected from each R is independently selected from F, H, Cl, —CH3, —OCH3, and —OCD3; R 1 is H or F, R 2 teeth, [ka] During the ceremony, one of X, Y, and Z is -OH; one of X, Y, and Z is selected from —CH2CH3 and cyclopropyl; one of X, Y, and Z is selected from —CH2OCH3, —CH2CH2OCH3, —CH2OCH2CH3, —CH2O-cyclopropyl, and —CH2O-isopropyl; [ka] and R 3 is selected from H and —CH 3 .

[0013] Another aspect of the present disclosure is a compound of formula Ia, which may be used in the treatment of AATD: [ka] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, wherein: R is selected from F, H, Cl, CH3, and OCH3.

[0014] The compound of formula Ia unexpectedly and significantly reduced the predicted human dose prediction (as measured by the compound quality score) compared to prior art compounds sharing this same scaffold. In one embodiment, the compound of formula Ia can be used to treat AATD. [Table 1] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives.

[0015] Another aspect of the present disclosure is a compound of formula Ib, which may be used in the treatment of AATD: [ka] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, wherein: each R is independently selected from F, H, Cl, CH3, -OCH3, and -OCD3; R 1 is H or F, R 2 teeth, [ka] During the ceremony, one of X, Y, and Z is -OH; one of X, Y, and Z is selected from —CH2CH3 and cyclopropyl; one of X, Y, and Z is selected from —CH2OCH3, —CH2CH2OCH3, —CH2OCH2CH3, —CH2O-cyclopropyl, and —CH2O-isopropyl; [ka] and R 3 is selected from H and —CH 3 .

[0016] Formula Ib represents a compound of formula Ib-i, which may be used in the treatment of AATD: [ka] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, wherein: each R is independently selected from F, H, Cl, CH3, -OCH3, and -OCD3; R 1 is H or F, X, Y, and Z are defined as follows: one of X, Y, and Z is -OH; one of X, Y and Z is selected from -CH2CH3 and cyclopropyl; one of X, Y, and Z is selected from —CH2OCH3, —CH2CH2OCH3, —CH2OCH2CH3, —CH2O-cyclopropyl, and —CH2O-isopropyl; and R 3 is selected from H and CH3.

[0017] Formula Ib can also be used in the treatment of AATD, compounds of formula Ib-ii: [ka] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, wherein: each R is independently selected from F, H, Cl, CH3, -OCH3, and -OCD3; R 1 is H or F, R 3 is selected from H and —CH3, and Ring A is [ka] is selected from.

[0018] The compounds of formula Ib, including compounds of formula Ib-i and formula Ib-ii, have unexpectedly and significantly lower predicted effective doses in humans (compound quality) than prior art compounds sharing this same scaffold. In one embodiment, the compounds of formula Ib are compounds 6-57, which may be used in the treatment of AATD. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives. Formula Ib-i includes compounds 6-21, 33-42, 44-50, 52, 53, and 57, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives. Formula Ib-ii includes compounds 22-32, 43, 51, and 54-56, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives.

[0019] Another aspect of the present disclosure is a compound of formula Ic, which may be used in the treatment of AATD: [ka] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, wherein: Ring X is [ka] is selected from R 2 teeth, [ka] During the ceremony, one of X, Y, and Z is -OH; one of X, Y, and Z is -CH2CH3; one of X, Y, and Z is selected from —CH2OCH3 and —CH2OCH2CH3, and Ring Z is [ka] is selected from.

[0020] The compound of formula Ic unexpectedly and significantly lowered the predicted effective dose in humans (compound quality) than prior art compounds sharing this same scaffold. In one embodiment, the compound of formula Ib is selected from compounds 58-67, which may be used in the treatment of AATD. [Table 3] and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives.

[0021] Compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, are modulators of AAT activity. In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC20 activity of 0.10 μM or less when tested in an AAT functional assay, such as, for example, the MSD assay NL20-SI cell line described in Example 6. 50 In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC of 0.06 μM or less when tested in an AAT functional assay. 50 In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC of 0.04 μM or less when tested in an AAT functional assay. 50In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC of 0.02 μM or less when tested in an AAT functional assay. 50 It has.

[0022] In some embodiments, compounds of Formula I and Formula II, including compounds of Formula IIa and Formula IIb, and tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, have an unbound hepatocyte clearance value of 27 μL / min / million cells or less when tested in a human hepatocyte clearance assay, such as the hepatocyte clearance assay described in Example 6 below. In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, have an unbound hepatocyte clearance value of 16 μL / min / million cells or less when tested in a human hepatocyte clearance assay. In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and 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 of 12 μL / min / million cells or less when tested in a human hepatocyte clearance assay.

[0023] In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, have a compound quality score (potency in an AAT functional assay multiplied by unbound clearance) of less than 0.40. In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, have a compound quality score of less than 0.30.

[0024] In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives, are provided for use in treating AATD.

[0025] In one embodiment of the present disclosure, the compound of formula Ia is selected from compounds 1-5, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD. The compound of formula Ib is selected from compounds 6-57, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD. The compound of formula Ib-i is selected from compounds 6-21, 33-42, 44-50, 52, 53, and 57, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD. The compound of formula Ib-ii is selected from compounds 22-32, 43, 51, and 54-56, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD. The compound of formula Ic is selected from compounds 58-67, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD.

[0026] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formula Ia, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions can include a compound selected from compounds 1-5, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions can further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0027] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formula Ib, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions can include compounds selected from compounds 6-57 (e.g., compounds 6-21, 33-42, 44-50, 52, 53, and 57, and compounds 22-32, 43, 51, and 54-56), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions can further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0028] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of formula Ib-i, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions can comprise compounds 6-21, 33-42, 44-50, 52, 53, and 57, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of formula Ib-ii, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions can comprise compounds 22-32, 43, 51, and 54-56, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0029] In some embodiments, the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formula Ic, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, pharmaceutical compositions can include compounds selected from compounds 58-67, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions can further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0030] Another aspect of the present disclosure provides a method of treating AATD, comprising administering to a subject in need thereof at least one compound selected from compounds of Formula Ia, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering a compound selected from Compounds 1-5, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0031] Another aspect of the present disclosure provides a method of treating AATD, comprising administering to a subject in need thereof at least one compound selected from compounds of Formula Ib, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or pharmaceutical compositions comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering a compound selected from compounds 6-57, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0032] Another aspect of the present disclosure provides a method of treating AATD, comprising administering to a subject in need thereof at least one compound selected from compounds of Formula Ib-i, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or pharmaceutical compositions comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering a compound selected from compounds 6-21, 33-42, 44-50, 52, 53, and 57, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0033] Another aspect of the present disclosure provides a method of treating AATD, comprising administering to a subject in need thereof at least one compound selected from compounds of Formula Ib-ii, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or pharmaceutical compositions comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering a compound selected from compounds 22-32, 43, 51, and 54-56, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0034] Another aspect of the present disclosure provides a method of treating AATD, comprising administering to a subject in need thereof at least one compound selected from compounds of Formula Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or pharmaceutical compositions comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering a compound selected from compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0035] In some embodiments, the method of treatment comprises administering at least one additional active agent to a subject in need thereof, either in the same pharmaceutical composition as at least one compound selected from compounds of Formula Ia, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or in a separate composition. In some embodiments, the method comprises administering a compound selected from compounds 1-5, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition. In some embodiments, the subject in need of treatment carries a ZZ mutation. In some embodiments, the subject in need of treatment carries an SZ mutation.

[0036] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, at least one compound selected from compounds of Formula Ib, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, a compound selected from compounds 6-57, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the subject in need thereof carries a ZZ mutation. In some embodiments, the subject in need thereof carries an SZ mutation.

[0037] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, at least one compound selected from compounds of Formula Ib-i, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, at least one compound selected from compounds 6-21, 33-42, 44-50, 52, 53, and 57, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the subject in need thereof carries a ZZ mutation. In some embodiments, the subject in need thereof carries an SZ mutation.

[0038] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, at least one compound selected from compounds of Formula Ib-ii, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, a compound selected from compounds 22-32, 43, 51, and 54-56, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the subject in need thereof carries a ZZ mutation. In some embodiments, the subject in need thereof carries an SZ mutation.

[0039] In some embodiments, the method of treatment comprises administering at least one additional active agent to a subject in need thereof, either in the same pharmaceutical composition or in a separate composition, with at least one compound selected from compounds of Formula Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method comprises administering a compound selected from compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition. In some embodiments, the subject in need of treatment carries a ZZ mutation. In some embodiments, the subject in need of treatment carries an SZ mutation.

[0040] In some embodiments, the method of treatment comprises administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, with at least one compound selected from compounds of Formula I (including Formulas Ia, Ib, Ib-i, Ib-ii, and Ic), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein the additional active agent is alpha-1 antitrypsin protein (AAT) derived from plasma of healthy human donors. In some embodiments, the method comprises administering a compound selected from compounds 1-5, compounds 6-21, 33-42, 44-50, 52, 53, and 57, compounds 22-32, 43, 51, and 54-56, and compounds 58-67, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, wherein the additional active agent is alpha-1 antitrypsin protein (AAT) derived from plasma of a healthy human donor.

[0041] In some embodiments, methods of treatment include administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, with at least one compound selected from compounds of Formula I (including Formulas Ia, Ib, Ib-i, Ib-ii, and Ic), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein the additional active agent is recombinant AAT. In some embodiments, methods include administering to a subject in need thereof at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, with at least one additional active agent, wherein the additional active agent is recombinant AAT.

[0042] Also provided are methods for modulating AAT, comprising administering to a subject in need thereof at least one compound selected from the group consisting of compounds of Formula I (including Formulas Ia, Ib, Ib-i, Ib-ii, and Ic), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or pharmaceutical compositions comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method for modulating AAT comprises administering at least one compound selected from the group consisting of compounds 1-5, compounds 6-21, 33-42, 44-50, 52, 53, and 57, compounds 22-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or pharmaceutical compositions comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0043] Also provided are compounds of Formula I (including Formulas Ia, Ib, Ib-i, Ib-ii, and Ic), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy. In some embodiments, a compound selected from compounds 1-5, compounds 6-21, 33-42, 44-50, 52, 53, and 57, compounds 22-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.

[0044] Also provided are pharmaceutical compositions comprising a compound of Formula I (including Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) for use in therapy. In some embodiments, pharmaceutical compositions are provided comprising a compound selected from Compounds 1-5, Compounds 6-21, 33-42, 44-50, 52, 53, and 57, Compounds 22-32, 43, 51, and 54-56, and Compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy. [Brief explanation of the drawings]

[0045] [Figure 1] FIG. 1 shows the XRPD diffractogram of Compound 5 free form monohydrate Form A. [Figure 2] FIG. 2 shows the TGA thermogram of Compound 5 free form monohydrate Form A. [Figure 3] FIG. 3 shows the DSC thermogram of Compound 5 free form monohydrate Form A. [Figure 4] FIG. 4 shows the solid-state 13C NMR spectrum of Compound 5 free form monohydrate Form A. [Figure 5] FIG. 5 shows the solid-state 19F NMR spectrum of Compound 5 free form monohydrate Form A. [Figure 6] FIG. 6 shows the XRPD diffractogram of Compound 5 free form Form A. [Figure 7] FIG. 7 shows the TGA thermogram of Compound 5 free form Form A. [Figure 8] FIG. 8 shows the DSC thermogram of Compound 5 free form Form A. [Figure 9] FIG. 9 shows the solid-state 13C NMR spectrum of Compound 5 free form Form A. [Figure 10] FIG. 10 shows the solid-state 19F NMR spectrum of Compound 5 free form Form A. [Figure 11]FIG. 11 shows the XRPD diffractogram of Compound 5 free form Form B. [Figure 12] FIG. 12 shows the TGA thermogram of Compound 5 free form Form B. [Figure 13] FIG. 13 shows the DSC thermogram of Compound 5 free form Form B. [Figure 14] FIG. 14 shows the XRPD diffractogram of Compound 5 free form NPA solvate Form A. [Figure 15] FIG. 15 shows the TGA thermogram of Compound 5 free form NPA solvate Form A. [Figure 16] FIG. 16 shows the DSC thermogram of Compound 5 free form NPA solvate Form A. [Figure 17] FIG. 17 shows the XRPD diffractogram of Compound 5 free form EtOH solvate Form A. [Figure 18] FIG. 18 shows the TGA thermogram of Compound 5 free form EtOH solvate Form A. [Figure 19] FIG. 19 shows the DSC thermogram of Compound 5 free form EtOH solvate Form A. [Figure 20] FIG. 20 shows the solid-state 13C NMR spectrum of Compound 5 free form EtOH solvate Form A. [Figure 21] FIG. 21 shows the solid-state 19F NMR spectrum of Compound 5 free form EtOH solvate Form A. [Figure 22] FIG. 22 shows the XRPD diffractogram of Compound 5 free form MeOH solvate hydrate Form A. [Figure 23] FIG. 23 shows the TGA thermogram of Compound 5 free form MeOH solvate hydrate Form A. [Figure 24] FIG. 24 shows the DSC thermogram of Compound 5 free form MeOH solvate hydrate Form A. [Figure 25] FIG. 25 shows the solid-state 13C NMR spectrum of Compound 5 free form MeOH solvate hydrate Form A. [Figure 26]FIG. 26 shows the solid-state 19F NMR spectrum of Compound 5 free form MeOH solvate hydrate Form A. [Figure 27] FIG. 27 shows the XRPD diffractogram of Compound 5 free form DCM solvate Form A. [Figure 28] FIG. 28 shows the TGA thermogram of Compound 5 free form DCM solvate Form A. [Figure 29] FIG. 29 shows the solid-state 13C NMR spectrum of Compound 5 free form DCM solvate Form A. [Figure 30] FIG. 30 shows the solid-state 19F NMR spectrum of Compound 5 free form DCM solvate Form A. [Figure 31] FIG. 31 shows the XRPD diffractogram of Compound 5 free form EtOAc heptane solvate Form A. [Figure 32] FIG. 32 shows the TGA thermogram of Compound 5 free form EtOAc heptane solvate Form A. [Figure 33] FIG. 33 shows the DSC thermogram of Compound 5 free form EtOAc heptane solvate Form A. [Figure 34] FIG. 34 shows the solid-state 13C NMR spectrum of Compound 5 free form EtOAc heptane solvate Form A. [Figure 35] FIG. 35 shows the solid-state 19F NMR spectrum of Compound 5 free form EtOAc heptane solvate Form A. [Figure 36] FIG. 36 shows the XRPD diffractogram of Compound 3 free form Form A. [Figure 37] FIG. 37 shows the TGA thermogram of Compound 3 free form Form A. [Figure 38] FIG. 38 shows the DSC thermogram of Compound 3 free form Form A. [Figure 39] FIG. 39 shows the solid-state 13C NMR spectrum of Compound 3 free form Form A. [Figure 40] FIG. 40 shows the solid-state 19F NMR spectrum of Compound 3 free form Form A. [Figure 41]FIG. 41 shows the XRPD diffractogram of Compound 3 free form Form B. [Figure 42] FIG. 42 shows the TGA thermogram of Compound 3 free form Form B. [Figure 43] FIG. 43 shows the DSC thermogram of Compound 3 free form Form B. [Figure 44] FIG. 44 shows the solid-state 13C NMR spectrum of Compound 3 free form Form B. [Figure 45] FIG. 45 shows the solid-state 19F NMR spectrum of Compound 3 free form Form B. [Figure 46] FIG. 46 shows the XRPD diffractogram of Compound 3 free form hydrate Form A. [Figure 47] FIG. 47 shows the TGA thermogram of Compound 3 free form hydrate Form A. [Figure 48] FIG. 48 shows the DSC thermogram of Compound 3 free form hydrate Form A. [Figure 49] FIG. 49 shows the XRPD diffractogram of Compound 3 free form hydrate Form B. [Figure 50] FIG. 50 shows the TGA thermogram of Compound 3 free form hydrate Form B. [Figure 51] FIG. 51 shows the DSC thermogram of Compound 3 free form hydrate Form B. [Figure 52] FIG. 52 shows the XRPD diffractogram of Compound 3 free form hydrate Form C. [Figure 53] FIG. 53 shows the TGA thermogram of Compound 3 free form hydrate Form C. [Figure 54] FIG. 54 shows the DSC thermogram of Compound 3 free form hydrate Form C. [Figure 55] FIG. 55 shows the XRPD diffractogram of Compound 3 free form MTBE solvate Form A. [Figure 56] FIG. 56 shows the TGA thermogram of Compound 3 free form MTBE solvate Form A. [Figure 57] FIG. 57 shows the DSC thermogram of Compound 3 free form MTBE solvate Form A. [Figure 58] FIG. 58 shows the solid-state 13C NMR spectrum of Compound 3 free form MTBE solvate Form A. [Figure 59] FIG. 59 shows the solid-state 19F NMR spectrum of Compound 3 free form MTBE solvate Form A. [Figure 60] FIG. 60 shows the XRPD diffractogram of Compound 4 free form Form A. [Figure 61] FIG. 61 shows the TGA thermogram of Compound 4 free form Form A. [Figure 62] FIG. 62 shows the DSC thermogram of Compound 4 free form Form A. [Figure 63] FIG. 63 shows the solid-state 13C NMR spectrum of Compound 4 free form Form A. [Figure 64] FIG. 64 shows the solid-state 19F NMR spectrum of Compound 4, free form Form A. [Figure 65] FIG. 65 shows the XRPD diffractogram of Compound 4 free form Form B. [Figure 66] FIG. 66 shows the TGA thermogram of Compound 4 free form Form B. [Figure 67] FIG. 67 shows the DSC thermogram of Compound 4 free form Form B. [Figure 68] FIG. 68 shows the solid-state 13C NMR spectrum of Compound 4 free form B. [Figure 69] FIG. 69 shows the solid-state 19F NMR spectrum of Compound 4 free form B. [Figure 70] FIG. 70 shows the XRPD diffractogram of Compound 4 free form Form C. [Figure 71] FIG. 71 shows the TGA thermogram of Compound 4 free form Form C. [Figure 72] FIG. 72 shows the DSC thermogram of Compound 4 free form Form C. [Figure 73] FIG. 73 shows the XRPD diffractogram of Compound 4 free form Form D. [Figure 74]FIG. 74 shows the TGA thermogram of Compound 4 free form Form D. [Figure 75] FIG. 75 shows the DSC thermogram of Compound 4 free form Form D. [Figure 76] FIG. 76 shows the solid-state 13C NMR spectrum of Compound 4 free form Form D. [Figure 77] FIG. 77 shows the solid-state 19F NMR spectrum of Compound 4 free form Form D. [Figure 78] FIG. 78 shows the XRPD diffractogram of Compound 4 free form hydrate Form A. [Figure 79] FIG. 79 shows the TGA thermogram of Compound 4 free form hydrate Form A. [Figure 80] FIG. 80 shows the DSC thermogram of Compound 4 free form hydrate Form A. [Figure 81] FIG. 81 shows the solid-state 13C NMR spectrum of Compound 4 free form hydrate Form A. [Figure 82] FIG. 82 shows the solid-state 19F NMR spectrum of Compound 4 free form hydrate Form A. [Figure 83] FIG. 83 shows the XRPD diffractogram of Compound 4 free form hydrate Form B. [Figure 84] FIG. 84 shows the TGA thermogram of Compound 4 free form hydrate Form B. [Figure 85] FIG. 85 shows the DSC thermogram of Compound 4 free form hydrate Form B. [Figure 86] FIG. 86 shows the XRPD diffractogram of Compound 4 free form hydrate Form C. [Figure 87] FIG. 87 shows the DSC thermogram of Compound 4 free form hydrate Form C. DETAILED DESCRIPTION OF THE INVENTION

[0046] I. Definition As used herein, the term "AAT" refers to alpha-1 antitrypsin or variants thereof, including, but not limited to, AAT gene variants such as the Z variant. As used herein, "Z-AAT" refers to an AAT variant having a Z variant.

[0047] As used herein, "mutation" can refer to a mutation in the SERPINA1 gene (the gene encoding AAT) or the effect of an alteration 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 a nucleotide within the gene, generally results in a mutation in the AAT protein translated from that gene.

[0048] As used herein, a patient who is "homozygous" for a particular genetic mutation has the same mutation on each allele.

[0049] As used herein, a patient with the PiZZ genotype is a patient who is homozygous for the Z mutation in the AAT protein.

[0050] The term "AATD" as used herein means alpha-1 antitrypsin deficiency, an inherited disorder characterized by low circulating levels of AAT.

[0051] The term "compound," when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variation may exist among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom shown also includes lesser amounts of isotopic substitutions having a hydrogen atom at one or more of the designated deuterium positions in the structure. The relative amounts of such isotopic substitutions in the compounds of the present disclosure will depend on several factors, including the isotopic purity of the reagents used to make the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as noted above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitution overall 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.

[0052] The compounds of the present disclosure can be optionally substituted with one or more substituents. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally," refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be either the same or different at all positions. Combinations of substituents envisioned by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0053] The term "isotopically modified" refers to a species whose chemical structure differs from a specific compound of this disclosure only in its isotopic composition. 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, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of carbon by C, are within the scope of this disclosure.

[0054] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms of the structure, e.g., geometric (or conformational) isomers, such as racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the present compounds are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds of this disclosure are within the scope of this disclosure.

[0055] 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 interchangeable due to migration of atoms or groups within the molecule.

[0056] "Stereoisomer" refers to both enantiomers and diastereomers.

[0057] It is to be understood that certain compounds of the present invention may exist as separate stereoisomers or enantiomers and / or mixtures of such stereoisomers or enantiomers. As used in the chemical structures disclosed herein, a "wedge" to a stereoatom [ka] or "hash" [ka] The bond denotes a chiral center of known absolute stereochemistry (i.e., one stereoisomer). As used in the chemical structures disclosed herein, a "wavy" bond to a stereoatom [ka] indicates that the compound was isolated as a mixture of isomers (e.g., a mixture of syn and / or anti isomers, or a racemic mixture).

[0058] As used in the chemical structures disclosed herein, a "wavy" bond to a double bond carbon [ka] indicates a mixture of E / Z isomers. When used in the chemical structures disclosed herein, [ka] A ("straight") bond indicates where a mixture (e.g., a racemate or concentrate) exists. As used herein, two bonds to a double bond carbon [ka] A ("straight") bond indicates that the double bond possesses E / Z stereochemistry as drawn. If the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. In some instances, the absolute configuration of some stereocenters is known, while only the relative configuration of other stereocenters is known. In these instances, the stereochemical designator associated with a stereocenter of known absolute configuration is represented by an asterisk ( * ), for example, (R * )- and (S * )-, while stereochemical designators associated with stereocenters of unknown absolute configuration are not so marked. Unmarked stereochemical designators associated with stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters with respect to other stereocenters of unknown absolute configuration, but not necessarily with respect to stereocenters of known absolute configuration.

[0059] When used in the chemical structures disclosed herein, [ka] (a "wavy" line perpendicular to the "straight" bond to group "A") indicates that group "A" is a substituent whose point of attachment is at the terminus of the bond that terminates in the "wavy" line.

[0060] As used herein, the prefix "rac-" when used in reference to a chiral compound refers to a racemic mixture of the compound.

[0061] As used herein, the prefix "rel-", when used in reference to a chiral compound, refers to a single enantiomer of unknown absolute configuration. In compounds bearing the "rel-" prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily the absolute stereochemistry of the compound. If the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided. In some instances, the absolute configuration of some stereocenters is known, while only the relative configuration of other stereocenters is known. In these instances, the stereochemical designator associated with a stereocenter of known absolute configuration is marked with an asterisk ( * ), for example, (R * )- and (S * )-, while stereochemical designators associated with stereocenters of unknown absolute configuration are not so marked. Unmarked stereochemical designators associated with stereocenters of unknown absolute configuration reflect the relative stereochemistry of those stereocenters with respect to other stereocenters of unknown absolute configuration, but not necessarily with respect to stereocenters of known absolute configuration.

[0062] Certain compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended, even if only a single tautomeric structure is shown. For example, a description of compound A is understood to include its tautomeric form, compound B, and vice versa, as well as mixtures thereof. [ka] Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0063] Unless otherwise specified, structures depicted herein are also meant to include all isomeric forms of the structure, for example, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds of the present disclosure are within the scope of the present disclosure.

[0064] As used herein, a "deuterated derivative" has the same chemical structure as a reference compound, but 2 A deuterated methyl group is a compound having one or more hydrogen atoms replaced by a deuterium atom, denoted as "H" or "D." For example, a deuterated methyl group is -CD3, [ka] It will be appreciated that some variation in natural isotopic abundance will occur in synthesized compounds depending on the origin of the chemicals used in their synthesis. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Thus, unless otherwise specified, when reference is made to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen is replaced with deuterium well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, deuterated derivatives of the present 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 least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0065] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0066] As used herein, the term "alkyl" refers to a straight-chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that may be fully saturated or contain one or more saturated units without being fully aromatic. Unless otherwise specified, alkyl groups contain 1-12 alkyl carbon atoms. In some embodiments, alkyl groups contain 1-10 aliphatic carbon atoms. In other embodiments, alkyl groups contain 1-8 aliphatic carbon atoms. In still other embodiments, alkyl groups contain 1-6 alkyl carbon atoms, in other embodiments, alkyl groups contain 1-4 alkyl carbon atoms, and in still other embodiments, alkyl groups contain 1-3 alkyl carbon atoms and 1-2 alkyl carbon atoms.

[0067] As used herein, the term "heteroalkyl" refers to an aliphatic group in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroalkyl groups can be substituted or unsubstituted, branched or unbranched.

[0068] As used herein, the term "alkenyl" means a straight-chain (ie, linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more carbon-carbon double bonds.

[0069] The terms "cycloalkyl," "cyclic alkyl," "carbocyclyl," or "carbocycle" refer to fused, spirocyclic, or bridged monocyclic C 3~9 hydrocarbon, or fused, spirocyclic, or bridged bicyclic or tricyclic C which may be fully saturated or contain one or more saturated units, but are not fully aromatic; 8-14 It refers to a hydrocarbon, where any individual ring of the aforementioned bicyclic ring system has 3 to 9 members. Typically, cycloalkyls are fully saturated, while carbocyclyls may contain one or more units of unsaturation but are not aromatic. In some embodiments, cycloalkyl or carbocyclic groups contain 3 to 12 carbon atoms. In some embodiments, cycloalkyl or carbocyclic groups contain 3 to 8 carbon atoms. In some embodiments, cycloalkyl or carbocyclic groups contain 3 to 6 carbon atoms.

[0070] As used herein, the terms "heterocycle," "heterocyclyl," or "heterocyclic" refer to a fused, spirocyclic, or bridged non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are heteroatoms. In some embodiments, a "heterocycle," "heterocyclyl," or "heterocyclic" group has 3 to 14 ring members in which one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and silicon, and each ring in the system contains 3 to 9 ring members. In some embodiments, a heterocyclyl contains 3 to 12 ring atoms. In some embodiments, a heterocyclyl contains 3 to 8 ring atoms. In some embodiments, a heterocyclyl contains 3 to 6 ring atoms.

[0071] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, e.g., N(3,4-dihydro-2H-pyrrolyl), NH (in pyrrolidinyl), or NR + (including the case of N-substituted pyrrolidinyl).

[0072] As used herein, the term "alkoxy" refers to an alkyl group, as previously defined, in which one carbon atom of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is connected between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, fused, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl.

[0073] The terms "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" refers to F, Cl, Br, or I. In some embodiments, halogen is selected from F, Cl, and Br. Examples of haloalkyl include -CHF, -CHF, -CF, -CF-, or perhaloalkyl, such as -CFCF.

[0074] As used herein, "=O" refers to an oxo group.

[0075] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0076] As used herein, a "hydroxy" group refers to an --OH group.

[0077] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having delocalized pi orbitals consisting of [4n+2]p orbitals, where n is an integer ranging from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0078] The term "aryl" refers to monocyclic, bicyclic, and tricyclic ring systems in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members, for a total of 5 to 14 ring members. In some embodiments, an aryl contains 6 or 10 carbon atoms. Non-limiting examples of aryl groups include phenyl rings.

[0079] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems in which at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members, for a total of 5 to 10 ring members. In some embodiments, heteroaryl contains 6 or 10 ring atoms.

[0080] Examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butylcarbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzylcarbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods for adding (a process generally referred to as "protecting") and removing (a process generally referred to as "deprotecting") such amine protecting groups are well known in the art and can be found, for example, in P.J. Kocienski, Protecting Groups, Thieme, 1994, and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which are incorporated herein by reference in their entireties.

[0081] Examples of suitable solvents that may be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0082] Examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0083] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds. A salt of a compound of the present disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0084] As used herein, the term "pharmaceutically acceptable" 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, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0085] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-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, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, 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-1,6-diol ... Included are oate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, 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 mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0086] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4

[0033] Suitable non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0087] As used herein, the term "pharmaceutically acceptable solid form" refers to a solid form of a reference compound of the present disclosure, which solid form (e.g., crystalline free form, crystalline salt, crystalline salt solvate, crystalline salt hydrate, and amorphous form) of a reference compound of the present disclosure is non-toxic and suitable for use in pharmaceutical compositions.

[0088] As used herein, the term "amorphous" refers to a solid material that lacks long-range order in the position of its molecules. Amorphous solids are generally glasses or supercooled liquids in which the molecules are randomly arranged, with no clearly defined arrangement, e.g., no 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 a distinct melting point. Instead, they typically exhibit a glass transition temperature that indicates the transition from a glassy amorphous state to a supercooled liquid amorphous state upon heating. For example, an amorphous material is a solid material that does not have sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. See US2004 / 0006237 for a comparison of XRPD of amorphous and crystalline materials. In some embodiments, a solid material may comprise an amorphous compound; for example, the solid material may be characterized by a lack of sharp, characteristic crystalline peaks in its XRPD spectrum (i.e., the material is amorphous, but not crystalline, as determined by XRPD). Instead, one or several broad peaks (e.g., halos) may be observed in the XRPD pattern of the material. See US2004 / 0006237 for a representative comparison of XRPD of amorphous and crystalline materials. A solid material comprising an amorphous compound may be characterized, for example, by a broader temperature range of melting of the solid material compared to the melting range of a pure crystalline solid. Other techniques, such as, for example, solid-state NMR, may also be used to characterize crystalline or amorphous forms.

[0089] As used herein, the terms "crystalline form," "crystalline form," and "form" refer interchangeably to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified by, for example, powder X-ray diffraction (XRPD), single crystal X-ray diffraction, and solid-state nuclear magnetic resonance (e.g., 13 C. 19 F,15 N, and 31 The compounds can be identified and distinguished from one another by one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and SSNMR. Accordingly, as used herein, the terms "crystalline Compound 5 free form Form A" and "crystalline Compound 5 free form NPA solvate Form A" refer to compounds that can be identified and distinguished from one another by one or more characterization techniques, including, for example, XRPD, single crystal X-ray diffraction, and SSNMR. 13 "C" refers to unique crystalline forms that can be identified and distinguished from one another by one or more characterization techniques, including C SSNMR. In some embodiments, novel crystalline forms are characterized by a powder X-ray diffractogram having one or more signals at one or more specified degrees two-theta (°2θ) values.

[0090] As used herein, the term "free form" refers to the non-ionized form of a compound in the solid state. Examples of free forms include the free base and the free acid.

[0091] As used herein, the term "neat form" refers to the unsolvated and unhydrated free form of a compound in the solid state.

[0092] As used herein, the term "solvate" refers to a crystalline form that contains one or more molecules of a compound of the present disclosure and one or more molecules of a solvent incorporated into a crystal lattice in a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is referred to as a "hydrate." A "solvate hydrate" refers to a solid form that has been scientifically determined to contain both a solvent and water, but it has not yet been determined whether the solvent and water are present in one crystal lattice or in many crystal lattices.

[0093] In some embodiments, the solid material may comprise a mixture of crystalline and amorphous solids. A solid material comprising an amorphous compound may also comprise, for example, up to 30% crystalline solids. In some embodiments, a solid material prepared to comprise an amorphous compound may also comprise, for example, up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solids. In embodiments where the solid material comprises a mixture of crystalline and amorphous solids, characterization data, such as XRPD, may include indicators of both crystalline and amorphous solids. In some embodiments, the crystalline forms of the present disclosure may contain up to 30% amorphous compound. In some embodiments, crystalline preparations of the reference compounds of the present disclosure may contain up to 25%, 20%, 15%, 10%, 5%, or 2% amorphous solids.

[0094] As used herein, the term "substantially amorphous" refers to a solid material that has little or no long-range order at the molecular level. For example, a substantially amorphous material has less than 15% crystallinity (e.g., less than 10% crystallinity, or less than 5% crystallinity, or less than 2% crystallinity). Note that the term "substantially amorphous" also includes the descriptor "amorphous," which refers to a material that has no crystallinity (0%).

[0095] As used herein, the term "substantially crystalline" refers to a solid material having few or no amorphous molecules. For example, a substantially crystalline material has less than 15% amorphous molecules (e.g., less than 10% amorphous molecules, less than 5% amorphous molecules, or less than 2% amorphous molecules). Note that the term "substantially crystalline" also includes the descriptor "crystalline," which refers to a material that is 100% crystalline in form.

[0096] As used herein, a crystalline form is "substantially pure" when the crystalline form accounts for 90% or more by weight of the sum of all solid forms in a sample as determined by methods according to the art, such as quantitative XRPD. In some embodiments, a solid form is "substantially pure" when it accounts for 95% or more by weight of the sum of all solid forms in a sample. In some embodiments, a solid form is "substantially pure" when it accounts for 99% or more by weight of the sum of all solid forms in a sample.

[0097] As used herein, the term "ambient conditions" refers to room temperature, open air conditions, and uncontrolled humidity conditions. As used herein, the terms "room temperature" and "ambient temperature" refer to temperatures between 15°C and 30°C.

[0098] As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," "XRPD pattern," and "XRPD spectrum" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) against signal intensity (on the ordinate).

[0099] "Signal" or "peak," as used herein, refers to a point on an XRPD pattern where the intensity, measured in counts, is locally maximum. An XRPD peak is identified by its angular value, measured in degrees two-theta (° 2θ), shown on the abscissa of an X-ray powder diffractogram, which may be expressed, for example, as "a signal at . . . degrees two-theta," "a signal with a two-theta value . . .," and / or "a signal with a two-theta value that is at least . . . selected from . . . ."

[0100] The repeatability of the measured angle values ​​is within ±0.2 degrees 2-theta, i.e., the angle value can be the recited angle value +0.2 degrees 2-theta, angle value -0.2 degrees 2-theta, or any value between those two endpoints (angle value +0.2 degrees 2-theta and angle value -0.2 degrees 2-theta).

[0101] Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent to the naked eye, for example. Indeed, those skilled in the art will recognize that several art-recognized methods are capable of and suitable for determining whether a signal is present by pattern analysis, such as Rietveld refinement.

[0102] The terms "signal intensity" and "peak intensity" refer interchangeably to relative signal intensities within a given powder X-ray diffractogram. Factors that can affect relative signal intensity or peak intensity include sample thickness and preferred orientation (e.g., crystalline particles are not randomly distributed).

[0103] As used herein, a powder X-ray diffractogram is "substantially similar to that in [a particular] figure" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the signals in the two diffractograms overlap. In determining "substantially similar," one skilled in the art will understand that variations in intensity and / or signal position may exist in XRPD diffractograms even for the same crystalline form. Thus, one skilled in the art will understand that, generally, the maximum value of a signal (in degrees 2-theta units) in an XRPD diffractogram means that the value is specified as ±0.2 degrees 2-theta of that reported value, which is an art-recognized variance.

[0104] As used herein, the term "TGA" refers to thermogravimetric analysis and "TGA / DSC" refers to thermogravimetric analysis and differential scanning calorimetry.

[0105] As used herein, the term "DSC" refers to the analytical method of differential scanning calorimetry.

[0106] 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).

[0107] As used herein, the term "glass transition temperature" or "Tg" refers to the temperature above which a hard, brittle "glassy" amorphous solid becomes viscous or rubbery.

[0108] As used herein, the terms "melting point," "melting temperature," and "Tm" refer to the temperature at which the solid and liquid states are in equilibrium.

[0109] As used herein, the term "compound quality" refers to the potency of a compound multiplied by the unbound clearance of the compound (x) as measured using the assay described in Example 6.

[0110] The term "unbound clearance" refers to the unbound intrinsic clearance in hepatocytes (unbound CLint), the intrinsic clearance a drug would have in the absence of protein binding. Unbound CLint = CLint,hep / fu,hep, where CLint,hep is the intrinsic clearance in hepatocytes and fu,hep is the unbound fraction in hepatocytes.

[0111] As used herein, "exposure fold" refers to the evaluation of relative compound exposure in toxicity testing. The exposure fold is calculated by comparing the exposure (AUC) achieved at the toxic species with the target effective exposure at steady state (AUCss). A larger exposure fold provides the opportunity to explore higher doses compared to the effective concentration in clinical development. However, the exposure that results in adverse toxicity outcomes is unpredictable.

[0112] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0113] The terms "effective dose," "effective amount," "therapeutically effective dose," and "therapeutically effective amount" are used interchangeably herein and refer to the amount of compound for which it is administered that produces the desired effect (e.g., amelioration of AATD or AATD symptoms, reduction in the severity of AATD or AATD symptoms, and / or reduction in the incidence or prevalence of AATD or AATD symptoms). The exact amount of an effective dose will depend on the purpose of treatment and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0114] As used herein, the term "treatment" and its cognates (e.g., "treat," "treating") refer to an improvement in AATD or a symptom thereof in a subject, a delay in the onset of AATD or a symptom thereof in a subject, or a reduction in the severity of AATD or a symptom thereof in a subject. As used herein, "treatment" and its cognates include, but are not limited to, improved liver and / or spleen function, reduction in macula, improved lung function, reduction in lung disease and / or lung exacerbations (e.g., emphysema), reduction in skin disease (e.g., necrotizing panniculitis), increased growth in children, improved appetite, and reduced fatigue. Improvement or reduction in severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0115] The terms "about" and "approximately," when used in connection with a temperature, peak, signal, dose, amount, or weight percent of a component of a composition or dosage form, include a particular temperature, peak, signal, dose, amount, or weight percent value, or a range of doses, amounts, or weight percents, that would be recognized by one of skill in the art as providing an equivalent pharmacological effect to that obtained from the particular temperature, peak, signal, dose, amount, or weight percent. Typically, the term "about" refers to a variation of up to 10%, up to 5%, or up to 2% of the stated value.

[0116] Compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered once daily, twenty-one times daily, or three times daily for the treatment of AATD. In some embodiments, any one or more compounds are selected from Compounds 1-67 (e.g., Compounds 1-5, Compounds 6-21, 33-42, 44-50, 52, 53, and 57, Compounds 22-32, 43, 51, and 54-56, and Compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, compounds of Formula Ia, Ib, Ib-i, Ic, and Ic can be administered once daily, twenty-one times daily, or three times daily for the treatment of AATD. At least one compound selected from the compounds of Formula I, including compounds b-ii, and Ic, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, compounds 1-67 (e.g., compounds 1-5, compounds 6-21, 33-42, 44-50, 52, 53, and 57, compounds 22-32, 43, 51, and 54-56, and compounds A compound selected from compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound selected from compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, a compound selected from compounds 1-67 (e.g., compounds 1-5, compounds 6-21, 33-42, 44-50, 52, 53, and 57, compounds 22-32, 43, 51, and 54-56, and compounds 58-67), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily.In some embodiments, at least one compound selected from compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily. In some embodiments, a compound selected from compounds 1-67 (e.g., compounds 1-5, compounds 6-21, 33-42, 44-50, 52, 53, and 57, compounds 22-32, 43, 51, and 54-56, and compounds 58-67), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily.

[0117] Any one or more of the compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, can 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 the compounds is selected from compounds 1-67 (e.g., compounds 1-5, compounds 6-21, 33-42, 44-50, 52, 53, and 57, compounds 22-32, 43, 51, and 54-56, and compounds 58-67), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0118] As used herein, "AAT augmentation therapy" refers to the use of alpha-1 antitrypsin protein (AAT) from the plasma of healthy human donors to enhance (increase) circulating alpha-1 antitrypsin levels in the blood. "AAT replacement therapy" refers to the administration of recombinant AAT.

[0119] 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 a compound of Formula I, including Formula Ia, Ib, Ib-i, Ib-ii, and Ic, a tautomer of such a compound, a deuterated derivative of such a compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing, is administered once a day, twenty-one times a day, or three times a day. 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, or 400 mg to 600 mg of a compound selected from Compounds 1-67 (e.g., Compounds 1-5, Compounds 6-21, 33-42, 44-50, 52, 53, and 57, Compounds 22-32, 43, 51, and 54-56, and Compounds 58-67) is administered once a day, 21 times a day, or three times a day.

[0120] Those skilled in the art will recognize that when a quantity of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. Note that the disclosed amounts of compounds, tautomers, deuterated derivatives, and pharmaceutically acceptable salts are based on the free base form of the reference compound. For example, "10 mg of at least one compound selected from compounds of Formula Ia, Ib, or Ic and pharmaceutically acceptable salts thereof" includes 10 mg of the compound of Formula Ia, Ib, or Ic and a concentration of a pharmaceutically acceptable salt of the compound of Formula Ia, Ib, or Ic equivalent to 10 mg of the compound of Formula Ia, Ib, or Ic.

[0121] Reference herein to methods of treatment (e.g., methods of treating AATD) using one or more compounds (e.g., compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) also refers to, e.g., compounds for use in methods of treating AATD. one or more compounds (e.g., compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds), and / or For example, it should be understood that this should be construed as a reference to the use of one or more compounds (e.g., compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) in the manufacture of a medicament for treating AATD.

[0122] II. Solid Forms of Compounds with Improved Compound Quality Values Non-limiting embodiments of the present disclosure include the following. 1. Substantially crystalline Compound 5 free form monohydrate Form A. [ka] 2. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by one or more XRPD signals selected from 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta. 3. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by two or more XRPD signals selected from 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta. 4. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by XRPD signals at 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta. 5. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by (a) one or more XRPD signals selected from 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 8.2±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 23.2±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.0±0.2 degrees two-theta. 6. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by (a) one or more XRPD signals selected from 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 8.2±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 23.2±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.0±0.2 degrees two-theta. 7. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by (a) one or more XRPD signals selected from 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 8.2±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 23.2±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.0±0.2 degrees two-theta. 8. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by (a) one or more XRPD signals selected from 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 8.2±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 23.2±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.0±0.2 degrees two-theta. 9. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by (a) one or more XRPD signals selected from 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta, and (b) XRPD signals at 8.2±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 23.2±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.0±0.2 degrees two-theta. 10. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by (a) two or more XRPD signals selected from 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta, and (b) XRPD signals at 8.2±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 23.2±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.0±0.2 degrees two-theta. 11. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by (a) XRPD signals at 12.1±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 19.8±0.2 degrees two-theta, and (b) XRPD signals at 8.2±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, 23.2±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.0±0.2 degrees two-theta. 12. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 3.3% from ambient temperature to about 160°C. 13. 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 141°C and 163°C. 14. having one or more signals selected from 140.9±0.2 ppm, 131.0±0.2 ppm, 128.1±0.2 ppm, 124.8±0.2 ppm, 59.6±0.2 ppm, and 7.6±0.2 ppm 13 The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by a C CPMAS. 15. Two or more signals selected from 140.9±0.2 ppm, 131.0±0.2 ppm, 128.1±0.2 ppm, 124.8±0.2 ppm, 59.6±0.2 ppm, and 7.6±0.2 ppm 13 The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by a C CPMAS. 16. Three or more signals selected from 140.9±0.2 ppm, 131.0±0.2 ppm, 128.1±0.2 ppm, 124.8±0.2 ppm, 59.6±0.2 ppm, and 7.6±0.2 ppm 13 The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by a C CPMAS. 17. Four or more signals selected from 140.9±0.2 ppm, 131.0±0.2 ppm, 128.1±0.2 ppm, 124.8±0.2 ppm, 59.6±0.2 ppm, and 7.6±0.2 ppm 13 The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by a C CPMAS. 18. Five or more signals selected from 140.9±0.2 ppm, 131.0±0.2 ppm, 128.1±0.2 ppm, 124.8±0.2 ppm, 59.6±0.2 ppm, and 7.6±0.2 ppm. 13The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by a C CPMAS. 19. with signals of 140.9±0.2 ppm, 131.0±0.2 ppm, 128.1±0.2 ppm, 124.8±0.2 ppm, 59.6±0.2 ppm, and 7.6±0.2 ppm. 13 The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by a C CPMAS. 20. having one or more signals selected from -134.4±0.2 ppm, -136.9±0.2 ppm, -143.5±0.2 ppm, and -146.8±0.2 ppm 19 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by F MAS. twenty one. Two or more signals selected from -134.4±0.2 ppm, -136.9±0.2 ppm, -143.5±0.2 ppm, and -146.8±0.2 ppm 19 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by F MAS. twenty two. Three or more signals selected from -134.4±0.2 ppm, -136.9±0.2 ppm, -143.5±0.2 ppm, and -146.8±0.2 ppm 19 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by F MAS. twenty three. with signals of -134.4±0.2 ppm, -136.9±0.2 ppm, -143.5±0.2 ppm, and -146.8±0.2 ppm 19 2. The substantially crystalline Compound 5 free form monohydrate Form A of embodiment 1, characterized by F MAS. twenty four. Cu K α2. The substantially crystalline Compound 5 free form monohydrate Form A according to embodiment 1, characterized by a monoclinic crystal system, P21 space group, and unit cell dimensions as measured at 100 K using a Bruker diffractometer equipped with a CMOS detector with radiation (λ=1.54178 Å) and the following properties: [Table 4] twenty five. Cu K α 2. The substantially crystalline Compound 5 free form monohydrate Form A according to embodiment 1, characterized by a monoclinic crystal system, P21 space group, and unit cell dimensions as measured at 293 K using a Bruker diffractometer equipped with a CMOS detector with radiation (λ=1.54178 Å) and the following properties: [Table 5] 26. Substantially crystalline Compound 5 free form Form A. [ka] 27. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by an XRPD signal of 3.3±0.2 degrees two-theta, or 8.1±0.2 degrees two-theta. 28. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by XRPD signals at 3.3±0.2 degrees two-theta and 8.1±0.2 degrees two-theta. 29. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by XRPD signals at 3.3±0.2 degrees two-theta, 8.1±0.2 degrees two-theta, and 10.7±0.2 degrees two-theta. 30. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by (a) an XRPD signal at 3.3±0.2 degrees two-theta or 8.1±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 3.0±0.2 degrees two-theta, 7.1±0.2 degrees two-theta, 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 31. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by (a) an XRPD signal at 3.3±0.2 degrees two-theta or 8.1±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 3.0±0.2 degrees two-theta, 7.1±0.2 degrees two-theta, 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 32. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by (a) an XRPD signal at 3.3±0.2 degrees two-theta or 8.1±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 3.0±0.2 degrees two-theta, 7.1±0.2 degrees two-theta, 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 33. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by (a) an XRPD signal at 3.3±0.2 degrees two-theta or 8.1±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 3.0±0.2 degrees two-theta, 7.1±0.2 degrees two-theta, 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 34. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by (a) an XRPD signal at 3.3±0.2 degrees two-theta or 8.1±0.2 degrees two-theta, and (b) XRPD signals at 3.0±0.2 degrees two-theta, 7.1±0.2 degrees two-theta, 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 35. 27. The substantially crystalline Compound 5 free form Form A of embodiment 26, characterized by (a) XRPD signals at 3.3±0.2 degrees two-theta and 8.1±0.2 degrees two-theta, and (b) XRPD signals at 3.0±0.2 degrees two-theta, 7.1±0.2 degrees two-theta, 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 36. 27. The substantially crystalline Compound 5 free form Form A of embodiment 26, characterized by (a) XRPD signals of 3.3±0.2 degrees two-theta, 8.1±0.2 degrees two-theta, and 10.7±0.2 degrees two-theta, and (b) 3.0±0.2 degrees two-theta, 7.1±0.2 degrees two-theta, 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 37. 27. The substantially crystalline Compound 5 Free Form Form A of embodiment 26, characterized by thermogravimetric analysis showing a weight loss of about 0.2% from ambient temperature to about 180°C. 38. 27. The substantially crystalline free form Form A of Compound 5 according to embodiment 26, characterized by differential scanning calorimetry analysis showing an endothermic peak at about 193°C. 39. having one or more signals selected from 77.7±0.2 ppm, 117.9±0.2 ppm, 125.8±0.2 ppm, 128.5±0.2 ppm, 130.1±0.2 ppm, 132.0±0.2 ppm, and 138.4±0.2 ppm 13 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by a C CPMAS. 40. Two or more signals selected from 77.7±0.2 ppm, 117.9±0.2 ppm, 125.8±0.2 ppm, 128.5±0.2 ppm, 130.1±0.2 ppm, 132.0±0.2 ppm, and 138.4±0.2 ppm 13 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by a C CPMAS. 41. Three or more signals selected from 77.7±0.2 ppm, 117.9±0.2 ppm, 125.8±0.2 ppm, 128.5±0.2 ppm, 130.1±0.2 ppm, 132.0±0.2 ppm, and 138.4±0.2 ppm 13 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by a C CPMAS. 42. having four or more signals selected from 77.7±0.2 ppm, 117.9±0.2 ppm, 125.8±0.2 ppm, 128.5±0.2 ppm, 130.1±0.2 ppm, 132.0±0.2 ppm, and 138.4±0.2 ppm; 13 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by a C CPMAS. 43. Five or more signals selected from 77.7±0.2 ppm, 117.9±0.2 ppm, 125.8±0.2 ppm, 128.5±0.2 ppm, 130.1±0.2 ppm, 132.0±0.2 ppm, and 138.4±0.2 ppm. 13 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by a C CPMAS. 44. with signals of 77.7±0.2 ppm, 117.9±0.2 ppm, 125.8±0.2 ppm, 128.5±0.2 ppm, 130.1±0.2 ppm, 132.0±0.2 ppm, and 138.4±0.2 ppm. 13 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by a C CPMAS. 45. having one or more signals selected from -134.3±0.2 ppm, -136.4±0.2 ppm, -137.4±0.2 ppm, -138.6±0.2 ppm, -140.1±0.2 ppm, and -141.6±0.2 ppm 19 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by F MASS. 46. Two or more signals selected from -134.3±0.2 ppm, -136.4±0.2 ppm, -137.4±0.2 ppm, -138.6±0.2 ppm, -140.1±0.2 ppm, and -141.6±0.2 ppm 19 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by F MASS. 47. Three or more signals selected from -134.3±0.2 ppm, -136.4±0.2 ppm, -137.4±0.2 ppm, -138.6±0.2 ppm, -140.1±0.2 ppm, and -141.6±0.2 ppm 19 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by F MASS. 48. having four or more signals selected from -134.3±0.2 ppm, -136.4±0.2 ppm, -137.4±0.2 ppm, -138.6±0.2 ppm, -140.1±0.2 ppm, and -141.6±0.2 ppm 19 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by F MASS. 49. with signals of -134.3±0.2 ppm, -136.4±0.2 ppm, -137.4±0.2 ppm, -138.6±0.2 ppm, -140.1±0.2 ppm, and -141.6±0.2 ppm 19 The substantially crystalline Compound 5 Free Form Form A according to embodiment 26, characterized by F MAS. 50. Cu K α 27. The substantially crystalline Compound 5 free form Form A according to embodiment 26, characterized by a triclinic crystal system, P1 space group, and unit cell dimensions, as measured at 100 K using a Bruker diffractometer equipped with a CMOS detector with radiation (λ=1.54178 Å) and the following properties: [Table 6] 51. Substantially crystalline Compound 5 free form Form B. [ka] 52. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by one or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 53. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by two or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 54. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by three or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 54. 52. The substantially crystalline Compound 5 free form Form B of embodiment 51, characterized by XRPD signals of 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 55. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by (a) one or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 23.9±0.2 degrees two-theta. 56. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by (a) one or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 23.9±0.2 degrees two-theta. 57. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by (a) one or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 23.9±0.2 degrees two-theta. 58. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by (a) one or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 23.9±0.2 degrees two-theta. 59. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by (a) one or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) XRPD signals at 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 23.9±0.2 degrees two-theta. 60. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by (a) two or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) XRPD signals at 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 23.9±0.2 degrees two-theta. 61. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by (a) three or more XRPD signals selected from 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) XRPD signals at 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 23.9±0.2 degrees two-theta. 62. 52. The substantially crystalline Compound 5 Free Form Form B of embodiment 51, characterized by (a) XRPD signals at 9.8±0.2 degrees two-theta, 11.2±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) signals at 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 18.4±0.2 degrees two-theta, and 23.9±0.2 degrees two-theta. 63. The substantially crystalline Compound 5 Free Form B of embodiment 51, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 1.0% from ambient temperature to about 200°C. 64. The substantially crystalline Compound 5 Free Form Form B according to embodiment 51, characterized by differential scanning calorimetry (DSC) analysis showing an endothermic peak at about 240°C. 65. Substantially crystalline Compound 5 free form NPA solvate Form A. [ka] 66. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by one or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 67. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by two or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 68. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by XRPD signals at 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 69. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by (a) one or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 9.6±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 21.4±0.2 degrees two-theta. 70. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by (a) one or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 9.6±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 21.4±0.2 degrees two-theta. 71. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by (a) one or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 9.6±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 21.4±0.2 degrees two-theta. 72. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by (a) one or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 9.6±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 21.4±0.2 degrees two-theta. 73. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by (a) one or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) five or more XRPD signals selected from 9.6±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 21.4±0.2 degrees two-theta. 74. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by (a) one or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) XRPD signals at 9.6±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 21.4±0.2 degrees two-theta. 75. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by (a) two or more XRPD signals selected from 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) XRPD signals at 9.6±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 21.4±0.2 degrees two-theta. 76. 66. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by (a) XRPD signals at 7.4±0.2 degrees two-theta, 10.1±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) XRPD signals at 9.6±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 21.4±0.2 degrees two-theta. 77. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 8.7% from ambient temperature to about 160°C. 78. The substantially crystalline Compound 5 free form NPA solvate Form A of embodiment 65, characterized by differential scanning calorimetry analysis exhibiting endothermic peaks at about 133°C, 166°C, and 219°C. 79. Substantially crystalline Compound 5 free form EtOH solvate Form A. [ka] 80. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta. 81. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by two or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta. 82. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by XRPD signals at 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta. 83. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 10.4±0.2 degrees two-theta, 12.4±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 23.1±0.2 degrees two-theta, and 25.1±0.2 degrees two-theta. 84. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 10.4±0.2 degrees two-theta, 12.4±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 23.1±0.2 degrees two-theta, and 25.1±0.2 degrees two-theta. 85. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 10.4±0.2 degrees two-theta, 12.4±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 23.1±0.2 degrees two-theta, and 25.1±0.2 degrees two-theta. 86. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 10.4±0.2 degrees two-theta, 12.4±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 23.1±0.2 degrees two-theta, and 25.1±0.2 degrees two-theta. 87. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta, and (b) XRPD signals at 10.4±0.2 degrees two-theta, 12.4±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 23.1±0.2 degrees two-theta, and 25.1±0.2 degrees two-theta. 88. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by (a) two or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta, and (b) XRPD signals at 10.4±0.2 degrees two-theta, 12.4±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 23.1±0.2 degrees two-theta, and 25.1±0.2 degrees two-theta. 89. 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by (a) XRPD signals at 7.7±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, and 18.7±0.2 degrees two-theta, and (b) XRPD signals at 10.4±0.2 degrees two-theta, 12.4±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, 23.1±0.2 degrees two-theta, and 25.1±0.2 degrees two-theta. 90. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 7.0% from ambient temperature to about 180°C. 91. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by differential scanning calorimetry (DSC) analysis showing an endothermic peak at about 163°C. 92. having one or more signals selected from 59.0±0.2 ppm, 76.2±0.2 ppm, 117.4±0.2 ppm, 123.6±0.2 ppm, 126.7±0.2 ppm, 127.6±0.2 ppm, 129.6±0.2 ppm, 132.1±0.2 ppm, and 140.2±0.2 ppm 13 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by a C CPMAS. 93. Two or more signals selected from 59.0±0.2 ppm, 76.2±0.2 ppm, 117.4±0.2 ppm, 123.6±0.2 ppm, 126.7±0.2 ppm, 127.6±0.2 ppm, 129.6±0.2 ppm, 132.1±0.2 ppm, and 140.2±0.2 ppm 13 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by a C CPMAS. 94. Three or more signals selected from 59.0±0.2 ppm, 76.2±0.2 ppm, 117.4±0.2 ppm, 123.6±0.2 ppm, 126.7±0.2 ppm, 127.6±0.2 ppm, 129.6±0.2 ppm, 132.1±0.2 ppm, and 140.2±0.2 ppm 13 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by a C CPMAS. 95. having four or more signals selected from 59.0±0.2 ppm, 76.2±0.2 ppm, 117.4±0.2 ppm, 123.6±0.2 ppm, 126.7±0.2 ppm, 127.6±0.2 ppm, 129.6±0.2 ppm, 132.1±0.2 ppm, and 140.2±0.2 ppm; 13 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by a C CPMAS. 96. Five or more signals selected from 59.0±0.2 ppm, 76.2±0.2 ppm, 117.4±0.2 ppm, 123.6±0.2 ppm, 126.7±0.2 ppm, 127.6±0.2 ppm, 129.6±0.2 ppm, 132.1±0.2 ppm, and 140.2±0.2 ppm 13 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by a C CPMAS. 97. Six or more signals selected from 59.0±0.2 ppm, 76.2±0.2 ppm, 117.4±0.2 ppm, 123.6±0.2 ppm, 126.7±0.2 ppm, 127.6±0.2 ppm, 129.6±0.2 ppm, 132.1±0.2 ppm, and 140.2±0.2 ppm 13 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by a C CPMAS. 98. with signals of 59.0±0.2 ppm, 76.2±0.2 ppm, 117.4±0.2 ppm, 123.6±0.2 ppm, 126.7±0.2 ppm, 127.6±0.2 ppm, 129.6±0.2 ppm, 132.1±0.2 ppm, and 140.2±0.2 ppm. 13 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by a C CPMAS. 99. having one or more signals selected from -130.0±0.2 ppm, -131.7±0.2 ppm, -135.6±0.2 ppm, and -139.0±0.2 ppm 19 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by F MAS. 100. Two or more signals selected from -130.0±0.2 ppm, -131.7±0.2 ppm, -135.6±0.2 ppm, and -139.0±0.2 ppm 19 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by F MAS. 101. Three or more signals selected from -130.0±0.2 ppm, -131.7±0.2 ppm, -135.6±0.2 ppm, and -139.0±0.2 ppm 19 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by F MAS. 102. with signals of -130.0±0.2 ppm, -131.7±0.2 ppm, -135.6±0.2 ppm, and -139.0±0.2 ppm 19 The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by F MAS. 103. Cu K α 80. The substantially crystalline Compound 5 free form EtOH solvate Form A of embodiment 79, characterized by a triclinic crystal system, P1 space group, and unit cell dimensions, as measured at 100 K using a Bruker diffractometer equipped with a CMOS detector with radiation (λ=1.54178 Å) and the following properties: [Table 7] 104. Substantially crystalline Compound 5 free form MeOH solvate hydrate Form A. [ka] 105. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta. 106. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by two or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta. 107. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by XRPD signals at 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta. 108. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 12.6±0.2 degrees two-theta, 17.3±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.4±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 109. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 12.6±0.2 degrees two-theta, 17.3±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.4±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 110. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 12.6±0.2 degrees two-theta, 17.3±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.4±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 111. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 12.6±0.2 degrees two-theta, 17.3±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.4±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 112. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by (a) one or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta, and (b) XRPD signals at 12.6±0.2 degrees two-theta, 17.3±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.4±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 113. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by (a) two or more XRPD signals selected from 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta, and (b) XRPD signals at 12.6±0.2 degrees two-theta, 17.3±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.4±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 114. 105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by (a) XRPD signals at 7.7±0.2 degrees two-theta, 10.4±0.2 degrees two-theta, and 19.0±0.2 degrees two-theta, and (b) XRPD signals at 12.6±0.2 degrees two-theta, 17.3±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.4±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 115. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 5.0% from ambient temperature to about 150°C. 116. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 31°C and 174°C, and an exothermic peak at about 246°C. 117. having one or more signals selected from 48.3±0.2 ppm, 116.5±0.2 ppm, 117.4±0.2 ppm, 123.5±0.2 ppm, 126.5±0.2 ppm, 127.5±0.2 ppm, 129.5±0.2 ppm, 132.1±0.2 ppm, and 140.1±0.2 ppm 13 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by a C CPMAS. 118. having two or more signals selected from 48.3±0.2 ppm, 116.5±0.2 ppm, 117.4±0.2 ppm, 123.5±0.2 ppm, 126.5±0.2 ppm, 127.5±0.2 ppm, 129.5±0.2 ppm, 132.1±0.2 ppm, and 140.1±0.2 ppm 13 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by a C CPMAS. 119. Three or more signals selected from 48.3±0.2 ppm, 116.5±0.2 ppm, 117.4±0.2 ppm, 123.5±0.2 ppm, 126.5±0.2 ppm, 127.5±0.2 ppm, 129.5±0.2 ppm, 132.1±0.2 ppm, and 140.1±0.2 ppm 13 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by a C CPMAS. 120. having four or more signals selected from 48.3±0.2 ppm, 116.5±0.2 ppm, 117.4±0.2 ppm, 123.5±0.2 ppm, 126.5±0.2 ppm, 127.5±0.2 ppm, 129.5±0.2 ppm, 132.1±0.2 ppm, and 140.1±0.2 ppm 13 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by a C CPMAS. 121. having five or more signals selected from 48.3±0.2 ppm, 116.5±0.2 ppm, 117.4±0.2 ppm, 123.5±0.2 ppm, 126.5±0.2 ppm, 127.5±0.2 ppm, 129.5±0.2 ppm, 132.1±0.2 ppm, and 140.1±0.2 ppm 13 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by a C CPMAS. 122. Six or more signals selected from 48.3±0.2 ppm, 116.5±0.2 ppm, 117.4±0.2 ppm, 123.5±0.2 ppm, 126.5±0.2 ppm, 127.5±0.2 ppm, 129.5±0.2 ppm, 132.1±0.2 ppm, and 140.1±0.2 ppm. 13 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by a C CPMAS. one two three. 48. 3105. The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A of embodiment 104, characterized by a C CPMAS having seven or more signals selected from: 116.5±0.2 ppm, 117.4±0.2 ppm, 123.5±0.2 ppm, 126.5±0.2 ppm, 127.5±0.2 ppm, 129.5±0.2 ppm, 132.1±0.2 ppm, and 140.1±0.2 ppm. 124. with signals of 48.3±0.2 ppm, 116.5±0.2 ppm, 117.4±0.2 ppm, 123.5±0.2 ppm, 126.5±0.2 ppm, 127.5±0.2 ppm, 129.5±0.2 ppm, 132.1±0.2 ppm, and 140.1±0.2 ppm. 13 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by a C CPMAS. 125. having one or more signals selected from -129.4±0.2 ppm, -129.9±0.2 ppm, -131.5±0.2 ppm, -135.6±0.2 ppm, and -139.0±0.2 ppm 19 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by F MAS. 126. Two or more signals selected from -129.4±0.2 ppm, -129.9±0.2 ppm, -131.5±0.2 ppm, -135.6±0.2 ppm, and -139.0±0.2 ppm 19 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by F MAS. 127. Three or more signals selected from -129.4±0.2 ppm, -129.9±0.2 ppm, -131.5±0.2 ppm, -135.6±0.2 ppm, and -139.0±0.2 ppm 19 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by F MAS. 128. with signals of -129.4±0.2 ppm, -129.9±0.2 ppm, -131.5±0.2 ppm, -135.6±0.2 ppm, and -139.0±0.2 ppm 19 The substantially crystalline Compound 5 free form MeOH solvate hydrate Form A according to embodiment 104, characterized by F MAS. 129. Substantially crystalline Compound 5 free form DCM solvate Form A. [ka] 130. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by one or more XRPD signals selected from 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta. 131. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by two or more XRPD signals selected from 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta. 132. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by XRPD signals of 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta. 133. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by (a) one or more XRPD signals selected from 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 24.3±0.2 degrees two-theta. 134. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by (a) two or more XRPD signals selected from 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 24.3±0.2 degrees two-theta. 135. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by (a) three or more XRPD signals selected from 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 24.3±0.2 degrees two-theta. 136. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by (a) four or more XRPD signals selected from 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 24.3±0.2 degrees two-theta. 137. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by (a) one or more XRPD signals selected from 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta, and (b) XRPD signals at 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 24.3±0.2 degrees two-theta. 138. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by (a) two or more XRPD signals selected from 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta, and (b) XRPD signals at 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 24.3±0.2 degrees two-theta. 139. 130. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by (a) XRPD signals at 8.1±0.2 degrees two-theta, 10.3±0.2 degrees two-theta, and 17.4±0.2 degrees two-theta, and (b) XRPD signals at 8.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.1±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 24.3±0.2 degrees two-theta. 140. The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 8.7% from ambient temperature to about 180°C. 141. having one or more signals selected from 6.5±0.2 ppm, 77.1±0.2 ppm, 78.4±0.2 ppm, 117.7±0.2 ppm, 125.8±0.2 ppm, 128.8±0.2 ppm, 129.9±0.2 ppm, and 131.2±0.2 ppm 13 The substantially crystalline Compound 5 free form DCM solvate Form A according to embodiment 129, characterized by a C CPMAS. 142. Two or more signals selected from 6.5±0.2 ppm, 77.1±0.2 ppm, 78.4±0.2 ppm, 117.7±0.2 ppm, 125.8±0.2 ppm, 128.8±0.2 ppm, 129.9±0.2 ppm, and 131.2±0.2 ppm 13 The substantially crystalline Compound 5 free form DCM solvate Form A according to embodiment 129, characterized by a C CPMAS. 143. Three or more signals selected from 6.5±0.2 ppm, 77.1±0.2 ppm, 78.4±0.2 ppm, 117.7±0.2 ppm, 125.8±0.2 ppm, 128.8±0.2 ppm, 129.9±0.2 ppm, and 131.2±0.2 ppm 13 The substantially crystalline Compound 5 free form DCM solvate Form A according to embodiment 129, characterized by a C CPMAS. 144. having four or more signals selected from 6.5±0.2 ppm, 77.1±0.2 ppm, 78.4±0.2 ppm, 117.7±0.2 ppm, 125.8±0.2 ppm, 128.8±0.2 ppm, 129.9±0.2 ppm, and 131.2±0.2 ppm; 13 The substantially crystalline Compound 5 free form DCM solvate Form A according to embodiment 129, characterized by a C CPMAS. 145. Five or more signals selected from 6.5±0.2 ppm, 77.1±0.2 ppm, 78.4±0.2 ppm, 117.7±0.2 ppm, 125.8±0.2 ppm, 128.8±0.2 ppm, 129.9±0.2 ppm, and 131.2±0.2 ppm 13 The substantially crystalline Compound 5 free form DCM solvate Form A according to embodiment 129, characterized by a C CPMAS. 146. Six or more signals selected from 6.5±0.2 ppm, 77.1±0.2 ppm, 78.4±0.2 ppm, 117.7±0.2 ppm, 125.8±0.2 ppm, 128.8±0.2 ppm, 129.9±0.2 ppm, and 131.2±0.2 ppm 13 The substantially crystalline Compound 5 free form DCM solvate Form A according to embodiment 129, characterized by a C CPMAS. 147. with signals of 6.5±0.2 ppm, 77.1±0.2 ppm, 78.4±0.2 ppm, 117.7±0.2 ppm, 125.8±0.2 ppm, 128.8±0.2 ppm, 129.9±0.2 ppm, and 131.2±0.2 ppm.13 The substantially crystalline Compound 5 free form DCM solvate Form A according to embodiment 129, characterized by a C CPMAS. 148. having one or more signals selected from -129.4±0.2 ppm, -131.8±0.2 ppm, -133.8±0.2 ppm, -136.8±0.2 ppm, 139.7±0.2 ppm, -141.5±0.2 ppm, -142.6±0.2 ppm, and -146.5±0.2 ppm 19 The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by F MAS. 149. Two or more signals selected from -129.4±0.2 ppm, -131.8±0.2 ppm, -133.8±0.2 ppm, -136.8±0.2 ppm, 139.7±0.2 ppm, -141.5±0.2 ppm, -142.6±0.2 ppm, and -146.5±0.2 ppm 19 The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by F MAS. 150. Three or more signals selected from -129.4±0.2 ppm, -131.8±0.2 ppm, -133.8±0.2 ppm, -136.8±0.2 ppm, 139.7±0.2 ppm, -141.5±0.2 ppm, -142.6±0.2 ppm, and -146.5±0.2 ppm 19 The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by F MAS. 151. -129.4±0.2 ppm, -131.8±0.2 ppm, -133.8±0.2 ppm, -136.8±0.2 ppm, 139.7±0.2 ppm, -141.5±0.2 ppm, -142.6±0.2 ppm, and -146.5±0.2 ppm. 19 The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by F MAS. 152. -129.4±0.2 ppm, -131.8±0.2 ppm, -133.8±0.2 ppm, -136.8±0.2 ppm, 139.7±0.2 ppm, -141.5±0.2 ppm, -142.6±0.2 ppm, and -146.5±0.2 ppm. 19 The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by F MAS. 153. with signals of -129.4±0.2 ppm, -131.8±0.2 ppm, -133.8±0.2 ppm, -136.8±0.2 ppm, 139.7±0.2 ppm, -141.5±0.2 ppm, -142.6±0.2 ppm, and -146.5±0.2 ppm. 19 The substantially crystalline Compound 5 free form DCM solvate Form A of embodiment 129, characterized by F MAS. 154. Substantially crystalline Compound 5 free form EtOAc heptane solvate Form A. [ka] 155. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by one or more XRPD signals selected from 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta. 156. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by two or more XRPD signals selected from 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta. 157. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by XRPD signals of 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta. 158. 155. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by (a) one or more XRPD signals selected from 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 23.8±0.2 degrees two-theta, 18.8±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, and 10.0±0.2 degrees two-theta. 159. 155. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by (a) one or more XRPD signals selected from 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 23.8±0.2 degrees two-theta, 18.8±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, and 10.0±0.2 degrees two-theta. 160. 155. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by (a) one or more XRPD signals selected from 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 23.8±0.2 degrees two-theta, 18.8±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, and 10.0±0.2 degrees two-theta. 161. 155. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by (a) one or more XRPD signals selected from 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 23.8±0.2 degrees two-theta, 18.8±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, and 10.0±0.2 degrees two-theta. 162. 155. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by (a) one or more XRPD signals selected from 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta, and (b) XRPD signals at 23.8±0.2 degrees two-theta, 18.8±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, and 10.0±0.2 degrees two-theta. 163. 155. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by (a) two or more XRPD signals selected from 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta, and (b) XRPD signals at 23.8±0.2 degrees two-theta, 18.8±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, and 10.0±0.2 degrees two-theta. 164. 155. The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A of embodiment 154, characterized by (a) XRPD signals at 17.7±0.2 degrees two-theta, 17.2±0.2 degrees two-theta, and 8.1±0.2 degrees two-theta, and (b) XRPD signals at 23.8±0.2 degrees two-theta, 18.8±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 12.6±0.2 degrees two-theta, and 10.0±0.2 degrees two-theta. 165. having one or more signals selected from 142.7±0.2 ppm, 139.0±0.2 ppm, 132.3±0.2 ppm, 130.4±0.2 ppm, 128.6±0.2 ppm, 125.9±0.2 ppm, 124.3±0.2 ppm, 118.00±0.2 ppm, and 6.6±0.2 ppm 13 The substantially crystalline compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by a C CPMAS. 166. Two or more signals selected from 142.7±0.2 ppm, 139.0±0.2 ppm, 132.3±0.2 ppm, 130.4±0.2 ppm, 128.6±0.2 ppm, 125.9±0.2 ppm, 124.3±0.2 ppm, 118.0±0.2 ppm, and 6.6±0.2 ppm. 13 The substantially crystalline compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by a C CPMAS. 167. Three or more signals selected from 142.7±0.2 ppm, 139.0±0.2 ppm, 132.3±0.2 ppm, 130.4±0.2 ppm, 128.6±0.2 ppm, 125.9±0.2 ppm, 124.3±0.2 ppm, 118.0±0.2 ppm, and 6.6±0.2 ppm. 13 The substantially crystalline compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by a C CPMAS. 168. having four or more signals selected from 142.7±0.2 ppm, 139.0±0.2 ppm, 132.3±0.2 ppm, 130.4±0.2 ppm, 128.6±0.2 ppm, 125.9±0.2 ppm, 124.3±0.2 ppm, 118.0±0.2 ppm, and 6.6±0.2 ppm; 13 The substantially crystalline compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by a C CPMAS. 169. having five or more signals selected from 142.7±0.2 ppm, 139.0±0.2 ppm, 132.3±0.2 ppm, 130.4±0.2 ppm, 128.6±0.2 ppm, 125.9±0.2 ppm, 124.3±0.2 ppm, 118.0±0.2 ppm, and 6.6±0.2 ppm; 13 The substantially crystalline compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by a C CPMAS. 170. Six or more signals selected from 142.7±0.2 ppm, 139.0±0.2 ppm, 132.3±0.2 ppm, 130.4±0.2 ppm, 128.6±0.2 ppm, 125.9±0.2 ppm, 124.3±0.2 ppm, 118.0±0.2 ppm, and 6.6±0.2 ppm. 13 The substantially crystalline compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by a C CPMAS. 171. with signals of 142.7±0.2 ppm, 139.0±0.2 ppm, 132.3±0.2 ppm, 130.4±0.2 ppm, 128.6±0.2 ppm, 125.9±0.2 ppm, 124.3±0.2 ppm, 118.0±0.2 ppm, and 6.6±0.2 ppm. 13 The substantially crystalline compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by a C CPMAS. 172. having one or more signals selected from -129.6±0.2 ppm, -132.2±0.2 ppm, -135.3±0.2 ppm, -136.9±0.2 ppm, ±0.2 ppm, 139.2±0.2 ppm, -141.0±0.2 ppm, -142.2±0.2 ppm, and -143.7±0.2 ppm 19 The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by F MAS. 173. having two or more signals selected from -129.6±0.2 ppm, -132.2±0.2 ppm, -135.3±0.2 ppm, -136.9±0.2 ppm, ±0.2 ppm, 139.2±0.2 ppm, -141.0±0.2 ppm, -142.2±0.2 ppm, and -143.7±0.2 ppm 19 The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by F MAS. 174. Three or more signals selected from -129.6±0.2 ppm, -132.2±0.2 ppm, -135.3±0.2 ppm, -136.9±0.2 ppm, ±0.2 ppm, 139.2±0.2 ppm, -141.0±0.2 ppm, -142.2±0.2 ppm, and -143.7±0.2 ppm 19 The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by F MAS. 175. -129.6±0.2 ppm, -132.2±0.2 ppm, -135.3±0.2 ppm, -136.9±0.2 ppm, ±0.2 ppm, 139.2±0.2 ppm, -141.0±0.2 ppm, -142.2±0.2 ppm, and -143.7±0.2 ppm. 19 The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by F MAS. 176. -129.6±0.2 ppm, -132.2±0.2 ppm, -135.3±0.2 ppm, -136.9±0.2 ppm, ±0.2 ppm, 139.2±0.2 ppm, -141.0±0.2 ppm, -142.2±0.2 ppm, and -143.7±0.2 ppm. 19 The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by F MAS. 177. Six or more signals selected from -129.6±0.2 ppm, -132.2±0.2 ppm, -135.3±0.2 ppm, -136.9±0.2 ppm, ±0.2 ppm, 139.2±0.2 ppm, -141.0±0.2 ppm, -142.2±0.2 ppm, and -143.7±0.2 ppm 19 The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by F MAS. 178. with signals of -129.6±0.2 ppm, -132.2±0.2 ppm, -135.3±0.2 ppm, -136.9±0.2 ppm, ±0.2 ppm, -139.2±0.2 ppm, -141.0±0.2 ppm, -142.2±0.2 ppm, and -143.7±0.2 ppm. 19 The substantially crystalline Compound 5 free form EtOAc heptane solvate Form A according to embodiment 154, characterized by F MAS. 179. A pharmaceutical composition comprising substantially crystalline Compound 5 according to any one of embodiments 1 to 178, and a pharmaceutically acceptable carrier. 180. A method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering to a patient in need thereof a therapeutically effective amount of substantially crystalline compound 5 of any one of embodiments 1 to 178, or a therapeutically effective amount of the pharmaceutical composition of embodiment 179. 181. Use of a substantially crystalline form of compound 5 according to any one of embodiments 1 to 178, or a pharmaceutical composition according to embodiment 179, in the manufacture of a medicament for the treatment of AATD. 182. A therapeutically effective amount of a substantially crystalline form of compound 5 according to any one of embodiments 1-178, or a pharmaceutical composition according to embodiment 179, for use in treating AATD. 183. A method for preparing substantially crystalline Compound 5 free form monohydrate Form A, the method comprising: (a) stirring a mixture of Compound 5 free form Form A and l-propanol with heating to obtain a clear solution; (b) slowly adding water with stirring until a slurry is formed; (c) cooling the slurry with continued stirring; (d) washing the filtered solid with a mixture of l-propanol and water and drying at 50°C in a vacuum oven equipped with a nitrogen bleed; and (e) collecting substantially crystalline Compound 5 free form monohydrate Form A by centrifugal filtration. 184. 1. A method for preparing substantially crystalline Compound 5 Free Form Form A, the method comprising: (a) dissolving Compound 5 Free Form EtOH solvate Form A in 4:1 DCM:MeOH and evaporating to dryness; (b) dissolving the residue from step (a) in DCM and refluxing to provide a uniform suspension; (c) slowly cooling to room temperature, filtering and washing with DCM; and (d) collecting the solid and drying under suction and on a rotovap, followed by vacuum oven drying at 75-90° C. to provide substantially crystalline Compound 5 Free Form Form A. 185. A method for preparing substantially crystalline Compound 5 Free Form Form B, comprising: (a) adding Compound 5 Free Form Form A and octanol to a vial with a stir bar; (b) stirring at 80°C for 3 days while protecting from exposure to light; and (c) collecting substantially crystalline Compound 5 Free Form Form B by centrifugal filtration. 186. A method for preparing substantially crystalline Compound 5 free form NPA solvate Form A, comprising: (a) adding Compound 5 free form Form A and l-propanol to a vial with a stir bar; (b) stirring at 20°C for 7 days while protecting from exposure to light; and (c) collecting substantially crystalline Compound 5 free form NPA solvate Form A by centrifugal filtration. 187. 1. A method for preparing substantially crystalline Compound 5 free form EtOH solvate Form A, the method comprising: (a) diluting crude Compound 5 in EtOAc and treating with activated carbon; (b) refluxing before filtering and washing with EtOAc, then cooling to room temperature to provide a yellow foam; (c) treating the yellow foam with EtOH and heating to reflux in a heating bath; (d) refluxing to provide a homogeneous suspension and cooling to room temperature; and (e) filtering the suspension to collect the solid, washing with EtOH, and drying under suction and rotovap to obtain substantially crystalline Compound 5 free form EtOH solvate Form A. 188. A method for preparing substantially crystalline Compound 5 free form MeOH solvate hydrate Form A, comprising: (a) adding EtOH to Compound 5 followed by water bath sonication; (b) stirring at room temperature and isolating a solid; (c) adding the solid and 9:1 (v / v) MeOH:water followed by sonication; and (d) stirring at ambient temperature for 5 days and isolating substantially crystalline Compound 5 free form MeOH solvate hydrate Form A. 189. A method for preparing substantially crystalline Compound 5 free form MeOH solvate hydrate Form A, comprising: (a) adding amorphous Compound 5 to 9:1 (v / v) MeOH:water, followed by sonication; and (b) stirring at ambient temperature for 5 days to isolate substantially crystalline Compound 5 free form MeOH solvate hydrate Form A. 190. A method for preparing substantially crystalline Compound 5 free form DCM solvate Form A, comprising: (a) combining Compound 5 with water acidified to pH 3 and 2N HCl and extracting with EtOAc; (b) filtering the dryness and evaporating the extract in vacuo to provide an orange-red oil; (c) dissolving the oil in DCM to form a clear red solution; (d) stirring the solution to crystallize the product; and (e) filtering the suspension and washing the resulting cake with DCM to obtain substantially crystalline Compound 5 free form DCM solvate Form A. 191. A method for preparing substantially crystalline Compound 5 free form EtOH heptane solvate Form A, comprising: (a) heating crude Compound 5 in EtOAc to 55° C. until dissolution; (b) cooling the slurry to room temperature and stirring overnight; and (c) filtering the solid to provide substantially crystalline Compound 5 free form EtOH heptane solvate Form A. 192. Substantially crystalline Compound 3 free form Form A. [ka] 193. 193. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by one or more XRPD signals selected from 5.7±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 194. 193. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by two or more XRPD signals selected from 5.7±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 195. 193. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by three or more XRPD signals at 5.7±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 196. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by XRPD signals at 5.7±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 197. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by XRPD signals at 12.3±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, and 22.4±0.2 degrees two-theta. 198. 193. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by (a) one or more XRPD signals selected from 12.3±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, and 22.4±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 5.7±0.2 degrees two-theta, 11.0±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 199. 193. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by (a) XRPD signals at 12.3±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, and 22.4±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 5.7±0.2 degrees two-theta, 11.0±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 200. 193. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by (a) XRPD signals at 12.3±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, and 22.4±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 5.7±0.2 degrees two-theta, 11.0±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 201. 193. The substantially crystalline Compound 3 Free Form Form A of embodiment 192, characterized by (a) XRPD signals at 12.3±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, and 22.4±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 5.7±0.2 degrees two-theta, 11.0±0.2 degrees two-theta, 15.9±0.2 degrees two-theta, 19.5±0.2 degrees two-theta, and 20.2±0.2 degrees two-theta. 202. with signals of 170.6±0.2 ppm, 128.1±0.2 ppm, and 116.8±0.2 ppm. 13 The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by a C CPMAS. 203. (a) signals at 170.6±0.2 ppm, 128.1±0.2 ppm, and 116.8±0.2 ppm, and (b) one or more signals selected from 141.1±0.2 ppm, 133.5±0.2 ppm, 126.7±0.2 ppm, 124.9±0.2 ppm, 80.0±0.2 ppm, and 54.6±0.2 ppm. 13The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by a C CPMAS. 204. (a) signals at 170.6±0.2 ppm, 128.1±0.2 ppm, and 116.8±0.2 ppm, and (b) two or more signals selected from 141.1±0.2 ppm, 133.5±0.2 ppm, 126.7±0.2 ppm, 124.9±0.2 ppm, 80.0±0.2 ppm, and 54.6±0.2 ppm. 13 The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by a C CPMAS. 205. (a) signals at 170.6±0.2 ppm, 128.1±0.2 ppm, and 116.8±0.2 ppm, and (b) three or more signals selected from 141.1±0.2 ppm, 133.5±0.2 ppm, 126.7±0.2 ppm, 124.9±0.2 ppm, 80.0±0.2 ppm, and 54.6±0.2 ppm. 13 The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by a C CPMAS. 206. (a) signals at 170.6±0.2 ppm, 128.1±0.2 ppm, and 116.8±0.2 ppm, and (b) four or more signals selected from 141.1±0.2 ppm, 133.5±0.2 ppm, 126.7±0.2 ppm, 124.9±0.2 ppm, 80.0±0.2 ppm, and 54.6±0.2 ppm. 13 The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by a C CPMAS. 207. with signals of 170.6±0.2 ppm, 141.1±0.2 ppm, 133.5±0.2 ppm, 128.1±0.2 ppm, 126.7±0.2 ppm, 124.9±0.2 ppm, 116.8±0.2 ppm, 80.0±0.2 ppm, and 54.6±0.2 ppm. 13 The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by a C CPMAS. 208. having one or more signals selected from -132.8±0.2 ppm, -134.8±0.2 ppm, and -138.3±0.2 ppm 19 The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by F MAS. 209. Two or more signals selected from -132.8±0.2 ppm, -134.8±0.2 ppm, and -138.3±0.2 ppm 19 The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by F MAS. 210. with signals of -132.8±0.2 ppm, -134.8±0.2 ppm, and -138.3±0.2 ppm 19 The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by F MAS. 211. The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 0.4% from ambient temperature to about 230°C. 212. The substantially crystalline Compound 3 Free Form Form A according to embodiment 192, characterized by differential scanning calorimetry (DSC) analysis showing an endothermic peak at about 244°C. 213. Substantially crystalline Compound 3 free form Form B. [ka] 214. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by one or more XRPD signals selected from 8.2±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, and 16.6±0.2 degrees two-theta. 215. 214. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by two or more XRPD signals selected from 8.2±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, and 16.6±0.2 degrees two-theta. 216. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by XRPD signals at 8.2±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, and 16.6±0.2 degrees two-theta. 217. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by XRPD signals at 10.5±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, and 16.6±0.2 degrees two-theta. 218. 214. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by (a) XRPD signals at 10.5±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, and 16.6±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 8.2±0.2 degrees two-theta, 8.5±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.8±0.2 degrees two-theta. 219. 214. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by (a) XRPD signals at 10.5±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, and 16.6±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 8.2±0.2 degrees two-theta, 8.5±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.8±0.2 degrees two-theta. 220. 214. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by (a) XRPD signals at 10.5±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, and 16.6±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 8.2±0.2 degrees two-theta, 8.5±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.8±0.2 degrees two-theta. 221. 214. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by (a) XRPD signals at 10.5±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, and 16.6±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 8.2±0.2 degrees two-theta, 8.5±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.8±0.2 degrees two-theta. 222. 214. The substantially crystalline Compound 3 Free Form Form B of embodiment 213, characterized by signals at 8.2±0.2 degrees two-theta, 8.5±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, 13.5±0.2 degrees two-theta, 16.6±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, and 21.8±0.2 degrees two-theta. 223. having one or more signals selected from 143.4±0.2 ppm, 142.5±0.2 ppm, 115.2±0.2 ppm, 76.9±0.2 ppm, 58.0±0.2 ppm, 7.2±0.2 ppm, and 6.7±0.2 ppm 13 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by a C CPMAS. 224. Two or more signals selected from 143.4±0.2 ppm, 142.5±0.2 ppm, 115.2±0.2 ppm, 76.9±0.2 ppm, 58.0±0.2 ppm, 7.2±0.2 ppm, and 6.7±0.2 ppm 13 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by a C CPMAS. 225. Three or more signals selected from 143.4±0.2 ppm, 142.5±0.2 ppm, 115.2±0.2 ppm, 76.9±0.2 ppm, 58.0±0.2 ppm, 7.2±0.2 ppm, and 6.7±0.2 ppm 13 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by a C CPMAS. 226. having four or more signals selected from 143.4±0.2 ppm, 142.5±0.2 ppm, 115.2±0.2 ppm, 76.9±0.2 ppm, 58.0±0.2 ppm, 7.2±0.2 ppm, and 6.7±0.2 ppm; 13 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by a C CPMAS. 227. Five or more signals selected from 143.4±0.2 ppm, 142.5±0.2 ppm, 115.2±0.2 ppm, 76.9±0.2 ppm, 58.0±0.2 ppm, 7.2±0.2 ppm, and 6.7±0.2 ppm 13 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by a C CPMAS. 228. with signals of 143.4±0.2 ppm, 142.5±0.2 ppm, 115.2±0.2 ppm, 76.9±0.2 ppm, 58.0±0.2 ppm, 7.2±0.2 ppm, and 6.7±0.2 ppm. 13 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by a C CPMAS. 229. having one or more signals selected from -129.4±0.2 ppm, -132.3±0.2 ppm, -137.6±0.2 ppm, -142.0±0.2 ppm, -145.1±0.2 ppm, and -146.9±0.2 ppm 19 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by F MAS. 230. Two or more signals selected from -129.4±0.2 ppm, -132.3±0.2 ppm, -137.6±0.2 ppm, -142.0±0.2 ppm, -145.1±0.2 ppm, and -146.9±0.2 ppm 19 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by F MAS. 231. Three or more signals selected from -129.4±0.2 ppm, -132.3±0.2 ppm, -137.6±0.2 ppm, -142.0±0.2 ppm, -145.1±0.2 ppm, and -146.9±0.2 ppm 19 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by F MAS. 232. having four or more signals selected from -129.4±0.2 ppm, -132.3±0.2 ppm, -137.6±0.2 ppm, -142.0±0.2 ppm, -145.1±0.2 ppm, and -146.9±0.2 ppm; 19 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by F MAS. 233. with signals of -129.4±0.2 ppm, -132.3±0.2 ppm, -137.6±0.2 ppm, -142.0±0.2 ppm, -145.1±0.2 ppm, and -146.9±0.2 ppm 19 The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by F MAS. 234. The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 0.6% from ambient temperature to about 260°C. 235. The substantially crystalline Compound 3 Free Form Form B according to embodiment 213, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 231 and 255°C. 236. Substantially crystalline Compound 3 free form hydrate Form A. [ka] 237. 237. The substantially crystalline Compound 3 free form hydrate Form A of embodiment 236, characterized by an XRPD signal at 10.0±0.2 degrees two-theta, and characterized by one or more XRPD signals selected from 11.6±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, 22.2±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 238. 237. The substantially crystalline Compound 3 free form hydrate Form A of embodiment 236, characterized by an XRPD signal at 10.0±0.2 degrees two-theta, and by two or more XRPD signals selected from 11.6±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, 22.2±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 239. 237. The substantially crystalline Compound 3 free form hydrate Form A of embodiment 236, characterized by an XRPD signal at 10.0±0.2 degrees two-theta, and by three or more XRPD signals selected from 11.6±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, 22.2±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 240. 237. The substantially crystalline Compound 3 free form hydrate Form A of embodiment 236, characterized by an XRPD signal at 10.0±0.2 degrees two-theta, and four or more XRPD signals selected from 11.6±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, 22.2±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 241. 237. The substantially crystalline Compound 3 free form hydrate Form A of embodiment 236, characterized by an XRPD signal at 10.0±0.2 degrees two-theta, and five or more XRPD signals selected from 11.6±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, 22.2±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 242. 237. The substantially crystalline Compound 3 free form hydrate Form A of embodiment 236, characterized by XRPD signals at 10.0±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, 12.3±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, 18.2±0.2 degrees two-theta, 22.2±0.2 degrees two-theta, and 24.4±0.2 degrees two-theta. 243. The substantially crystalline Compound 3 free form hydrate Form A according to embodiment 236, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 1.6% from ambient temperature to about 170°C. 244. The substantially crystalline Compound 3 free form hydrate Form A according to embodiment 236, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 155°C and 242°C, and an exothermic peak at about 172°C. 245. Substantially crystalline Compound 3 free form hydrate Form B. [ka] 246. 246. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by one or more XRPD signals selected from 19.0±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 26.4±0.2 degrees two-theta, and 27.4±0.2 degrees two-theta. 247. 246. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by two or more XRPD signals selected from 19.0±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 26.4±0.2 degrees two-theta, and 27.4±0.2 degrees two-theta. 248. 246. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by three or more XRPD signals selected from 19.0±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 26.4±0.2 degrees two-theta, and 27.4±0.2 degrees two-theta. 249. 246. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by XRPD signals of 19.0±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 26.4±0.2 degrees two-theta, and 27.4±0.2 degrees two-theta. 250. 246. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by (a) one or more XRPD signals selected from 19.0±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 26.4±0.2 degrees two-theta, and 27.4±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 11.5±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, 17.6±0.2 degrees two-theta, and 17.9±0.2 degrees two-theta. 251. 246. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by (a) one or more XRPD signals selected from 19.0±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 26.4±0.2 degrees two-theta, and 27.4±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 11.5±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, 17.6±0.2 degrees two-theta, and 17.9±0.2 degrees two-theta. 252. 246. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by (a) one or more XRPD signals selected from 19.0±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 26.4±0.2 degrees two-theta, and 27.4±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 11.5±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, 17.6±0.2 degrees two-theta, and 17.9±0.2 degrees two-theta. 253. 246. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by (a) one or more XRPD signals selected from 19.0±0.2 degrees two-theta, 21.1±0.2 degrees two-theta, 26.4±0.2 degrees two-theta, and 27.4±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 11.5±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, 17.6±0.2 degrees two-theta, and 17.9±0.2 degrees two-theta. 254. The substantially crystalline Compound 3 free form hydrate Form B of embodiment 245, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 4.8% from ambient temperature to about 200°C. 255. The substantially crystalline Compound 3 free form hydrate Form B according to embodiment 245, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 79°C and 244°C, and an exothermic peak at about 184°C. 256. Substantially crystalline Compound 3 free form hydrate Form C. [ka] 257. The substantially crystalline Compound 3 free form hydrate Form C of embodiment 256, characterized by an XRPD signal selected from 5.7±0.2 degrees two-theta and 19.7±0.2 degrees two-theta. 258. The substantially crystalline Compound 3 free form hydrate Form C of embodiment 256, characterized by XRPD signals of 5.7±0.2 degrees two-theta and 19.7±0.2 degrees two-theta. 259. 257. The substantially crystalline Compound 3 free form hydrate Form C of embodiment 256, characterized by (a) an XRPD signal at 5.7±0.2 degrees two-theta and / or 19.7±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 11.4±0.2 degrees two-theta, 15.2±0.2 degrees two-theta, 18.5±0.2 degrees two-theta, 22.0±0.2 degrees two-theta, and 22.9±0.2 degrees two-theta. 260. 257. The substantially crystalline Compound 3 free form hydrate Form C of embodiment 256, characterized by (a) an XRPD signal at 5.7±0.2 degrees two-theta and / or 19.7±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 11.4±0.2 degrees two-theta, 15.2±0.2 degrees two-theta, 18.5±0.2 degrees two-theta, 22.0±0.2 degrees two-theta, and 22.9±0.2 degrees two-theta. 261. 257. The substantially crystalline Compound 3 free form hydrate Form C of embodiment 256, characterized by (a) an XRPD signal at 5.7±0.2 degrees two-theta and / or 19.7±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 11.4±0.2 degrees two-theta, 15.2±0.2 degrees two-theta, 18.5±0.2 degrees two-theta, 22.0±0.2 degrees two-theta, and 22.9±0.2 degrees two-theta. 262. 257. The substantially crystalline Compound 3 free form hydrate Form C of embodiment 256, characterized by (a) an XRPD signal at 5.7±0.2 degrees two-theta and / or 19.7±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 11.4±0.2 degrees two-theta, 15.2±0.2 degrees two-theta, 18.5±0.2 degrees two-theta, 22.0±0.2 degrees two-theta, and 22.9±0.2 degrees two-theta. 263. 257. The substantially crystalline Compound 3 free form hydrate Form C of embodiment 256, characterized by (a) XRPD signals at 5.7±0.2 degrees two-theta and / or 19.7±0.2 degrees two-theta, and (b) XRPD signals at 11.4±0.2 degrees two-theta, 15.2±0.2 degrees two-theta, 18.5±0.2 degrees two-theta, 22.0±0.2 degrees two-theta, and 22.9±0.2 degrees two-theta. 264. The substantially crystalline Compound 3 free form hydrate Form C according to embodiment 256, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 4.2% from ambient temperature to about 180°C. 265. The substantially crystalline Compound 3 free form hydrate Form C according to embodiment 256, characterized by differential scanning calorimetry (DSC) analysis showing an endothermic peak at about 241°C. 266. Substantially crystalline Compound 3 free form MTBE solvate Form A. [ka] 267. 267. The substantially crystalline Compound 3 free form MTBE solvate Form A of embodiment 266, characterized by one or more XRPD signals selected from 15.6±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 268. 267. The substantially crystalline Compound 3 free form MTBE solvate Form A of embodiment 266, characterized by two or more XRPD signals selected from 15.6±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 269. 267. The substantially crystalline Compound 3 free form MTBE solvate Form A of embodiment 266, characterized by XRPD signals of 15.6±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta. 270. 267. The substantially crystalline Compound 3 free form MTBE solvate Form A of embodiment 266, characterized by (a) one or more XRPD signals selected from 15.6±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 9.1±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 13.6±0.2 degrees two-theta, 17.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta. 271. 267. The substantially crystalline Compound 3 free form MTBE solvate Form A of embodiment 266, characterized by (a) one or more XRPD signals selected from 15.6±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 9.1±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 13.6±0.2 degrees two-theta, 17.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta. 272. 267. The substantially crystalline Compound 3 free form MTBE solvate Form A of embodiment 266, characterized by (a) one or more XRPD signals selected from 15.6±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 9.1±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 13.6±0.2 degrees two-theta, 17.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta. 273. 267. The substantially crystalline Compound 3 free form MTBE solvate Form A of embodiment 266, characterized by (a) one or more XRPD signals selected from 15.6±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 9.1±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 13.6±0.2 degrees two-theta, 17.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta. 274. 267. The substantially crystalline Compound 3 free form MTBE solvate Form A of embodiment 266, characterized by (a) one or more XRPD signals selected from 15.6±0.2 degrees two-theta, 17.9±0.2 degrees two-theta, and 22.1±0.2 degrees two-theta, and (b) XRPD signals at 9.1±0.2 degrees two-theta, 10.2±0.2 degrees two-theta, 13.6±0.2 degrees two-theta, 17.0±0.2 degrees two-theta, and 19.7±0.2 degrees two-theta. 275. having one or more signals selected from 131.0±0.2 ppm, 129.1±0.2 ppm, 125.2±0.2 ppm, 124.5±0.2 ppm, 76.6±0.2 ppm, 55.1±0.2 ppm, 48.1±0.2 ppm, and 25.9±0.2 ppm 13 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by a C CPMAS. 276. Two or more signals selected from 131.0±0.2 ppm, 129.1±0.2 ppm, 125.2±0.2 ppm, 124.5±0.2 ppm, 76.6±0.2 ppm, 55.1±0.2 ppm, 48.1±0.2 ppm, and 25.9±0.2 ppm 13 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by a C CPMAS. 277. Three or more signals selected from 131.0±0.2 ppm, 129.1±0.2 ppm, 125.2±0.2 ppm, 124.5±0.2 ppm, 76.6±0.2 ppm, 55.1±0.2 ppm, 48.1±0.2 ppm, and 25.9±0.2 ppm 13 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by a C CPMAS. 278. Four or more signals selected from 131.0±0.2 ppm, 129.1±0.2 ppm, 125.2±0.2 ppm, 124.5±0.2 ppm, 76.6±0.2 ppm, 55.1±0.2 ppm, 48.1±0.2 ppm, and 25.9±0.2 ppm 13 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by a C CPMAS. 279. Five or more signals selected from 131.0±0.2 ppm, 129.1±0.2 ppm, 125.2±0.2 ppm, 124.5±0.2 ppm, 76.6±0.2 ppm, 55.1±0.2 ppm, 48.1±0.2 ppm, and 25.9±0.2 ppm 13 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by a C CPMAS. 280. Six or more signals selected from 131.0±0.2 ppm, 129.1±0.2 ppm, 125.2±0.2 ppm, 124.5±0.2 ppm, 76.6±0.2 ppm, 55.1±0.2 ppm, 48.1±0.2 ppm, and 25.9±0.2 ppm 13 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by a C CPMAS. 281. with signals of 131.0±0.2 ppm, 129.1±0.2 ppm, 125.2±0.2 ppm, 124.5±0.2 ppm, 76.6±0.2 ppm, 55.1±0.2 ppm, 48.1±0.2 ppm, and 25.9±0.2 ppm. 13 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by a C CPMAS. 282. having one or more signals selected from -131.4±0.2 ppm, -135.0±0.2 ppm, and -146.5±0.2 ppm 19 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by F MAS. 283. Two or more signals selected from -131.4±0.2 ppm, -135.0±0.2 ppm, and -146.5±0.2 ppm 19 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by F MAS. 284. with signals of -131.4±0.2 ppm, -135.0±0.2 ppm, and -146.5±0.2 ppm 19 The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by F MAS. 285. The substantially crystalline Compound 3 free form MTBE solvate Form A according to embodiment 266, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 14.7% from ambient temperature to about 175°C. 286. 267. The substantially crystalline Compound 3 free MTBE solvate Form A of embodiment 266, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 159°C and 251°C, and an exothermic peak at about 201°C. 287. A pharmaceutical composition comprising substantially crystalline Compound 3 according to any one of embodiments 192 to 286, and a pharmaceutically acceptable carrier. 288. A method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering to a patient in need thereof a therapeutically effective amount of substantially crystalline compound 3 according to any one of embodiments 192-286, or a therapeutically effective amount of the pharmaceutical composition according to embodiment 287. 289. Use of a substantially crystalline form of compound 3 according to any one of embodiments 192 to 286, or a pharmaceutical composition according to embodiment 287, in the manufacture of a medicament for the treatment of AATD. 290. A therapeutically effective amount of a substantially crystalline form of compound 3 according to any one of embodiments 192-286, or the pharmaceutical composition according to embodiment 287, for use in treating AATD. 291. 1. A method for preparing substantially crystalline Compound 3 Free Form Form A, comprising: (a) concentrating a reaction mixture in vacuo; (b) combining Compound 3 with water acidified to pH 3 and 2N HCl, cooling to 0° C., and extracting with EtOAc; (c) drying, filtering, and evaporating the extract in vacuo to provide a foam; (d) treating the foam with acetonitrile, refluxing, water, further refluxing, and then allowing to reach room temperature; (e) filtering the suspension obtained from (d) and washing the collected solid with acetonitrile:water (1:1); and (f) drying to provide substantially crystalline Compound 3 Free Form Form A. 292. A method for preparing substantially crystalline Compound 3 Free Form Form B, comprising: (a) slurrying amorphous Compound 3 in a chlorobenzene or toluene solution at room temperature for about two weeks; and (b) isolating the solid to provide substantially crystalline Compound 3 Free Form Form B. 293. A method for preparing substantially crystalline Compound 3 free form hydrate Form A, comprising: (a) dissolving Compound 3 free form Form A in 1,2-dimethoxyethane; (b) slowly adding the resulting solution to a vial containing water while stirring; (c) stirring the resulting solution until a precipitate appears; and (d) isolating the precipitate to provide substantially crystalline Compound 3 free form hydrate Form A. 294. A method for preparing substantially crystalline Compound 3 free form hydrate Form B, comprising: (a) dissolving Compound 3 free form Form A in acetone; (b) slowly adding the resulting solution to a vial containing water while stirring; (c) stirring the resulting solution until a precipitate appears; and (d) isolating the precipitate to obtain substantially crystalline Compound 3 free form hydrate Form B. 295. A method for preparing substantially crystalline Compound 3 free form hydrate Form C, comprising: (a) dissolving Compound 3 free form Form A in THF; (b) slowly adding methyl tert-butyl ether (MTBE) to the resulting solution while stirring until a precipitate appears; and (c) isolating the precipitate to obtain substantially crystalline Compound 3 free form hydrate Form C. 296. A method for preparing substantially crystalline Compound 3 free form MTBE solvate Form A, comprising: (a) triturating crude Compound 3 with MTBE; (b) dissolving the solid isolated for resin treatment in THF at 50° C.; (c) concentrating the THF filtrate; (d) recrystallizing from MTBE; and (e) isolating the solid to provide substantially crystalline Compound 3 free form MTBE solvate Form A. 297. Substantially crystalline Compound 4 free form Form A. [ka] 298. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by an XRPD signal of 16.2±0.2 degrees two-theta or 26.3±0.2 degrees two-theta. 299. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by XRPD signals at 16.2±0.2 degrees two-theta and 26.3±0.2 degrees two-theta. 300. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by one or more XRPD signals selected from (a) 16.2±0.2 degrees two-theta and 26.3±0.2 degrees two-theta, and (b) 11.6±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 301. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by (a) an XRPD signal at 16.2±0.2 degrees two-theta or 26.3±0.2 degrees two-theta, and (b) XRPD signals at 11.6±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 302. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by XRPD signals at 11.6±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, 18.9±0.2 degrees two-theta, and 26.3±0.2 degrees two-theta. 303. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by (a) an XRPD signal at 16.2±0.2 degrees two-theta and / or 26.3±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 10.8±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.9±0.2 degrees two-theta, and 23.3±0.2 degrees two-theta. 304. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by (a) an XRPD signal at 16.2±0.2 degrees two-theta and / or 26.3±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 10.8±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.9±0.2 degrees two-theta, and 23.3±0.2 degrees two-theta. 305. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by (a) an XRPD signal at 16.2±0.2 degrees two-theta and / or 26.3±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 10.8±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.9±0.2 degrees two-theta, and 23.3±0.2 degrees two-theta. 306. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by (a) an XRPD signal at 16.2±0.2 degrees two-theta and / or 26.3±0.2 degrees two-theta, and (b) five or more XRPD signals selected from 10.8±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 18.9±0.2 degrees two-theta, and 23.3±0.2 degrees two-theta. 307. 298. The substantially crystalline Compound 4 Free Form Form A of embodiment 297, characterized by XRPD signals at 10.8±0.2 degrees two-theta, 11.6±0.2 degrees two-theta, 12.0±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 16.2±0.2 degrees two-theta, 18.9±0.2 degrees two-theta, 23.3±0.2 degrees two-theta, and 26.3±0.2 degrees two-theta. 308. having one or more signals selected from 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and 124.4±0.2 ppm 13 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 309. Two or more signals selected from 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and 124.4±0.2 ppm 13 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 310. Three or more signals selected from 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and 124.4±0.2 ppm 13 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 311. with signals of 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and 124.4±0.2 ppm. 13The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 312. (a) having signals of 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and / or 124.4±0.2 ppm, and (b) having one or more signals selected from 141.5±0.2 ppm, 138.7±0.2 ppm, 132.9±0.2 ppm, 130.5±0.2 ppm, 127.3±0.2 ppm, and 117.6±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 313. (a) having signals of 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and / or 124.4±0.2 ppm, and (b) having two or more signals selected from 141.5±0.2 ppm, 138.7±0.2 ppm, 132.9±0.2 ppm, 130.5±0.2 ppm, 127.3±0.2 ppm, and 117.4±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 314. (a) having signals of 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and / or 124.4±0.2 ppm, and (b) having three or more signals selected from 141.5±0.2 ppm, 138.7±0.2 ppm, 132.9±0.2 ppm, 130.5±0.2 ppm, 127.3±0.2 ppm, and 117.4±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 315. (a) having signals of 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and / or 124.4±0.2 ppm, and (b) having four or more signals selected from 141.5±0.2 ppm, 138.7±0.2 ppm, 132.9±0.2 ppm, 130.5±0.2 ppm, 127.3±0.2 ppm, and 117.4±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 316. (b) signals at 171.0±0.2 ppm, 131.3±0.2 ppm, 126.8±0.2 ppm, and / or 124.4±0.2 ppm, and (b) signals at 141.5±0.2 ppm, 138.7±0.2 ppm, 132.9±0.2 ppm, 130.5±0.2 ppm, 127.3±0.2 ppm, and 117.4±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a C CPMAS. 317. -Having a signal of 100.1±0.2 ppm and / or 116.5±0.2 ppm 19 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by F MAS. 318a. with signals of -100.1±0.2 ppm, -105.0±0.2 ppm, -114.7±0.2 ppm, and -116.5±0.2 ppm 19 The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by F MAS. 318b. The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 0.6% from ambient temperature to about 200°C. 318c. The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by differential scanning calorimetry (DSC) analysis showing an endothermic peak at about 253°C. 318d. Cu K α 298. The substantially crystalline Compound 4 Free Form Form A according to embodiment 297, characterized by a monoclinic crystal system, a P21 space group, and unit cell dimensions, as measured at 100 K using a Bruker diffractometer equipped with a CMOS detector with radiation (λ=1.54178 Å) and the following characteristics: [Table 8] 319. Substantially crystalline Compound 4 free form Form B. [ka] 320. 319. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by one or more XRPD signals selected from 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta. 321. 319. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by two or more XRPD signals selected from 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta. 322. 319. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by three or more XRPD signals selected from 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta. 323. 320. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by XRPD signals at 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta. 324. 320. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by (a) one or more XRPD signals selected from 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 10.7±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 16.9±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 325. 320. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by (a) two or more XRPD signals selected from 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 10.7±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 16.9±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 326. 320. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by (a) three or more XRPD signals selected from 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 10.7±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 16.9±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 327. 320. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by one or more XRPD signals selected from: (a) 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta, and (b) 10.7±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 16.9±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 328. 320. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by two or more XRPD signals selected from: (a) 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta, and (b) 10.7±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 16.9±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 329. 320. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by three or more XRPD signals selected from: (a) 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, and 8.7±0.2 degrees two-theta, and (b) 10.7±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 16.9±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 330. 320. The substantially crystalline Compound 4 Free Form Form B of embodiment 319, characterized by XRPD signals at 3.2±0.2 degrees two-theta, 6.4±0.2 degrees two-theta, 8.3±0.2 degrees two-theta, 8.7±0.2 degrees two-theta, 10.7±0.2 degrees two-theta, 11.7±0.2 degrees two-theta, 16.9±0.2 degrees two-theta, and 18.9±0.2 degrees two-theta. 331. having one or more signals selected from 134.0±0.2 ppm, 128.9±0.2 ppm, 125.9±0.2 ppm, and 123.6±0.2 ppm 13 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by a C CPMAS. 332. Two or more signals selected from 134.0±0.2 ppm, 128.9±0.2 ppm, 125.9±0.2 ppm, and 123.6±0.2 ppm 13 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by a C CPMAS. 333. Three or more signals selected from 134.0±0.2 ppm, 128.9±0.2 ppm, 125.9±0.2 ppm, and 123.6±0.2 ppm 13 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by a C CPMAS. 334. with signals of 134.0±0.2 ppm, 128.9±0.2 ppm, 125.9±0.2 ppm, and 123.6±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by a C CPMAS. 335a. (a) having signals of 134.0±0.2 ppm, 128.9±0.2 ppm, 125.9±0.2 ppm, and / or 123.6±0.2 ppm, and (b) having one or more signals selected from 143.3±0.2 ppm, 138.7±0.2 ppm, 130.7±0.2 ppm, 129.5±0.2 ppm, 117.6±0.2 ppm, and 6.7±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by a C CPMAS. 335b. (a) having signals of 134.0±0.2 ppm, 128.9±0.2 ppm, 125.9±0.2 ppm, and / or 123.6±0.2 ppm, and (b) having two or more signals selected from 143.3±0.2 ppm, 138.7±0.2 ppm, 130.7±0.2 ppm, 129.5±0.2 ppm, 117.6±0.2 ppm, and 6.7±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by a C CPMAS. 335c. (a) having signals of 134.0±0.2 ppm, 128.9±0.2 ppm, 125.9±0.2 ppm, and / or 123.6±0.2 ppm, and (b) having three or more signals selected from 143.3±0.2 ppm, 138.7±0.2 ppm, 130.7±0.2 ppm, 129.5±0.2 ppm, 117.6±0.2 ppm, and 6.7±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by a C CPMAS. 336. (a) with signals of 134.0±0.2 ppm, 128.9±0.2 ppm, 125.9±0.2 ppm, and / or 123.6±0.2 ppm, and (b) with signals of 143.3±0.2 ppm, 138.7±0.2 ppm, 130.7±0.2 ppm, 129.5±0.2 ppm, 117.6±0.2 ppm, and 6.7±0.2 ppm. 13 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by a C CPMAS. 337. -109.4±0.2 ppm, with a signal of -110.5±0.2 ppm and / or -113.6±0.2 ppm 19 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by F MAS. 338a. with signals of -105.0±0.2 ppm, -109.4±0.2 ppm, -110.5±0.2 ppm, and -113.6±0.2 ppm 19 The substantially crystalline Compound 4 Free Form Form B according to embodiment 319, characterized by F MAS. 338b. The substantially crystalline Compound 4 Free Form B according to embodiment 319, characterized by thermogravimetric analysis (TGA) showing minimal weight loss from ambient temperature to about 200°C. 338c. The substantially crystalline Compound 4 Free Form Form A according to embodiment 319, characterized by differential scanning calorimetry (DSC) analysis showing an endothermic peak at about 246°C. 339. Substantially crystalline Compound 4 free form Form C. [ka] 340. 339. The substantially crystalline Compound 4 Free Form Form C of embodiment 339, characterized by (a) an XRPD signal at 13.9±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 5.6±0.2 degrees two-theta, 9.2±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.2±0.2 degrees two-theta, 17.4±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 25.3±0.2 degrees two-theta. 341. 339. The substantially crystalline Compound 4 Free Form Form C of embodiment 339, characterized by (a) an XRPD signal at 13.9±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 5.6±0.2 degrees two-theta, 9.2±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.2±0.2 degrees two-theta, 17.4±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 25.3±0.2 degrees two-theta. 342. 339. The substantially crystalline Compound 4 Free Form Form C of embodiment 339, characterized by (a) an XRPD signal at 13.9±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 5.6±0.2 degrees two-theta, 9.2±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.2±0.2 degrees two-theta, 17.4±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 25.3±0.2 degrees two-theta. 343. 339. The substantially crystalline Compound 4 Free Form Form C of embodiment 339, characterized by (a) an XRPD signal at 13.9±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 5.6±0.2 degrees two-theta, 9.2±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.2±0.2 degrees two-theta, 17.4±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 25.3±0.2 degrees two-theta. 345. 339. The substantially crystalline Compound 4 Free Form Form C of embodiment 339, characterized by (a) an XRPD signal at 13.9±0.2 degrees two-theta, and (b) five or more XRPD signals selected from 5.6±0.2 degrees two-theta, 9.2±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.2±0.2 degrees two-theta, 17.4±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 25.3±0.2 degrees two-theta. 346. 339. The substantially crystalline Compound 4 Free Form Form C of embodiment 339, characterized by (a) an XRPD signal at 13.9±0.2 degrees two-theta, and (b) six or more XRPD signals selected from 5.6±0.2 degrees two-theta, 9.2±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.2±0.2 degrees two-theta, 17.4±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 25.3±0.2 degrees two-theta. 347a. 339. The substantially crystalline Compound 4 Free Form Form C of embodiment 339, characterized by XRPD signals at 5.6±0.2 degrees two-theta, 9.2±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 12.2±0.2 degrees two-theta, 13.9±0.2 degrees two-theta, 17.4±0.2 degrees two-theta, 18.3±0.2 degrees two-theta, and 25.3±0.2 degrees two-theta. 347b. The substantially crystalline Compound 4 Free Form C according to embodiment 339, characterized by thermogravimetric analysis (TGA) showing negligible weight loss from ambient temperature to about 200°C. 347c. The substantially crystalline Compound 4 Free Form C according to embodiment 339, characterized by differential scanning calorimetry (DSC) analysis showing an endothermic peak at about 252°C. 348. Substantially crystalline Compound 4 free form Form D. [ka] 349. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by one or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta. 350. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by two or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta. 350. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by three or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta. 351. 349. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by (a) one or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 11.1±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 19.0±0.2 degrees two-theta, and 24.9±0.2 degrees two-theta. 352. 349. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by (a) one or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 11.1±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 19.0±0.2 degrees two-theta, and 24.9±0.2 degrees two-theta. 353. 349. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by (a) one or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 11.1±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 19.0±0.2 degrees two-theta, and 24.9±0.2 degrees two-theta. 354. 349. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by (a) one or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 11.1±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 19.0±0.2 degrees two-theta, and 24.9±0.2 degrees two-theta. 355. 349. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by (a) one or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta, and (b) XRPD signals at 11.1±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 19.0±0.2 degrees two-theta, and 24.9±0.2 degrees two-theta. 356. 349. The substantially crystalline Compound 4 Free Form Form D of embodiment 348, characterized by (a) two or more XRPD signals selected from 9.9±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta, and (b) XRPD signals at 11.1±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 19.0±0.2 degrees two-theta, and 24.9±0.2 degrees two-theta. 357. 349. The substantially crystalline Compound 4 free form Form D of embodiment 348, characterized by an XRPD signal selected from 9.9±0.2 degrees two-theta, 11.1±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 17.1±0.2 degrees two-theta, 19.0±0.2 degrees two-theta, 23.9±0.2 degrees two-theta, 24.9±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta. 358. having one or more signals selected from 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and 125.0±0.2 ppm 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 359. Two or more signals selected from 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and 125.0±0.2 ppm 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 360. Three or more signals selected from 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and 125.0±0.2 ppm 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 361. with signals of 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and 125.0±0.2 ppm. 13The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 362. (a) having signals of 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and / or 125.0±0.2 ppm, and (b) having one or more signals selected from 141.9±0.2 ppm, 132.9±0.2 ppm, 129.8±0.2 ppm, 127.4±0.2 ppm, 116.0±0.2 ppm, and 7.3±0.2 ppm. 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 363. (a) having signals of 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and / or 125.0±0.2 ppm, and (b) having two or more signals selected from 141.9±0.2 ppm, 132.9±0.2 ppm, 129.8±0.2 ppm, 127.4±0.2 ppm, 116.0±0.2 ppm, and 7.3±0.2 ppm. 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 364. (a) having signals of 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and / or 125.0±0.2 ppm, and (b) having three or more signals selected from 141.9±0.2 ppm, 132.9±0.2 ppm, 129.8±0.2 ppm, 127.4±0.2 ppm, 116.0±0.2 ppm, and 7.3±0.2 ppm. 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 364. (a) with signals of 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and / or 125.0±0.2 ppm, and (b) with signals of 141.9±0.2 ppm, 132.9±0.2 ppm, 129.8±0.2 ppm, 127.4±0.2 ppm, 116.0±0.2 ppm, and 7.3±0.2 ppm. 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 365. (a) having two or more signals selected from 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and / or 125.0±0.2 ppm, and (b) having signals of 141.9±0.2 ppm, 132.9±0.2 ppm, 129.8±0.2 ppm, 127.4±0.2 ppm, 116.0±0.2 ppm, and 7.3±0.2 ppm. 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 366. (a) having three or more signals selected from 170.0±0.2 ppm, 140.6±0.2 ppm, 131.8±0.2 ppm, and / or 125.0±0.2 ppm, and (b) having signals of 141.9±0.2 ppm, 132.9±0.2 ppm, 129.8±0.2 ppm, 127.4±0.2 ppm, 116.0±0.2 ppm, and 7.3±0.2 ppm. 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 367. with signals of 170.0±0.2 ppm, 141.9±0.2 ppm, 140.6±0.2 ppm, 132.9±0.2 ppm, 131.8±0.2 ppm, 129.8±0.2 ppm, 127.4±0.2 ppm, 125.0±0.2 ppm, 116.0±0.2 ppm, and 7.3±0.2 ppm. 13 The substantially crystalline Compound 4 free form Form D according to embodiment 348, characterized by a C CPMAS. 368. -108.6±0.2 ppm or -115.9±0.2 ppm signal 19 The substantially crystalline Compound 4 Free Form Form D according to embodiment 348, characterized by F MAS. 369. -108.6±0.2ppm and -115.9±0.2 ppm signal 19 The substantially crystalline Compound 4 Free Form Form D according to embodiment 348, characterized by F MAS. 370a. -105.0±0.2 ppm, -115.0±0.2 ppm, or -115.9±0.2 ppm 19 The substantially crystalline Compound 4 Free Form Form D according to embodiment 348, characterized by F MAS. 370b. The substantially crystalline Compound 4 Free Form D according to embodiment 348, characterized by thermogravimetric analysis (TGA) showing negligible weight loss from ambient temperature to about 200°C. 370c. The substantially crystalline Compound 4 Free Form D according to embodiment 348, characterized by differential scanning calorimetry (DSC) analysis showing an endothermic peak at about 268°C. 371. Substantially crystalline Compound 4 free form hydrate Form A. [ka] 372. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by an XRPD signal of 20.3±0.2 degrees two-theta or 23.3±0.2 degrees two-theta. 373. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by an XRPD signal at 20.3±0.2 degrees two-theta and a signal at 23.3±0.2 degrees two-theta. 374. 372. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by (a) an XRPD signal at 20.3±0.2 degrees two-theta and / or a signal at 23.3±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 11.8±0.2 degrees two-theta, 12.1±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 22.4±0.2 degrees two-theta, and 23.6±0.2 degrees two-theta. 375. 372. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by (a) an XRPD signal at 20.3±0.2 degrees two-theta and / or a signal at 23.3±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 11.8±0.2 degrees two-theta, 12.1±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 22.4±0.2 degrees two-theta, and 23.6±0.2 degrees two-theta. 376. 372. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by (a) an XRPD signal at 20.3±0.2 degrees two-theta and / or a signal at 23.3±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 11.8±0.2 degrees two-theta, 12.1±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 22.4±0.2 degrees two-theta, and 23.6±0.2 degrees two-theta. 377. 372. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by (a) an XRPD signal at 20.3±0.2 degrees two-theta and / or a signal at 23.3±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 11.8±0.2 degrees two-theta, 12.1±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 22.4±0.2 degrees two-theta, and 23.6±0.2 degrees two-theta. 378. 372. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by (a) an XRPD signal at 20.3±0.2 degrees two-theta and / or a signal at 23.3±0.2 degrees two-theta, and (b) five or more XRPD signals selected from 11.8±0.2 degrees two-theta, 12.1±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 22.4±0.2 degrees two-theta, and 23.6±0.2 degrees two-theta. 379. 372. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by (a) an XRPD signal at 20.3±0.2 degrees two-theta and / or a signal at 23.3±0.2 degrees two-theta, and (b) XRPD signals at 11.8±0.2 degrees two-theta, 12.1±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 22.4±0.2 degrees two-theta, and 23.6±0.2 degrees two-theta. 380. 372. The substantially crystalline Compound 4 free form hydrate Form A of embodiment 371, characterized by XRPD signals at 11.8±0.2 degrees two-theta, 12.1±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 18.0±0.2 degrees two-theta, 20.3±0.2 degrees two-theta, 22.4±0.2 degrees two-theta, 23.3±0.2 degrees two-theta, and 23.6±0.2 degrees two-theta. 381. having one or more signals selected from 142.4±0.2 ppm, 136.2±0.2 ppm, 134.1±0.2 ppm, 133.2±0.2 ppm, 131.8±0.2 ppm, 128.8±0.2 ppm, 127.7±0.2 ppm, 124.2±0.2 ppm, 117.9±0.2 ppm, and 7.9±0.2 ppm 13 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by a C CPMAS. 382. Two or more signals selected from 142.4±0.2 ppm, 136.2±0.2 ppm, 134.1±0.2 ppm, 133.2±0.2 ppm, 131.8±0.2 ppm, 128.8±0.2 ppm, 127.7±0.2 ppm, 124.2±0.2 ppm, 117.9±0.2 ppm, and 7.9±0.2 ppm. 13 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by a C CPMAS. 383. Three or more signals selected from 142.4±0.2 ppm, 136.2±0.2 ppm, 134.1±0.2 ppm, 133.2±0.2 ppm, 131.8±0.2 ppm, 128.8±0.2 ppm, 127.7±0.2 ppm, 124.2±0.2 ppm, 117.9±0.2 ppm, and 7.9±0.2 ppm 13 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by a C CPMAS. 384. having four or more signals selected from 142.4±0.2 ppm, 136.2±0.2 ppm, 134.1±0.2 ppm, 133.2±0.2 ppm, 131.8±0.2 ppm, 128.8±0.2 ppm, 127.7±0.2 ppm, 124.2±0.2 ppm, 117.9±0.2 ppm, and 7.9±0.2 ppm; 13 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by a C CPMAS. 385. Five or more signals selected from 142.4±0.2 ppm, 136.2±0.2 ppm, 134.1±0.2 ppm, 133.2±0.2 ppm, 131.8±0.2 ppm, 128.8±0.2 ppm, 127.7±0.2 ppm, 124.2±0.2 ppm, 117.9±0.2 ppm, and 7.9±0.2 ppm. 13 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by a C CPMAS. 386. Six or more signals selected from 142.4±0.2 ppm, 136.2±0.2 ppm, 134.1±0.2 ppm, 133.2±0.2 ppm, 131.8±0.2 ppm, 128.8±0.2 ppm, 127.7±0.2 ppm, 124.2±0.2 ppm, 117.9±0.2 ppm, and 7.9±0.2 ppm. 13 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by a C CPMAS. 387. Seven or more signals selected from 142.4±0.2 ppm, 136.2±0.2 ppm, 134.1±0.2 ppm, 133.2±0.2 ppm, 131.8±0.2 ppm, 128.8±0.2 ppm, 127.7±0.2 ppm, 124.2±0.2 ppm, 117.9±0.2 ppm, and 7.9±0.2 ppm. 13 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by a C CPMAS. 388. with signals of 142.4±0.2 ppm, 136.2±0.2 ppm, 134.1±0.2 ppm, 133.2±0.2 ppm, 131.8±0.2 ppm, 128.8±0.2 ppm, 127.7±0.2 ppm, 124.2±0.2 ppm, 117.9±0.2 ppm, and 7.9±0.2 ppm. 13 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by a C CPMAS. 389. having one or more signals selected from -104.7±0.2 ppm, -105.5±0.2 ppm, -114.4±0.2 ppm, and -115.2±0.2 ppm 19 The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by F MAS. 390a. with signals of -104.7±0.2 ppm, -105.5±0.2 ppm, -114.4±0.2 ppm, and -115.2±0.2 ppm 19The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by F MAS. 390b. The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by thermogravimetric analysis (TGA) showing a weight loss of 3.3% from ambient temperature to about 200°C. 390c. The substantially crystalline Compound 4 free form hydrate Form A according to embodiment 371, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 103, 178, and 257°C, and exothermic peaks at about 126 and 204°C. 391. Substantially crystalline Compound 4 free form hydrate Form B. [ka] 392. The substantially crystalline Compound 4 free form hydrate Form B of embodiment 391, characterized by an XRPD signal of 16.7±0.2 degrees two-theta. 393. 392. The substantially crystalline Compound 4 free form hydrate Form B of embodiment 391, characterized by (a) an XRPD signal of 16.7±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 13.2±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, and 19.1±0.2 degrees two-theta. 394. 392. The substantially crystalline Compound 4 free form hydrate Form B of embodiment 391, characterized by (a) an XRPD signal at 16.7±0.2 degrees two-theta, and (b) two or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 13.2±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, and 19.1±0.2 degrees two-theta. 395. 392. The substantially crystalline Compound 4 free form hydrate Form B of embodiment 391, characterized by (a) an XRPD signal at 16.7±0.2 degrees two-theta, and (b) three or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 13.2±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, and 19.1±0.2 degrees two-theta. 396. 392. The substantially crystalline Compound 4 free form hydrate Form B of embodiment 391, characterized by (a) an XRPD signal at 16.7±0.2 degrees two-theta, and (b) four or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 13.2±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, and 19.1±0.2 degrees two-theta. 397. 392. The substantially crystalline Compound 4 free form hydrate Form B of embodiment 391, characterized by (a) an XRPD signal at 16.7±0.2 degrees two-theta, and (b) five or more XRPD signals selected from 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 13.2±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, and 19.1±0.2 degrees two-theta. 398a. 392. The substantially crystalline Compound 4 free form hydrate Form B of embodiment 391, characterized by XRPD signals of 9.4±0.2 degrees two-theta, 11.8±0.2 degrees two-theta, 13.2±0.2 degrees two-theta, 15.3±0.2 degrees two-theta, 15.8±0.2 degrees two-theta, 16.7±0.2 degrees two-theta, and 19.1±0.2 degrees two-theta. 398b. The substantially crystalline Compound 4 free form hydrate Form B according to embodiment 391, characterized by thermogravimetric analysis (TGA) showing a weight loss of 5.2% from ambient temperature to about 200°C. 398c. 392. The substantially crystalline Compound 4 free form hydrate Form B according to embodiment 391, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 96, 179, and 244°C and an exothermic peak at about 198°C. 399. Substantially crystalline Compound 4 free form hydrate Form C. [ka] 400. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by one or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 401. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by two or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 402. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by three or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 403. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by four or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 404. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by XRPD signals of 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta. 405. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by (a) one or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) one or more XRPD signals selected from 11.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 18.1±0.2 degrees two-theta. 406. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by (a) one or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) XRPD signals of 11.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 18.1±0.2 degrees two-theta. 407. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by (a) two or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) XRPD signals of 11.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 18.1±0.2 degrees two-theta. 408. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by (a) three or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) XRPD signals of 11.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 18.1±0.2 degrees two-theta. 409. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by (a) four or more XRPD signals selected from 3.0±0.2 degrees two-theta, 6.6±0.2 degrees two-theta, 10.5±0.2 degrees two-theta, 21.0±0.2 degrees two-theta, and 28.1±0.2 degrees two-theta, and (b) XRPD signals of 11.6±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, and 18.1±0.2 degrees two-theta. 410. 399. The substantially crystalline Compound 4 free form hydrate Form C of embodiment 399, characterized by XRPD signals of 3.0±0.2 degrees 2-theta, 6.6±0.2 degrees 2-theta, 10.5±0.2 degrees 2-theta, 11.6±0.2 degrees 2-theta, 15.5±0.2 degrees 2-theta, 18.1±0.2 degrees 2-theta, 21.0±0.2 degrees 2-theta, and 28.1±0.2 degrees 2-theta. 411. The substantially crystalline Compound 4 free form hydrate Form C according to embodiment 399, characterized by differential scanning calorimetry (DSC) analysis showing endothermic peaks at about 234 and 249°C. 412. A pharmaceutical composition comprising substantially crystalline compound 4 according to any one of embodiments 297 to 411, and a pharmaceutically acceptable carrier. 413. A method for treating alpha-1 antitrypsin deficiency (AATD), comprising administering to a patient in need thereof a therapeutically effective amount of substantially crystalline compound 4 according to any one of embodiments 297-411, or a therapeutically effective amount of the pharmaceutical composition according to embodiment 412. 414. Use of a substantially crystalline form of compound 3 according to any one of embodiments 297 to 411, or a pharmaceutical composition according to embodiment 412, in the manufacture of a medicament for the treatment of AATD. 415. A therapeutically effective amount of a substantially crystalline form of compound 3 according to any one of embodiments 297-411, or the pharmaceutical composition according to embodiment 412, for use in treating AATD. 416. 1. A method for preparing substantially crystalline Compound 4 Free Form Form A, comprising: (a) adding 1:2 EtOH:water (v / v) to amorphous Compound 4; (b) stirring at room temperature for 2 hours; (c) centrifuging to collect the solid as seeds; (d) adding 1:2 EtOH:water (v / v) to amorphous Compound 4 again; (e) adding the seeds from step (c) and stirring for about 2 days; and (f) centrifuging, collecting, and drying the solid to provide substantially crystalline Compound 4 Free Form Form A. 417. (c) washing the organic phase sequentially with water, brine, and drying over MgSO4; (d) filtering and concentrating under reduced pressure to provide Compound 4 as an oil; (e) treating the residue with methylene chloride and concentrating under reduced pressure to provide a tan, crisp foam; (f) treating the foam with methylene chloride, heating to reflux for 4 hours, and stirring at room temperature for 1 hour; (f) filtering the resulting suspension and washing the collected solid with DCM; and (g) drying in a vacuum oven at 80°C to remove the DCM and provide substantially crystalline Compound 4, Free Form Form B. 418. A method for preparing substantially crystalline Compound 4 Free Form C, comprising: (a) suspending a sample of Compound 4 Free Form B in MBTE; (b) stirring at 50°C for 3 days; and (c) isolating the solid and heating at 200°C until all MBTE is removed to obtain substantially crystalline Compound 4 Free Form C. 419. A method for preparing substantially crystalline free form Form D of Compound 4, comprising: (a) suspending a sample of amorphous Compound 4 in n-propyl acetate; (b) stirring at 5°C for 4 days; and (c) isolating and drying the solid at 150°C until all n-propyl acetate is removed to obtain crystalline free form Form D of Compound 4. 420. 1. A method for preparing substantially crystalline Compound 4 free form hydrate Form A, comprising: (a) adding water to a sample of amorphous Compound 4 in a container; (b) sealing the container and shaking at 800 rpm for approximately two weeks; (c) isolating the solid as a seed; (d) mixing water with Compound 4 free form Form B; (e) bath sonicating for 3 minutes, followed by adding the seed from step (c) and shaking at 30°C overnight; (f) adding water and shaking at 30°C for four days; and (g) isolating the solid to obtain substantially crystalline Compound 4 free form hydrate Form A. 420. A method for preparing substantially crystalline Compound 4 free form hydrate form B, comprising: (a) suspending Compound 4 free form form B in acetone / water; (b) stirring at room temperature for four days; and (c) isolating the solid to provide substantially crystalline Compound 4 free form hydrate form B. 421. A method for preparing substantially crystalline Compound 4 free form hydrate Form C, comprising the steps of: (a) suspending Compound 4 free form Form B in chlorobenzene or methylchlorobenzene; (b) stirring at room temperature for 8 days; and (c) isolating the solid to provide substantially crystalline Compound 4 free form hydrate Form C.

[0123] III. Pharmaceutical Compositions Another aspect of the present disclosure provides pharmaceutical compositions comprising a compound of Formula Ia, 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 compound of Formula Ia selected from Compounds 1-5. In some embodiments, a pharmaceutical composition comprising a compound of Formula Ia, any of Compounds 1-5, 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.

[0124] Some aspects provide pharmaceutical compositions comprising a compound of Formula Ib, 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 compound of Formula Ib selected from compounds 6-59. In some embodiments, a pharmaceutical composition comprising a compound of Formula Ib, any of compounds 6-57, 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.

[0125] Some aspects provide pharmaceutical compositions comprising a compound of Formula Ib-i, 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 compound of Formula Ib-i selected from compounds 6-21, 33-42, 44-50, 52, 53, and 57. In some embodiments, a pharmaceutical composition comprising a compound of Formula Ib-i, any of compounds 6-21, 33-42, 44-50, 52, 53, and 57, 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.

[0126] Some aspects provide pharmaceutical compositions comprising a compound of Formula Ib-ii, 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 compound of Formula Ib-ii selected from compounds 22-32, 43, 51, and 54-56. In some embodiments, a pharmaceutical composition comprising a compound of Formula Ib-ii, any of compounds 22-32, 43, 51, and 54-56, 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.

[0127] Some aspects provide pharmaceutical compositions comprising a compound of Formula Ic, 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 compound of Formula Ic selected from compounds 58-67. In some embodiments, a pharmaceutical composition comprising a compound of Formula Ic, any of compounds 58-67, 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.

[0128] The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, or lubricant.

[0129] It is also understood that the pharmaceutical compositions of the present disclosure may be used in combination therapy, i.e., the pharmaceutical compositions described herein may further comprise at least one other active agent. Pharmaceutical compositions comprising at least one compound of Formula I, including compounds of Formulae Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered as separate compositions simultaneously with, before, or after a composition comprising at least one additional active agent. In some embodiments, pharmaceutical compositions comprising at least one compound selected from Compounds 1-5, Compounds 6-21, Compounds 22-27, and Compounds 28-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered as separate compositions simultaneously with, before, or after a composition comprising at least one additional active agent.

[0130] In some embodiments, compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, are combined with at least one additional active agent for simultaneous, separate, or sequential use in the treatment of AATD. In some embodiments, when used simultaneously, the compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and the at least one additional active agent are in separate pharmaceutical compositions. In some embodiments, when used simultaneously, the compounds of Formula I, including compounds of Formulae Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one additional active agent are all in the same pharmaceutical composition. In some embodiments, the compound is a compound selected from compounds 1-5, 6-21, 22-27, 33-42, 44-50, 52, 53, and 57, 28-32, 43, 51, and 54-56, and 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0131] In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, are provided for use in methods of treating AATD, the methods comprising co-administering the compound and an additional active agent. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compound is selected from compounds 1-5, compounds 6-21, compounds 22-27, compounds 33-42, 44-50, 52, 53, and 57, compounds 28-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0132] In some embodiments, combinations of compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and an additional active agent are provided for use in methods of treating AATD. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compound is selected from compounds 1-5, compounds 6-21, compounds 22-27, compounds 33-42, 44-50, 52, 53, and 57, compounds 28-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0133] In some embodiments, an additional active agent is provided for use in a method for treating AATD, the method comprising co-administering the additional active agent with a compound of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compound is selected from compounds 1-5, compounds 6-21, compounds 22-27, compounds 33-42, 44-50, 52, 53, and 57, compounds 28-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0134] In some embodiments, compounds of Formula I, including compounds of Formula Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, are provided for use in methods of treating AATD, wherein the compounds are prepared for administration in combination with an additional active agent. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential administration. In some embodiments, the compound is selected from compounds 1-5, compounds 6-21, compounds 22-27, compounds 33-42, 44-50, 52, 53, and 57, compounds 28-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0135] In some embodiments, combinations of compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and an additional active agent are provided for use in methods of treating AATD. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential administration. In some embodiments, the compound is selected from compounds 1-5, compounds 6-21, compounds 22-27, compounds 33-42, 44-50, 52, 53, and 57, compounds 28-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0136] In some embodiments, an additional active agent is provided for use in a method for treating AATD, wherein the additional active agent is prepared for administration in combination with a compound of Formula I, including compounds of Formulae Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential administration. In some embodiments, the compound is selected from compounds 1-5, compounds 6-21, compounds 22-27, compounds 33-42, 44-50, 52, 53, and 57, compounds 28-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0137] In some embodiments, the additional active agent is selected from the group consisting of alpha-1 antitrypsin protein (AAT) from plasma of a healthy human donor and recombinant AAT. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) from plasma of a healthy human donor. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) from plasma of a healthy human donor.

[0138] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. As used herein, the at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for the specific 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, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include 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, polyvinylpyrrolidone, 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 carboxymethylcellulose), and the like. Ingredients include, but are not limited to, corn starch, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), 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, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0139] In another aspect of the present invention, the compounds and pharmaceutical compositions described herein are used to treat AATD. In some embodiments, the subject in need of treatment with the compounds and compositions of the present disclosure has a ZZ mutation. In some embodiments, the subject in need of treatment with the compounds and compositions of the present disclosure has an SZ mutation.

[0140] In some embodiments, the methods of the disclosure comprise administering to a patient in need thereof a compound selected from any of the compounds of Formula I, including compounds of Formulae Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound is selected from compounds 1-5, 6-21, 22-27, 33-42, 44-50, 52, 53, and 57, 28-32, 43, 51, and 54-56, and 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the patient in need thereof has a Z mutation in the alpha-1 antitrypsin gene. In some embodiments, the patient in need thereof is homozygous for a Z mutation in the alpha-1 antitrypsin gene.

[0141] Another aspect of the present disclosure provides a method for modulating alpha-1 antitrypsin activity, comprising contacting the aforementioned alpha-1 antitrypsin with at least one compound of Formula I, including compounds of Formulae Ia, Ib, Ib-i, Ib-ii, and Ic, tautomers thereof, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method for modulating alpha-1 antitrypsin activity comprises contacting the aforementioned alpha-1 antitrypsin with at least one compound selected from compounds 1-5, compounds 6-21, compounds 22-27, compounds 33-42, 44-50, 52, 53, and 57, compounds 28-32, 43, 51, and 54-56, and compounds 58-67, tautomers of the compounds, deuterated derivatives of the compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0142] In some embodiments, the method of modulating alpha-1 antitrypsin activity is performed in vivo. In some embodiments, the method of modulating alpha-1 antitrypsin activity is performed ex vivo, and the alpha-1 antitrypsin is derived from a biological sample obtained from a human subject. In some embodiments, the method of modulating AAT is performed in vitro, and the alpha-1 antitrypsin is derived 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 obtained from a liver biopsy.

[0143] Preparation of Compound IV All generic, subgeneric, and specific compound formulae disclosed herein are considered to be part of the present invention.

[0144] The compounds of the invention can be made according to standard chemical practices or as described herein. The following abbreviations are used throughout the following synthetic schemes and in describing the preparation of compounds of Formula I, including compounds of Formulas Ia, Ib, Ib-i, Ib-ii, and Ic, compounds 1-5, compounds 6-21, compounds 22-27, compounds 33-42, 44-50, 52, 53, and 57, compounds 28-32, 43, 51, and 54-56, and compounds 58-67, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing:

[0145] A. Abbreviation Unless otherwise specified, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: [Table 9-1] [Table 9-2]

[0146] B. Starting Materials 6-Bromo-7-fluoro-N-(4-fluoro-3-methoxyphenyl)-1H-indazol-5-amine (S1) and 6-Bromo-7-fluoro-5-((4-fluoro-3-methoxyphenyl)amino)-1H-indazole-1-carboxylate benzyl (S2) [ka] Step 1: 4-Fluoro-3-methoxyaniline (18 g, 126.25 mmol) was dissolved in 6-bromo-7-fluoro-5-iodo-1H-indazole (33 g, 90.989 mmol), NaO in anhydrous 1,4-dioxane (300 mL) at ambient temperature under a nitrogen atmosphere. t To a stirred and degassed suspension of Bu (26.5 g, 267.47 mmol) and XantPhos Pd G3 (4.5 g, 4.513 mmol) was added. The synthesis of 6-bromo-7-fluoro-5-iodo-1H-indazole is described in WO2021203010 (compound 55). The mixture was stirred at 85 °C for 1.5 hours and then cooled to ambient temperature. Saturated aqueous NH4Cl (10 vol), aqueous KHCO3 (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 at ambient temperature for 3 days. The suspension was filtered and the solid was 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. 1 H NMR(400MHz,DMSO-d6,80℃)δ 13.45(s,1H),8.07(s,1H),7.42(s,1H),7.28(s,1H),6.99(dd,J=11.5,8.8Hz, 1H),6.74(dd,J=7.6,2.7Hz,1H),6.41(dt,J=8.6,3.1Hz,1H),3.78(s,3H)ppm. 19F NMR (376MHz, DMSO-d6, 80℃) δ -119.43(s,1F), -145.92(s,1F)ppm. ESI-MS m / z calculated value 352.998, measured value 354.0 (M+1) + .

[0147] Step 2: In a 5 L three-necked round bottom flask equipped with a magnetic stirrer, J-Kem temperature probe, and nitrogen inlet / outlet, 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 a rate to keep the temperature below 0° C. t BuOK (40 g, 356.5 mmol) was added. Cbz-Cl (50 mL, 350.2 mmol) was added dropwise to the reaction mixture via an addition funnel at a rate that kept the temperature below 0 °C. The reaction mixture was stirred at this temperature for 30 min. The reaction was quenched by adding saturated aqueous NH4Cl (50 mL) and allowed to warm to ambient temperature over 30 min. The mixture was partitioned between saturated aqueous NH4Cl (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 at ambient temperature for 12 h. The solid was filtered, rinsed with MTBE (500 mL), dried under air suction at ambient temperature for 1 hour, and further dried in a vacuum oven at 80° C. for 2 hours 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 containing small amounts of MTBE and ethyl acetate. 1 H NMR(300MHz,DMSO-d6)δ 8.38(d,J=2.0Hz,1H),7.70(s,1H),7.57~7.49(m,2H),7.49~7.34(m,4H),7.13(dd,J=11.4,8.7Hz ,1H),6.97(dd,J=7.8,2.6Hz,1H),6.68(ddd,J=8.7,3.7,2.6Hz,1H),5.50(s,2H),3.79(s,3H)ppm.19 F NMR (282MHz, DMSO-d6) δ -103.16, -143.49ppm.

[0148] The following starting materials were made using the same method as described for Starting Material 1, except that in step 1, a different aniline was used as the Buchwald coupling partner instead of 4-fluoro-3-methoxyaniline. For S3 and S5, the reactions were carried out at 90° C. For S4, step 1 was carried out at 75° C. and step 2 was carried out in 2-MeTHF as the solvent. [Table 10]

[0149] The following starting materials were made using the same method as described for Starting Material 1, except that in step 1, a different aniline was used as the Buchwald coupling partner instead of 4-fluoro-3-methoxyaniline. Step 2 was omitted. For S6, step 1 was carried out at 100°C in the presence of rac-BINAP-Pd-G3 as a catalyst instead of XantPhos Pd G3. For S7, S14, S15, and S16, step 1 was carried out at 90°C. For S8, step 1 was carried out at 100°C in the presence of rac-BINAP-Pd-G3 as a catalyst instead of XantPhos Pd G3. t It was carried out in the presence of BuBrettPhos Pd G3 at 80° C. For S21, step 1 was carried out at 75° C. For S35 and S36, step 1 was carried out at 100° C. [Table 11-1] [Table 11-2] [Table 11-3]

[0150] The following starting materials were made using the same method as described for Starting Material 1, except that in step 1, a different aniline was used as the Buchwald coupling partner instead of 4-fluoro-3-methoxyaniline. In step 2, pivaloyl chloride was used instead of CbzCl, and the reaction was carried out at 0°C. For S25, S27, S29, and S37, step 1 was carried out at 90°C. For S26, step 1 was carried out at 75°C. For S28, step 1 was carried out at 100°C. [Table 12]

[0151] C. intermediate 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). [ka] Step 1: 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. After the addition was complete, the cooling bath was removed, and the solution was stirred at ambient temperature for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (1:1 solution in 20 mL) and stirred for 30 min. The mixture was extracted with EtOAc (3x). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (80 g SiO2, 0-50% EtOAc in heptane) gave the syn and anti diastereoisomers of methyl 4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate.

[0152] Peak A: Methyl (rac)-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate (N1, 4.2 g, 90%) as a yellow oil. 1 H 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.

[0153] 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.

[0154] Step 2: 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 Daicel Chiralpak IC column, 5 μm particle size, 15 cm × 30 mm (mobile phase: 40% methanol (supplemented with 5 mM ammonia), 60% CO, flow rate 100 mL / min).

[0155] Peak AA (rt = 1.70 min): methyl rel-4-((1-hydroxy-2-methoxycyclohexyl)ethynyl)benzoate (N3, 1.211 g, 47%) as a yellow oil. 1 H NMR(400MHz,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=7.4,3.7Hz,1H),2.94(s,1 H),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.

[0156] 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.

[0157] The following reagents were made using the same method as described for Intermediate 1, except that in step 1, a different ketone was used as starting material instead of (rac)-2-methoxycyclohexan-1-one. [Table 13-1] [Table 13-2]

[0158] The following intermediates were made using the same method as described for Intermediate 1, except that a different starting material was used in place of (rac)-2-methoxycyclohexan-1-one in step 1. Step 2 was omitted. [Table 14]

[0159] Intermediate 2 (rac)-4-(3-(cyclobutoxymethyl)-3-hydroxypent-1-yn-1-yl)benzoate methyl ester (N35) [ka] Step 1: Oxalyl chloride (1.746 g, 1.2 mL, 13.756 mmol) was added dropwise over 5 min to a stirred solution of 2-cyclobutoxyacetic acid (1.5 g, 11.526 mmol) in DCM (35 mL) and DMF (84.016 mg, 0.089 mL, 1.149 mmol) at 0 °C, and the reaction mixture was allowed to warm to ambient temperature for 1 h. The resulting acid chloride solution was added to an ice-cold solution of N-methoxymethanamine hydrochloride (1.23 g, 12.610 mmol) and KCO (4.77 g, 34.514 mmol) in HO (14 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The organic phase was separated. The residue was partitioned between water (30 mL) and EtOAc (2 × 100 mL), and the organic layer was separated. The combined organic extracts were washed with brine (50 mL), dried (NaSO), filtered, and concentrated in vacuo. Purification by flash chromatography (24 g SiO, 0-25% EtOAc in heptane) gave 2-cyclobutoxy-N-methoxy-N-methylacetamide (1.5 g, 63%) as a pale yellow oil. ESI-MS m / z calculated 173.105, found 174.2 (M+1). + .

[0160] Step 2: A solution of EtMgBr (1.82 mL, 0.456 M solution in 2-MeTHF, 0.830 mmol) was added dropwise over 10 min to a solution of 2-cyclobutoxy-N-methoxy-N-methylacetamide (160 mg, 0.670 mmol) in EtO (3 mL) at 0 °C. THF (1.5 mL) was added to dissolve the white solid that formed during the addition. The mixture was stirred at 0 °C for 10 min. The reaction was then warmed to ambient temperature and stirred for 4 h. The reaction was quenched by adding saturated aqueous NH Cl (10 mL) and water (5 mL) and extracted with DCM (2 × 30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na SO ), filtered, and concentrated in vacuo to give 1-cyclobutoxybutan-2-one (100 mg, 95%) as a yellow oil. 1H NMR (400MHz, chloroform-d) δ3.99~392(m, 3H), 2.50(q,J=7.3Hz, 2H), 2.26~2.16(m, 2H) , 2.03~1.93(m, 2H), 1.76~1.67(m, 1H), 1.56~1.43(m, 2H), 1.08(t,J=7.3Hz,3H)ppm.

[0161] Step 3: LiHMDS (6.74 mL, 1 M solution in THF, 6.740 mmol) was added dropwise over 10 min to a stirred solution of methyl 4-ethynylbenzoate (900 mg, 5.6191 mmol) in THF (8 mL) at −78° C., and the mixture was stirred at −78° C. for 2 h. A solution of 1-cyclobutoxybutan-2-one (719 mg, 5.056 mmol) in THF (14 mL) was added over 10 min, and the reaction was warmed to ambient temperature and stirred for 18 h. The mixture was quenched by the addition of saturated aqueous NH4Cl (40 mL), water (5 mL), and brine (5 mL), and the mixture was extracted with DCM (2 × 100 mL). The combined organic extracts were dried (NaSO), filtered, and concentrated in vacuo to give methyl (rac)-4-(3-(cyclobutoxymethyl)-3-hydroxypent-1-yn-1-yl)benzoate (N35, 2.5 g, 93%) as a brown oil. ESI-MS m / z calculated 302.152, found 285.2 (M-17). + .

[0162] The following reagent was made using the same method as described for Intermediate 2, except that 2-ethoxyacetic acid was used as the starting material instead of 2-cyclobutoxyacetic acid in step 1. In step 2, cyclopropylmagnesium bromide was used instead of ethylmagnesium bromide, and the reaction was carried out in THF as the only solvent. [Table 15]

[0163] Intermediate 3 Methyl (rac)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)-3-methoxybenzoate (N43), methyl (rel)-(R)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)-3-methoxybenzoate (Peak A, N44), and methyl (rel)-(S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)-3-methoxybenzoate (Peak B, N45) [ka] Step 1: CuI (44 mg, 0.231 mmol) and Pd(PPh)Cl (69 mg, 0.098 mmol) were added to a stirred and degassed solution of methyl 4-bromo-3-methoxybenzoate (513 mg, 2.093 mmol) and 3-(methoxymethyl)pent-1-yn-3-ol (402 mg, 3.136 mmol) in a mixture of 1,4-dioxane (5.5 mL) and EtN (5.5 mL) at ambient temperature, and the reaction mixture was heated to 80 °C for 1 h. The mixture was cooled to ambient temperature and filtered through a pad of Celite. The mother liquor was concentrated in vacuo. Purification by flash chromatography (40 g SiO, 0 to 100% EtOAc in heptane) gave methyl (rac)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)-3-methoxybenzoate (N43, 409 mg, 67%) as a viscous pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.61~7.41(m,3H),5.45(s,1H),3.89~3.84(m,6H),3.46~3.37(m,2H),3.36(s,3H),1.79~1.49(m,2H),1.00(t,J=7.4Hz,3H)ppm. ESI-MS m / z calculated value 292.131, measured value 293.1(M+1) + .

[0164] Step 2: The enantiomers of methyl (rac)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)-3-methoxybenzoate (N43, 340 mg, 1.159 mmol) were separated by chiral SFC using a Daicel Chiralpak IG column, 5 μm particle size, 15 cm x 30 mm (mobile phase: 20% methanol (supplemented with 5 mM ammonia), 80% CO, flow rate 100 mL / min):

[0165] Peak A (rt=0.76 min): Methyl (rel)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)-3-methoxybenzoate (N44, 145 mg, 43%) as a pale yellow viscous oil. 1 H NMR(400MHz,DMSO-d6)δ 7.56~7.43(m,3H),5.45(s,1H),3.87(m,6H),3.45~3.37(m,2H),3.36(s,3H),1.79~1.55(m,2H),1.00(t,J=7.4Hz,3H)ppm. ESI-MS m / z calculated value 292.131, measured value 293.0 (M+1) + .

[0166] Peak B (rt=0.85 min): Methyl (rel)-(S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)-3-methoxybenzoate (N45, 175 mg, 51%) as a pale yellow viscous oil. 1 H NMR(400MHz,DMSO-d6)δ 7.57~7.44(m,3H),5.45(s,1H),3.89~3.85(m,6H),3.46~3.37(m,2H),3.32~3.29(m,3H),1.79~1.49(m,2H),1.00(t,J=7.4Hz,3H)ppm. ESI-MS m / z calculated value 292.131, measured value 293.1(M+1) + .

[0167] The following reagent was made using the same method as described for Intermediate 3, except that in step 1, a different alkyne was used as the starting material instead of 3-(methoxymethyl)pent-1-yn-3-ol and the reaction was carried out in DMF as the solvent. Step 2 was omitted. [Table 16]

[0168] Intermediate 4 Methyl (rac)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl-4,4,5,5,5-d5)benzoate (N67) [ka] Step 1: A solution of CD3CD2I (29.5 g, 183 mmol) in dry Et2O (10 mL) was added dropwise to a stirred mixture of magnesium turnings (5.35 g, 220 mmol) and a small crystal of I2 in dry Et2O (380 mL) maintained at a steady reflux. The resulting gray mixture was stirred at ambient temperature for 2 h. The prepared Grignard solution was added dropwise to a solution of methoxy-4-(trimethylsilyl)but-3-yn-2-one (25.0 g, 147 mmol) in dry Et2O (700 mL) at −78 °C under a N2 atmosphere over 5.5 h, and the resulting milky-yellow mixture was stirred at 0 °C overnight. The mixture was quenched at −78 °C by the addition of saturated NH4Cl solution (200 mL). The aqueous phase was separated and extracted with Et2O (3 × 200 mL). The combined organic extracts were washed with brine (3 × 300 mL), dried (NaSO), filtered, and concentrated in vacuo. Purification by flash chromatography (SiO, 25% EtO in hexanes) afforded (rac)-3-(methoxymethyl)-1-(trimethylsilyl)pent-1-yn-4,4,5,5,5-d5-3-ol (22.9 g, 76%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 3.48 (d, J = 9.2 Hz, 1H), 3.46 (s, 3H), 3.38 (d, J = 9.2 Hz, 1H), 2.61 (br d, 1H), 0.17 (s, 9H) ppm.

[0169] Step 2: Silver triflate (4.30 g, 16.7 mmol) was added to a stirred solution of (rac)-3-(methoxymethyl)-1-(trimethylsilyl)pent-1-yn-4,4,5,5,5-d5-3-ol (22.9 g, 112 mmol) in a mixture of DCM (595 mL), MeOH (340 mL), and deionized water (85 mL), and the reaction mixture was stirred at ambient temperature under N for 15 h. After the mixture was cooled to 0 °C, saturated NH4Cl solution (290 mL) was added. The organic layer was separated and concentrated in vacuo. The residue was dissolved in Et2O (200 mL), and the aqueous phase was further extracted with Et2O (3 × 250 mL). The combined organic extracts were washed with brine (2 × 300 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (SiO2, 40% Et2O in hexanes) gave (rac)-3-(methoxymethyl)pent-1-yn-4,4,5,5,5-d5-3-ol (10.3 g, 69%) as a light yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 3.50 (d, J = 9.2 Hz, 1H), 3.47 (s, 3H), 3.36 (d, J = 9.2 Hz, 1H), 2.72 (br d, 1H), 2.44 (s, 1H) ppm.

[0170] Step 3: Piperidine (12.5 mL, 126.5 mmol) was added to a stirred mixture of methyl 4-iodobenzoate (26.1 g, 99.6 mmol), Pd(PPh3)2Cl2 (2.19 g, 3.12 mmol), and CuI (1.36 g, 7.13 mmol) in toluene (80 mL), and the mixture was flushed with N2 at ambient temperature for 15 minutes. A nitrogen-degassed solution of (rac)-3-(methoxymethyl)pent-1-yn-4,4,5,5,5-d5-3-ol (13.0 g, 97.4 mmol) in toluene (40 mL) was added dropwise to the above mixture over 15 minutes. The flask was sealed with a Teflon screw cap and placed in an oil bath set at 30 °C. The resulting yellow / brown mixture was stirred for 22 hours. The dark brown suspension was filtered through a pad of Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to give a red residue (74.9 g), which was purified by flash chromatography (SiO, 0–25% EtOAc in hexanes) to give methyl (rac)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl-4,4,5,5,5-d5)benzoate (N67, 17.5 g, 67%) as a pink solid. 1 H NMR (400 MHz, chloroform-d) δ 7.97 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H), 3.58 (d, J = 9.2 Hz, 1H), 3.50 (s, 3H), 3.46 (d, J = 9.2 Hz, 1H), 2.82 (br s, 1H) ppm.

[0171] Intermediate 5 Methyl (rac)-4-((2-ethoxy-1-hydroxycyclopentyl)ethynyl)benzoate (Peak A, N82) and Methyl (rac)-4-((2-ethoxy-1-hydroxycyclopentyl)ethynyl)benzoate (Peak B, N83) [ka] Step 1: nBuLi (4.2 mL, 1.6 M solution in hexanes, 6.720 mmol) was added dropwise to a stirred solution of DIPA (1.1 mL, 7.848 mmol) in THF (20 mL) at 0 °C. After complete addition, the reaction was cooled in a dry ice / acetone bath. A solution of methyl 4-ethynylbenzoate (840 mg, 5.244 mmol) in THF (10 mL) was added dropwise, and the reaction mixture was stirred at −78 °C for 30 min. A solution of (rac)-2-ethoxycyclopentan-1-one (860 mg, 6.710 mmol) in THF (10 mL) was added dropwise, the cooling bath was removed, and the reaction was stirred at ambient temperature for 4 h. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc (2 ×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography (40 g SiO2, 0-50% EtOAc in heptane) gave:

[0172] Peak A: Methyl (rac)-4-((2-ethoxy-1-hydroxycyclopentyl)ethynyl)benzoate (N82, 630 mg, 42%) as a yellow oil. 1 H NMR(400MHz,chloroform-d)δ 8.01~7.94(m,2H),7.52~7.43(m,2H),3.95(t,J=7.3Hz,1H),3.91(s,3H),3.84 (dq,J=9.5,7.0Hz,1H),3.71 (dq,J=9.4,7.0Hz,1H),3.25(s,1H),2.22~2.06(m,2H),1.93~1.60(m,4H),1.26(t,J=7.0Hz,3H)ppm.

[0173] Peak B: Methyl (rac)-4-((2-ethoxy-1-hydroxycyclopentyl)ethynyl)benzoate (N83, 310 mg, 21%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 8.05–7.95 (m, 2H), 7.55–7.49 (m, 2H), 3.94 (s, 3H), 3.92–3.81 (m, 1H), 3.80–3.74 (m, 1H), 3.68 (dq, J = 9.4, 6.9 Hz, 1H), 2.29–2.12 (m, 2H), 2.04–1.97 (m, 1H), 1.89–1.75 (m, 3H), 1.25 (t, J = 7.0 Hz, 3H) ppm; no OH alcohol was observed.

[0174] The following reagents were made using the same method as described for Intermediate 5, except that in step 1, a different ketone was used as starting material instead of (rac)-2-ethoxycyclopentan-1-one. [Table 17]

[0175] Intermediate 6 (rel)-4-((1-hydroxy-2-(methoxy-d3)cyclohexyl-2,3,3,4,4,5,5,6,6-d9)ethynyl)benzoate methyl (N86) [ka] Step 1: Under a nitrogen atmosphere, BuLi (41 mL, 2.5 M solution in hexane, 102.5 mmol) was added dropwise to a stirred solution of DIPA (15.6 mL, 111.3 mmol) in THF (200 mL) at 0 °C, and the reaction mixture was cooled to -78 °C. Cyclohexan-1-one-d 10(10 g, 92.42 mmol) was added dropwise and the mixture was stirred at −78° C. for 15 minutes. TMSCl (18 mL, 141.8 mmol) was added and the reaction was stirred at −78° C. for 15 minutes and at ambient temperature for 1 hour. The reaction was quenched by the addition of saturated NaHCO solution. The aqueous layer was separated and extracted with pentane (3×). The combined organic extracts were dried (NaSO), filtered, and concentrated in vacuo to afford ((cyclohex-1-en-1-yl-d9)oxy)trimethylsilane (16.96 g, 97%) as a colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 0.17 (s, 9H) ppm.

[0176] Step 2: BF3.OEt2 (7 mL, 56.72 mmol) was added to a stirred solution of iodosylbenzene (6.7 g, 30.45 mmol) in methanol-d4 (22.5 mL) under nitrogen, and the reaction mixture was cooled to -78 °C. ((cyclohex-1-en-1-yl-d9)oxy)trimethylsilane (5 g, 27.87 mmol) was added, and the mixture was allowed to warm slowly to ambient temperature and stirred overnight. The reaction was quenched by the addition of saturated NaHCO3 solution. The aqueous phase was separated and extracted with Et2O (2x). The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to give rac-2-(methoxy-d3)cyclohexan-1-one-2,3,3,4,4,5,5,6,6-d9 (16.11 g, 97%) as a yellow oil, which was used in the next step without further purification.

[0177] Step 3: Under nitrogen, a solution of ZnEt (13 mL, 1 M solution in hexane, 13.0 mmol) and methyl 4-ethynylbenzoate (1 g, 6.243 mmol) in a mixture of toluene (5 mL) and 2-MeTHF (5 mL) was added dropwise successively to a stirred solution of (1R,2S)-1-phenyl-2-(pyrrolidin-1-yl)propan-1-ol (270 mg, 1.315 mmol) in 2-MeTHF (4 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The solution was cooled to −10 °C. rac-2-(methoxy-d)cyclohexan-1-one-2,3,3,4,4,5,5,6,6-d (5.3 g, 7.596 mmol) was added dropwise, and the mixture was stirred at −10 °C for 18 h. The reaction was quenched by adding saturated NH Cl solution. The aqueous layer was separated and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na2SO4), and passed through a silica gel plug. The filter cake was washed with EtOAc, and the mother liquor was concentrated in vacuo. Purification by flash chromatography (330 g SiO2, 0 to 60% EtOAc in heptane) afforded methyl (rel)-4-((1-hydroxy-2-(methoxy-d3)cyclohexyl-2,3,3,4,4,5,5,6,6-d9)ethynyl)benzoate (Peak A, N86, 860 mg, 46%) as a single diastereomer. 1 H NMR (400 MHz, chloroform-d) δ 8.07–7.89 (m, 2H), 7.57–7.37 (m, 2H), 3.92 (s, 3H) ppm; no OH alcohol was observed. Peak B, the other diastereomer, was observed but not collected.

[0178] The following reagents were used in the same manner as described for Intermediate 6, except that steps 1 and 2 were omitted. In step 3, (rac)-2-methoxycyclohexan-1-one-2,3,3,4,4,5,5,6,6-d9 was used as the starting material instead of 2-(methoxy-d3)cyclohexan-1-one-2,3,3,4,4,5,5,6,6-d9. [Table 18]

[0179] Intermediate 7 (rel)-(S)-4-(3-hydroxy-3-((methoxy-d3)methyl)pent-1-yn-1-yl)benzoate methyl ester (N88) [ka] Step 1: ZnEt (15.5 mL, 1 M solution in hexane, 15.5 mmol) was slowly added over 12 min to a stirred solution of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol (315 mg, 1.504 mmol) in tetrahydrofuran (10 mL) at 0 °C, and the resulting suspension was stirred at 0 °C for 22 min. A solution of ethynyltrimethylsilane (2.015 g, 2.9 mL, 20.105 mmol) in toluene (2.5 mL) was added via cannula, and the reaction was stirred at 0 °C for 10 min. 1-(Methoxy-d)butan-2-one (108.8 g, 1.05% w / w solution in EtO, 10.864 mmol) was then added, and the reaction mixture was allowed to warm slowly to ambient temperature over 20.5 h. The reaction was quenched by the careful addition of saturated aqueous NH4Cl (100 mL). The aqueous layer was separated and extracted with MTBE (3 x 100 mL). The combined organic extracts were washed with brine (1 x 50 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography (50 g SiO2, 0-15% EtOAc in heptane) gave rel-(S)-3-((methoxy-d3)methyl)-1-(trimethylsilyl)pent-1-yn-3-ol (1.565 g, 67%) as a light yellow oil. 1 H NMR (400MHz, chloroform-d) δ 3.51~3.45(m,1H),3.42~3.37(m,1H),1.76~1.61(m,3H),1.05(t,J=7.5Hz,3H),0.18(s,9H)ppm. ESI-MS m / z calculated value 203.142, actual value 186.2 (M-17) + .

[0180] Step 2: CuI (59.1 mg, 0.304 mmol) and EtN (3.612 g, 5 mL, 35.516 mmol) were added sequentially to a stirred mixture of methyl 4-iodobenzoate (1.654 g, 6.121 mmol) and rel-(S)-3-((methoxy-d)methyl)-1-(trimethylsilyl)pent-1-yn-3-ol (1.56 g, 7.287 mmol) in THF (12 mL), and the reaction mixture was flushed with nitrogen gas at ambient temperature for 10 minutes. PdCl(PPh) (220.1 mg, 0.307 mmol) and TBAF (7 mL, 1 M solution in THF, 7.0 mmol) were added, and the reaction was flushed with nitrogen gas for an additional 10 minutes. The flask was sealed, and the mixture was heated at 70 °C for 2 hours. After cooling to ambient temperature, the mixture was stirred for 66.5 hours. The mixture was partitioned between EtOAc (20 mL) and half-saturated aqueous NH4Cl (20 mL). The aqueous layer was separated and extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography (50 g SiO2, 0–20% EtOAc in heptane) afforded methyl (rel)-(S)-4-(3-hydroxy-3-((methoxy-d3)methyl)pent-1-yn-1-yl)benzoate (N88, 1.268 g, 78%) as an orange oil. 1 H NMR(400MHz,DMSO-d6)δ 7.96~7.91(m,2H),7.55~7.50(m,2H),5.52(s,1H),3.86(s,3H),3.45~3.36(m,2H),1.78~1.57(m,2H),0.99(t,J=7.5Hz,3H)ppm. ESI-MS m / z calculated value 265.139, measured value 248.1 (M-17) + .

[0181] The following reagents were made using the same method as described for Intermediate 7, except that a different ketone starting material was used in place of 1-(methoxy-d3)butan-2-one in step 1 and / or a different halide was used in place of methyl 4-iodobenzoate in step 2. [Table 19]

[0182] Intermediate 8 Methyl 4-(((2S)-1-(rel)-hydroxy-2-methoxycyclohexyl)ethynyl)-2-methylbenzoate (N99) [ka] Step 1: To a solution of (1R,2S)-2-methoxycyclohexanol (10.2 g, 70.515 mmol) in DCM (300 mL) was added Dess-Martin periodinane (49.9 g, 105.88 mmol) in one portion at room temperature. The resulting mixture was stirred at room temperature for 18 h. The reaction was quenched by the slow addition of saturated aqueous sodium thiosulfate (350 mL) and saturated aqueous sodium bicarbonate (350 mL). The resulting biphasic mixture was stirred vigorously for 20 min. The phases were separated, and the aqueous layer was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (1-(rel),2S)-2-methoxycyclohexanone (11.4 g, 99%) as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ 3.75~3.69(m,1H),3.43(s,3H),2.57~2.49(m,1H),2.35~2.20(m,2H),1.99~1.89(m,2H),1.76~1.64(m,3H). Step 2:

[0183] To a 100 mL fire-dried round-bottom flask equipped with a magnetic stir bar was added LDA (6.93 mL of 1 M, 6.9300 mmol) under an inert atmosphere. The solution was cooled to -78 °C and diluted with THF (25 mL). Ethynyl(trimethyl)silane (553.02 mg, 0.78 mL, 5.6305 mmol) was added dropwise with stirring under N2. The reaction was then stirred at -78 °C for an additional 30 minutes. Afterwards, (2S)-2-methoxycyclohexanone (1.11 g, 6.4953 mmol) was added dropwise via syringe. Upon completion, the cooling bath was removed and the solution was stirred for 2 hours before being quenched with 20 mL of 1:1 saturated NH4Cl / HO. The mixture was allowed to stir for 30 minutes and then extracted with EtOAc (3 × 20 mL). The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure to give the crude product. Purification by normal phase silica gel chromatography (0-10% EtOAc-EtOAc / heptane) gave (1-(rel),2S)-2-methoxy-1-(2-trimethylsilylethynyl)cyclohexanol.

[0184] (Peak A) (486 mg, 36%) 1H NMR (400 MHz, CDCl3) δ 3.48 (s, 3H), 3.33 (dd, J = 7.0, 4.0 Hz, 1H), 2.80 (s, 1H), 1.96–1.84 (m, 1H), 1.82–1.64 (m, 3H), 1.62–1.41 (m, 4H), 0.25–0.12 (m, 9H), and (1-(rel),2S)-2-methoxy-1-(2-trimethylsilylethynyl)cyclohexanol (Peak B) (210 mg, 7%) 1H NMR (400 MHz, CDCl3) δ 3.44(s,3H),3.10(s,1H),3.00(dd,J=11.2,3.9Hz,1H),2.08~1.97(m,3H),1.82~1.70(m,1H),1.68~1.36(m,4H),0.19(s,9H).

[0185] Step 3: A slurry of (2S)-2-methoxy-1-(2-trimethylsilylethynyl)cyclohexanol (1 g, 4.417 mmol), methyl 4-bromo-2-methyl-benzoate (1.1 g, 4.802 mmol), CuI (50 mg, 0.2625 mmol), Pd dppf G3 (400 mg, 0.4328 mmol), TBAF (4.5 mL of 1 M, 4.500 mmol), and triethylamine (3.8 mL, 27.26 mmol) in THF (20 mL) was heated at 65° C. for 15 h under N. Upon completion, the reaction was cooled to rt, passed through a silica gel plug containing EtOAc, and concentrated under reduced pressure. The crude product was purified by column chromatography (80 g silica, 0-50% EtOAc / heptane) to give methyl 4-[2-[(2S)-1-(rel)-hydroxy-2-methoxy-cyclohexyl]ethynyl]-2-methyl-benzoate (916 mg, 69%) as a yellow oil. .1H NMR(400MHz,CDCl3)δ 7.85(d,J= 8.0Hz,1H),7.35~7.27(m,2H),3.88(s,3H),3.50(s,3H),3.42(dd,J= 7.4,3.7Hz,1H),2.94(s,1H),2.56(s,3H),2.07~1.92(m,1H),1.88~1.67(m,3H),1.63~1.55(m,3H),1.43~1.27(m,1H).

[0186] The following reagent was made using the same method as described for Intermediate 8, except that in step 3, a different halide starting material was used instead of methyl 4-bromo-2-methyl-benzoate. [Table 20]

[0187] Intermediate 9: (S)-4-(3-hydroxy-3-((methoxy-d3)methyl)pent-1-yn-1-yl-4,4,5,5,5-d5)benzoate methyl (N100) [ka] Step 1: To a stirred solution of sodium hydride (6.91 g, 60% w / w, 172.77 mmol) in THF (55 mL) at 0 °C under N2, trideuterio(deuteriooxy)methane (26.973 g, 34.1 mL, 747.87 mmol) was added. After stirring at 0 °C for 0.5 h, 2-bromoacetic acid (8 g, 57.575 mmol) was added, and the resulting solution was stirred at 0 °C for 5 min, followed by reflux at 80 °C for 4 h. The reaction was stirred at 60 °C for 18 h. The reaction mixture was quenched with water (30 mL) and washed with hexane (30 mL). The aqueous layer was adjusted to pH 2-3 and extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a maximum of 80% of the total volume, and the remaining solvent was reduced with a stream of N to give 2-(trideuteriomethoxy)acetic acid (5.43 g, 86%) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 3.92 (s, 2H).

[0188] Step 2: N-Methoxy-N-methyl-2-(trideuteriomethoxy)acetamide 2-(Trideuteriomethoxy)acetic acid (65.18 g, 32.906 mmol) was dissolved in DCM (70 mL) and cooled to 0 °C. Subsequently, triethylamine (4.9368 g, 6.8 mL, 48.787 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (hydrochloride, 9.5 g, 49.556 mmol), N-methoxymethanamine (hydrochloride, 3.21 g, 32.908 mmol), and DMAP (41 mg, 0.3356 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was washed with 1 M aqueous HCl (25 mL), 1 M aqueous NaOH (25 mL), dried over anhydrous NaSO, and concentrated in vacuo to give N-methoxy-N-methyl-2-(trideuteriomethoxy)acetamide (4.63 g, 96%) as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ 4.22 (s, 2H), 3.69 (s, 3H), 3.20 (s, 3H).

[0189] Step 3: 3,3,4,4,4-pentadeuterio-1-(trideuteriomethoxy)butan-2-one To a solution of N-methoxy-N-methyl-2-(trideuteriomethoxy)acetamide (7 g, 44.211 mmol) in diethyl ether (200 mL) was added iodine (1,1,2,2,2-pentadeuterioethyl)magnesium (50 mL, 1.6149 M, 80.745 mmol) dropwise over 25 minutes at 0°C. The reaction mixture was allowed to warm slowly to room temperature over 18 hours. The reaction mixture was cooled to 0°C and quenched with 3 M aqueous HCl (22 mL): brine (15 mL). The layers were separated, and the organic layer was washed with a mixture of 3 M aqueous HCl (15 mL) and brine (15 mL), and finally with brine (20 mL). All aqueous layers were combined and extracted with diethyl ether (3 x 20 mL). The organic layers were combined and dried over anhydrous NaSO to give 3,3,4,4,4-pentadeuterio-1-(trideuteriomethoxy)butan-2-one (338 g, 92%) as a solution in diethyl ether. 1H NMR (400 MHz, CDCl3) δ 4.01 (s, 2H). The product was stored over molecular sieves and used directly in the next step.

[0190] Step 4: (3S)-4,4,5,5,5-pentadeuterio-3-(trideuteriomethoxymethyl)-1-trimethylsilyl-pent-1-yn-3-ol In a round-bottom flask, (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)propan-1-ol (1.08 g, 5.2607 mmol) was dissolved in THF (30 mL) and the solution was cooled to 0 °C. A solution of diethylzinc in hexanes (52.3 mL of 1 M, 52.300 mmol) was slowly added over 10 minutes, and the resulting suspension was stirred at 0 °C for 5 minutes. A solution of ethynyl(trimethyl)silane (6.4094 g, 9.04 mL, 65.257 mmol) in toluene (10 mL) was added, and the reaction was stirred at 0 °C for 5 minutes. A solution of 3,3,4,4,4-pentadeuterio-1-(trideuteriomethoxy)butan-2-one (218 g, 26.117 mmol) was finally added. The reaction was stirred and allowed to warm to room temperature over 18 hours. The reaction mixture was quenched with a 1:1 v / v mixture of saturated aqueous NH4Cl and water (80 mL total), and the aqueous layer was extracted with ethyl acetate (3 × 40 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Purification by silica gel chromatography (gradient: 0–30% EtOAc in heptane) gave (3S)-4,4,5,5,5-pentadeuterio-3-(trideuteriomethoxymethyl)-1-trimethylsilyl-pent-1-yn-3-ol (3.102 g, 49%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 3.51–3.45 (m, 1H), 3.42–3.36 (m, 1H), 0.18 (s, 9H); no exchangeable hydrogens were observed.

[0191] Step 5: Methyl 4-[(3S)-4,4,5,5,5-pentadeuterio-3-hydroxy-3-(trideuteriomethoxymethyl)pent-1-ynyl]benzoate (N100) To a sealed tube was added methyl 4-iodobenzoate (3.7 g, 14.120 mmol), (3S)-4,4,5,5,5-pentadeuterio-3-(trideuteriomethoxymethyl)-1-trimethylsilyl-pent-1-yn-3-ol (3.102 g, 12.801 mmol), CuI (176.8 mg, 0.9283 mmol), triethylamine (7.7682 g, 10.7 mL, 76.768 mmol), and THF (40 mL). The mixture was purged with nitrogen for 20 minutes. PdCl(PPh) (539.2 mg, 0.7682 mmol) and TBAF in THF solution (14 mL of 1 M, 14.000 mmol) were added to the mixture, which was then purged with nitrogen for an additional 5 minutes. The mixture was heated at 70°C for 20 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and half-saturated aqueous ammonium chloride solution (100 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-30% EtOAc / heptane) afforded methyl 4-[(3S)-4,4,5,5,5-pentadeuterio-3-hydroxy-3-(trideuteriomethoxymethyl)pent-1-ynyl]benzoate (3 g, 85%) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ 7.97~7.92(m,2H),7.56~7.51(m,2H),5.51(s,1H),3.86(s,3H),3.45~3.37(m,2H). ESI-MS m / z calculated value 270.1707, measured value 253.2 (M-17)+; retention time: 2.55 minutes. [Example]

[0192] Example 1 (S)-4-(8-fluoro-5-(4-fluoro-3-methylphenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 2) [ka] Step 1: In a 20 L jacketed reactor, N,N-dicyclohexylmethylamine (416.09 g, 2.130 mol) was added to a solution of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate (S4, 330.02 g, 691.8 mmol) and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate (Peak B, N6, 190.4 g, 725.9 mmol) in 1,4-dioxane (3.5 L), and the reaction mixture was flushed with nitrogen for 30 minutes. t Bu3P2 (17.9 g, 35.03 mmol) was added and the mixture was flushed with nitrogen for an additional 5 minutes. The reaction was heated to 100°C for 90 minutes and then cooled to ambient temperature. The reaction mixture was quenched by the addition of 2 M HCl (2.5 L) and extracted with EtOAc (2.5 L). The organic phase was washed with 2 M HCl (1.5 L) and saturated brine solution (1.5 L). The aqueous phase was back-extracted with EtOAc (2.5 L). The combined organic extracts were concentrated in vacuo. Purification by flash chromatography (3 × 3 kg SiO, then 1 × 750 g SiO, 0–40% EtOAc in heptane) gave (S)-8-fluoro-5-(4-fluoro-3-methylphenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-7-(4-(methoxycarbonyl)phenyl)pyrrolo[2,3-f]indazole-1(5H)-benzyl carboxylate (381 g, 84%). 1 H NMR(400MHz,DMSO-d6)δ 8.40(d,J=1.6Hz,1H),8.16~7.92(m,2H),7.58(ddd,J=10.0,7.3,1.9Hz,2H),7.51~7.23(m,8H),6.90(d,J=1.0Hz,1H),5.37(s,2 H),4.60(d,J=7.7Hz,1H),3.92(s,3H),3.27~3.15(m,2H),3.12(s,3H),2.33(m,3H),1.59~1.36(m,2H),0.73(t,J=7.3Hz,3H)ppm. ESI-MS m / z calculated 653.234, observed 654.0 (M+1) +;652.0(M-1) - .

[0193] Step 2: A solution of LiOH monohydrate (193 g, 4.599 mol) in water (1.6 L) was added to a solution of (S)-8-fluoro-5-(4-fluoro-3-methylphenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-7-(4-(methoxycarbonyl)phenyl)pyrrolo[2,3-f]indazole-1(5H)-benzyl carboxylate (380 g, 581.3 mmol) in THF (3.5 L) and MeOH (1.6 L), and the mixture was heated to 50° C. for 30 min. The mixture was cooled to ambient temperature, and the volatiles were removed in vacuo. The aqueous suspension was diluted with EtOAc (1.2 L) and acidified to pH 4 by the addition of citric acid (600 mL, 2 M aqueous solution, 1.200 mol). The mixture was stirred vigorously at 20° C. A white solid crashed out of solution. The solid was filtered and allowed to dry on the filter for several hours. The solid was suspended in DCM (4 L), heated under reflux for 4 h, cooled to ambient temperature, filtered, and dried in vacuo overnight to give (S)-4-(8-fluoro-5-(4-fluoro-3-methylphenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (compound 2, 271.38 g, 92%). 1 H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.04 (d, J = 3.3 Hz, 1H), 7.97 (dt, J = 8.9, 2.4 Hz, 2H), 7.57 (t, J = 7.3 Hz, 2H), 7.43-7.26 (m, 3H), 6.69 (s, 1H), 4.47 (d, J = 7.8 Hz, 1H), 3.31-3.14 (m, 2H), 3.13 (s, 3H), 2.33 (m, 3H), 1.48 (m, 2H), 0.73 (t, J = 7.3 Hz, 3H) ppm; no exchangeable H was observed. ESI-MS m / z calculated 505.181, found 506.2 (M+1). + .

[0194] The following compounds were made using the same method as described in Example 1, except that different starting materials and reagents were used in step 1 instead of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, and the reaction was carried out at 110°C. [Table 21]

[0195] The following compounds were made using the same method as described in Example 1, except that different starting materials and reagents were used in step 1 instead of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, and the reaction was carried out at 110° C. Step 2 was carried out at 65° C. [Table 22]

[0196] The following compounds were made using the same method as described in Example 1, except that different starting materials and / or reagents were used in place of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate in Step 1. Step 2 was carried out at ambient temperature. [Table 23-1] [Table 23-2]

[0197] The following compounds were made using the same method as described in Example 1, except that different starting materials and / or reagents were used in step 1 instead of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, and the reaction was carried out at 110° C. Step 2 was carried out at 60° C. [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5] [Table 24-6]

[0198] The following compounds were prepared using the same method as described in Example 1, except that different starting materials and reagents were used in step 1 instead of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively. Step 2 was carried out at 60 °C. In the case of compound 66, a final SFC step was introduced to separate the enantiomers (Daicel Chiralpak IG column, 5 μm particle size, 25 cm × 10 mm (mobile phase: 30% methanol (supplemented with 0.1% ammonia), 70% CO, flow rate 15 mL / min), rt = 2.05 min). [Table 25-1] [Table 25-2]

[0199] The following compounds were made using the same method as described in Example 1, except that in step 1, different starting materials and reagents were used in place of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, and the reaction was carried out at 110° C. Step 2 was carried out at ambient temperature. [Table 26-1] [Table 26-2]

[0200] The following compounds were made using the same method as described in Example 1, except that different starting materials and reagents were used in step 1 instead of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively. Step 2 was carried out at 65° C. [Table 27]

[0201] The following compounds were made using the method described in Example 1, except that different starting materials and reagents were used in place of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, in Step 1, and the reaction was carried out at 110° C. Step 2 was carried out using 1,4-dioxane instead of THF. [Table 28-1] [Table 28-2] [Table 28-3]

[0202] The following compounds were made using the same method as described in Example 1, except that different starting materials and reagents were used in step 1 instead of benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methylphenyl)amino)-1H-indazole-1-carboxylate and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, and the reaction was carried out at 110° C. Step 2 was carried out in the absence of THF. [Table 29-1] [Table 29-2] [Table 29-3] [Table 29-4] [Table 29-5]

[0203] Example 2 (S)-4-(8-fluoro-5-(4-fluorophenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 1) [ka] Step 1: N,N-Dicyclohexylmethylamine (800 μL, 3.735 mmol) was added to a stirred mixture of 6-bromo-7-fluoro-N-(4-fluorophenyl)-1H-indazol-5-amine (S6, 505 mg, 1.480 mmol) and (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)methylbenzoate (Peak B, N6, 463 mg, 1.765 mmol) in 1,4-dioxane (9.5 mL), and the reaction mixture was flushed with nitrogen for 15 minutes. t Bu3P)2 (78 mg, 0.1526 mmol) was added in one portion, and the reaction was heated to 110 °C for 80 min. The reaction was cooled to ambient temperature and diluted with EtOAc (10 mL). The solution was washed with saturated aqueous NH4Cl (10 mL), water (10 mL), and brine (10 mL), and the combined organic extracts were passed through a phase separation cartridge and dried. The filtrate was concentrated in vacuo. Purification by flash chromatography (40 g SiO2, 0–40% EtOAc in heptane) gave methyl (S)-4-(8-fluoro-5-(4-fluorophenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (453 mg, 61%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 12.99~12.94(m,1H),8.07~7.97(m,3H),7.63(t,J=7.5Hz,2H),7.54(m,1H),7.49~7.37(m,3H),6.68(s,1H) ),4.56(s,1H),3.90(s,3H),3.29~3.14(m,2H),3.11(s,3H),1.54~1.36(m,2H),0.72(t,J=7.3Hz,3H)ppm.19 F NMR(376MHz,DMSO-d6)δ -113.76,-143.65ppm. ESI-MS m / z calculated value 505.181, measured value 506.11 (M+1) + .

[0204] Step 2: 2 M aqueous NaOH (154 mL, 308.0 mmol) was added to a stirred solution of methyl (S)-4-(8-fluoro-5-(4-fluorophenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (15.71 g, 31.08 mmol) in a mixture of THF (312 mL) and MeOH (156 mL), and the reaction was heated to 50° C. for 1 h. The reaction mixture was cooled to ambient temperature, and the volatiles were removed in vacuo. The resulting aqueous solution was diluted with water (312 mL) and extracted with DCM (2×300 mL). The aqueous layer was collected and acidified to pH 3.05 (pH meter) by adding 2 M HCl. The fluffy white solid was filtered, washed with water (3 × 300 mL), and dried in a vacuum oven at 50–60 °C overnight to give (S)-4-(8-fluoro-5-(4-fluorophenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (compound 1, 14.165 g, 93%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 12.94(m,2H),8.04(d,J=3.3Hz,1H),8.00~7.95(m,2H),7.63~7.49(m,3H),7.49~7.35(m,3H),6.67(s,1 H),4.55(s,1H),3.28~3.15(m,2H),3.11(s,3H),1.55~1.36(m,J=7.2Hz,2H),0.72(t,J=7.3Hz,3H)ppm. 19 F NMR (376MHz, DMSO-d6) δ -113.86, -143.68ppm. ESI-MS m / z calculated value 491.166, measured value 492.1(M+1) + .

[0205] The following compounds were made using the same method as described in Example 2, except that different starting materials and reagents were used in step 1 instead of 6-bromo-7-fluoro-N-(4-fluorophenyl)-1H-indazol-5-amine and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively. [Table 30-1] [Table 30-2]

[0206] The following compounds were made using the same method as described in Example 2, except that different starting materials and reagents were used in place of 6-bromo-7-fluoro-N-(4-fluorophenyl)-1H-indazol-5-amine and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, in step 1. In step 2, the reaction was carried out in the presence of 1 M NaOH. [Table 31-1] [Table 31-2]

[0207] The following compound was made using the same method as described in Example 2, except that different starting materials and reagents were used in place of 6-bromo-7-fluoro-N-(4-fluorophenyl)-1H-indazol-5-amine and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, in step 1, and the reaction was carried out in DMA instead of 1,4-dioxane. Step 2 was carried out at 60° C. [Table 32]

[0208] The following compounds were made using the same method as described in Example 2, except that in step 1 different starting materials and reagents were used in place of 6-bromo-7-fluoro-N-(4-fluorophenyl)-1H-indazol-5-amine and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, and the reaction was carried out in DMA instead of 1,4 dioxane. Step 2 was carried out at ambient temperature. [Table 33]

[0209] The following compounds were made using the same method as described in Example 2, except that different starting materials and reagents were used in place of 6-bromo-7-fluoro-N-(4-fluorophenyl)-1H-indazol-5-amine and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate, respectively, in Step 1. In Step 2, the reaction was carried out at ambient temperature. [Table 34]

[0210] The following compounds were prepared by using different starting materials and reagents in place of 6-bromo-7-fluoro-N-(4-fluorophenyl)-1H-indazol-5-amine and methyl (S)-4-(3-hydroxy-3-(methoxymethyl)pent-1-yn-1-yl)benzoate in step 1, respectively, and the reaction was carried out in place of N,N-dicyclohexylmethylamine. t Made using the same method as described in Example 2, except BuNMe2 was used as the base. Step 2 was carried out at ambient temperature. [Table 35]

[0211] Example 3 (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 5) [ka] Step 1: Pd( t BuP) (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 1 M aqueous HCl (1 L). The organic layer was separated, washed with 1M aqueous HCl (1 L) and a mixture of water and saturated brine solution (2:1, 1.5 L), dried (MgSO), filtered, and concentrated in vacuo. Purification by flash chromatography (3 Kg SiO, 0-60% 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 calculated 657.209, found 658.3 (M+1). + .

[0212] Step 2: Pd / C (27 g, 5% w / w, 12.69 mmol) and ammonium formate (135 g, 2.141 mol) were added sequentially to a stirred solution of (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 allowed to cool slowly while standing at ambient temperature overnight. The mixture was diluted with EtOAc (1 L) and heated to approximately 85° C. The mixture was filtered hot through a pad of Celite, washing with hot EtOAc (3×500 mL). The reaction was concentrated in vacuo to a volume of approximately 300 mL. The mixture was cooled and 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 liquor was concentrated in vacuo to give a gold solid (75 g). The solid was recrystallized from EtOAc (approximately 150 mL, 2 volumes) and heptane (3 volumes) 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 (114 g, 97%) as a beige solid. ESI-MS m / z calculated 523.172, found 524.2 (M+1). + .

[0213] Step 3: 2 M NaOH (70 mL, 140.0 mmol) was added to a stirred solution of (S)-4-(5-(3,4-difluorophenyl)-8-fluoro-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)methyl 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 can 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 the addition of 1 M HCl. The solid that formed 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 5, 6.705 g, 93%) as an off-white solid. 1 H NMR(400MHz,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=1.6Hz,1H),4.69(d, J=23.5Hz,1H),3.27~3.16(m,2H),3.12(d,J=9.4Hz,3H),1.52~1.37(m,2H),0.72(t,J=7.3Hz,3H)ppm. ESI-MS m / z calculated value 509.156, actual value 510.1 (M+1) + .

[0214] The following compound was made using the same method as described in Example 3, except that benzyl 6-bromo-7-fluoro-5-((4-fluoro-3-methoxyphenyl)amino)-1H-indazole-1-carboxylate was used as the starting material in step 1 instead of benzyl 6-bromo-5-((3,4-difluorophenyl)amino)-7-fluoro-1H-indazole-1-carboxylate. Step 2 was carried out at 50° C. using MeOH as the solvent instead of EtOH. The conditions used for saponification step 3 were those described in step 2 of Example 1, and the reaction was carried out at ambient temperature. [Table 36]

[0215] Compounds were analyzed by LC / MS according to one of the following methods, as shown in Table 1. [Table 37]

[0216] Example 4 Alternative synthesis of compounds 3 and 5 A. Synthesis of (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 5) Step 1 - Reductive Coupling Step A [ka] To a heated solution of 3,4-difluorophenylboronic acid (2 equiv.), 1,2,2,3,4,4-hexamethylphosphetan-1-oxide (0.3 equiv.), and 6-bromo-7-fluoro-5-nitro-1(H)-indazole (0.1 equiv.) in dioxane, a solution of the nitroindazole 6-bromo-7-fluoro-5-nitro-1(H)-indazole (0.9 equiv.) in dioxane and unmodified TMDS (6 equiv.) were added simultaneously. The mixture was stirred at 100 °C until the reaction was complete. The reaction was quenched with saturated NaOH. 2-MeTHF was added and the phases were separated. The organic layer was washed with aqueous HCl. The organic layer was concentrated, and the residue was taken up in toluene. The product S14 was isolated by crystallization, filtration, and drying. Step B [ka]

[0217] To a heated solution of 6-bromo-7-fluoro-5-nitro-1(H)-indazole (1 equivalent), 3,4-difluorophenylboronic acid (2 equivalents), and 1,2,2,3,4,4-hexamethylphosphetan-1-oxide (0.3 equivalents) was added neat PMHS (6 equivalents). The mixture was stirred at 100 °C until the reaction was complete. The mixture was quenched with aqueous NaOH and the phases were separated. Dioxane was distilled and 2-MeTHF was added. The mixture was stirred with aqueous sorbitol, and the aqueous phase was then separated. The solvent was distilled, and the product S14 was isolated by crystallization from toluene and acetonitrile, filtration, and drying.

[0218] Step 2 - Larocque cyclization [ka] Step A: N,N-Dicyclohexylmethylamine (2.5 equiv.) was reacted with S14 (1 equiv.), Peak B N6 (1.25 equiv.), and Pd( t To a heated mixture of (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 added (0.03 equiv.). The reaction mixture was stirred at 120° C. until complete. The mixture was cooled, 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, (S)-methyl 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.

[0219] Step B: This procedure is t Instead of (Bu3P)2, a catalyst mixture consisting of AmPhos and (MeCN)2PdCl2 can be used. Step 3 - Ester Hydrolysis [ka]

[0220] 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 equivalent) in THF and MeOH was added aqueous LiOH (4 equivalents). The mixture was stirred at 20°C until the reaction was complete. The mixture was 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 the addition of heptane, the product Compound 5 was isolated as the free EtOAc-heptane solvate Form A by crystallization, filtration, and drying.

[0221] Step 4 - Formation of the monohydrate [ka] A solution of Compound 5 free form, EtOAc heptane solvate Form A, in n-propanol was heated to 55°C and then diluted with water. The mixture was seeded with Compound 5 monohydrate Form A at 47°C and then diluted with additional water. The mixture was cooled to 18°C, and the product, Compound 5 monohydrate Form A, was isolated by filtration and drying.

[0222] 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 3) Step 1 - Buchwald Coupling [ka] 6-Bromo-7-fluoro-5-iodo...

Claims

1. Compound of formula I: 【Chemistry 71】 The tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of the compound, the tautomer, or a deuterated derivative, wherein in the formula Ring X is, 【Chemistry 72】 Selected from, Ring Z is, 【Transformation 73】 Selected from, Each R is independent of F, H, Cl, and -CH. ３ , -OCH ３ , and -OCD ３ Selected from, R １ is H or F, R ２ teeth, 【Chemistry 74】 During the ceremony, One of X, Y, and Z is -OH, - One of X, Y, and Z is -CH ２ CH ３ and selected from cyclopropyl, One of X, Y, and Z is -CH ２ OCH ３ , -CH ２ CH ２ OCH ３ , -CH ２ OCH ２ CH ３ , -CH ２ O-cyclopropyl, and -CH ２ O-isopropyl; 【Chemistry 75】 Selected from, and R ３ H and -CH ３ A compound of formula I, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of the compound, tautomer, or deuterated derivative, selected from the above.

2. The compound of formula I is the compound of formula Ia: 【Transformation 76】 Selected from the tautomers, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of the aforementioned compounds, tautomers, and deuterated derivatives, where R is F, H, Cl, -CH ３ , and -OCH ３ A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

3. The compound of formula I is the compound of formula Ib: [Formula 77] Selected from the tautomers, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of the aforementioned compounds, tautomers, and deuterated derivatives, in the formula Each R is independent of F, H, Cl, and -CH. ３ , -OCH ３ , and -OCD ３ Selected from, R １ is H or F, R ２ teeth, 【Transformation 78】 During the ceremony, One of X, Y, and Z is -OH, - One of X, Y, and Z is -CH ２ CH ３ and selected from cyclopropyl, - One of X, Y, and Z is -CH ２ OCH ３ ien-CH ２ CH ２ OCH ３ ien-CH ２ OCH ２ CH ３ ien-CH ２ O-cyclopropyl and -CH ２ Selected from O-isopropyl; 【Transformation 79】 Selected from, and R ３ H and -CH ３ A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

4. The compound of formula Ib is the compound of formula Ib-i: 【Chemistry 80】 Selected from the tautomers, their compounds and deuterated derivatives of the tautomers, and pharmaceutically acceptable salts of their compounds, tautomers, and deuterated derivatives, in the formula Each R is independent of F, H, Cl, and -CH. ３ , -OCH ３ , and -OCD ３ Selected from, R １ is H or F, X, Y, and Z are defined as follows: One of X, Y, and Z is -OH. - One of X, Y, and Z is -CH ２ CH ３ and selected from cyclopropyl, - One of X, Y, and Z is -CH ２ OCH ３ ien-CH ２ CH ２ OCH ３ ien-CH ２ OCH ２ CH ３ ien-CH ２ O-cyclopropyl and -CH ２ Selected from O-isopropyl; and R ３ H and -CH ３ A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 3.

5. The compound of formula Ib is the compound of formula Ib-ii: 【Chemistry 81】 Selected from the tautomers, their compounds and deuterated derivatives of the tautomers, and pharmaceutically acceptable salts of their compounds, tautomers, and deuterated derivatives, in the formula Each R is independent of F, H, Cl, and -CH. ３ , -OCH ３ , and -OCD ３ Selected from, R １ is H or F, R ３ H and -CH ３ Selected from, and Ring A is, 【Chemistry 82】 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 3.

6. The compound of formula I is the compound of formula Ic: 【Chemistry 83】 Selected from the tautomers, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of the aforementioned compounds, tautomers, and deuterated derivatives, in the formula Ring X is, 【Chemical 84】 Selected from, R ２ teeth, 【Chemical 85】 During the ceremony, One of X, Y, and Z is -OH, - One of X, Y, and Z is -CH ２ CH ３ And, - One of X, Y, and Z is -CH ２ OCH ３ , and -CH ２ OCH ２ CH ３ Selected from, selected from, and Ring Z is, [Chem. 86] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

7. The compound of formula I is Table 110-1 Table 110-2 Table 110-3 Table 110-4 Table 110-5 Table 110-6 Table 110-7 Table 110-8 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds, tautomers, and deuterated derivatives.

8. A substantially crystalline form selected from the substantially crystalline forms of compound 5, compound 3, and compound 4, (i) Compound 5 【Transformation 87】 The substantially crystalline form of compound 5 is selected from compound 5 free form monohydrate type A, compound 5 free form type A, compound 5 free form type B, compound 5 free form NPA solvate type A, compound 5 free form EtOH solvate type A, compound 5 free form MeOH solvate hydrate type A, compound 5 free form DCM solvate type A, and compound 5 free form EtOAc heptane solvate type A; (ii) Compound 3 [Chemical 88] The substantially crystalline form of compound 3 is selected from free form A of compound 3, free form B of compound 3, free form hydrate A of compound 3, free form hydrate B of compound 3, free form hydrate C of compound 3, and free form MTBE solvate A of compound 3; (iii) Compound 4 【Chemistry 89】 A substantially crystalline form of compound 4, selected from free form A of compound 4, free form B of compound 4, free form C of compound 4, free form D of compound 4, free form hydrate A of compound 4, free form hydrate B of compound 4, and free form hydrate C of compound 4.

9. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 7, or a substantially crystalline form according to claim 8, and a pharmaceutically acceptable carrier.

10. A composition for use in the treatment of alpha-1 antitrypsin deficiency (AATD), comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 7, or a substantially crystalline form according to claim 8.

11. A method for preparing compound 5, 【Chemistry 90】 (a) Intermediate S14 【Chemistry 91】 【Chemistry 92】 The process involves preparing the product by reductive coupling, (b) Intermediate S14 with reagent N6 【Chemistry 93】 A method comprising the step of reacting the compound via Laroc cyclization to obtain compound 5.

12. A method for preparing compound 3, 【Chemistry 94】 (a) A step of reacting 6-bromo-7-fluoro-5-iodo-1H-indazole and 4-fluoro-3-methoxyaniline via Buchwald coupling to produce intermediate S1, 【Chemical 95】 (b) A step of reacting intermediate S1 with a reagent via Laroc cyclization to produce ((S)-4-(8-fluoro-5-(4-fluoro-3-methoxyphenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazole-7-yl)methyl benzoate, 【Chemistry 96】 (c) A method comprising the step of subjecting ((S)-4-(8-fluoro-5-(4-fluoro-3-methoxyphenyl)-6-(2-hydroxy-1-methoxybutan-2-yl)-1,5-dihydropyrrolo[2,3-f]indazole-7-yl)methyl benzoate to ester hydrolysis to produce compound 3.

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