WO2021067584A1 - Methods of treatment for alpha-1 antitrypsin deficiency - Google Patents

Abstract

This application describes methods of treating alpha-1 antitrypsin deficiency (AATD) comprising administering Compound I and/or a pharmaceutically acceptable salt thereof. (I) The application also describes pharmaceutical compositions comprising Compound I and/or a pharmaceutically acceptable salt thereof.

Description

METHODS OF TREATMENT FOR ALPHA-1 ANTITRYPSIN DEFICIENCY

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 62/909,365, filed October 2, 2019, and U.S. Provisional Application No. 63/028,304, filed May 21, 2020, the entire disclosures of each of which are incorporated herein by reference.

[0002] Disclosed herein is a compound capable of modulating alpha- 1 antitypsin (AAT) activity, pharmaceutical compositions containing the compound, methods of treatment of alpha- 1 antitrypsin deficiency (AATD), and a process for making the compound.

[0003] AATD is a genetic disorder characterized by low circulating levels of alpha- 1 antitrypsin (AAT). AAT is produced primarily in the liver and secreted into the blood, although other cell types, including lung epithelial cells, monocytes, macrophages, and neutrophils, produce small amounts of the protein locally (Bergin, et al, Sci Tr ansi Med. 2014; 6(217):217ral; Geraghty, et al. ,Am JRespir Crit Care Med. 2014; 190(11): 1229- 42). AAT inhibits several serine proteinases secreted by polymorphonuclear neutrophils (PMNs; most notably neutrophil elastase, cathepsin G, and proteinase-3) and thus protects organs such as the lung from damage by these proteinases, especially during periods of infection and increasedinflammation.

[0004] The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene that encodes the AAT protein. This mutation, known as the Z mutation, leads to misfolding of the translated protein, which polymerizes within hepatocytes and is not secreted into the bloodstream. Consequently, circulating AAT levels in individuals homozygous for the Z mutation ( PiZZ) are markedly reduced; only approximately 15% of mutant Z AAT protein folds correctly and is secreted by hepatocytes into the circulation.

[0005] The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene that encodes the AAT protein. This mutation, known as the Z mutation, leads to misfolding of the translated protein, which polymerizes within cells and is not secreted into the bloodstream. Consequently, circulating AAT levels in individuals homozygous for the Z mutation ( PiZZ) are markedly reduced; only approximately 15% of mutant Z AAT protein folds correctly and is secreted by the cell. [0006] The accumulation of polymerized Z-AAT protein within hepatocytes causes cytotoxicity that can result in neonatal liver disease or progressive liver disease in adulthood that can lead to cirrhosis or liver cancer. The reduced levels of circulating, active AAT result in an imbalance between proteinase and antiproteinase activity, which has its greatest impact in the lung. Consequently, lung tissue is damaged over time resulting in emphysema, which is one pathology occurring in the lungs of subjects with chronic obstructive pulmonary disease (COPD) that contributes to the poorly reversible airflow obstruction that is characteristic of COPD. Emphysema in PiZZ individuals typically manifests in middle age, and usually results in a progressive decline in lung function, a decline in quality of life and shortened lifespan (mean 67 years of age). Piitulainen and Tanash, COPD 2015; 12(1):36-41. PiZZ individuals account for the majority (-95%) of those with clinically relevant AATD-related lung disease. The accumulation of polymerized Z-AAT protein within hepatocytes causes cytotoxicity that can result in neonatal liver disease or progressive liver disease in adulthood that can lead to cirrhosis or liver cancer.

[0007] A milder form of AATD is associated with a mutation in alpha- 1 antritrypsin known as the SZ mutation, which results in clinically significant lung disease but not liver disease. Fregonese and Stolk, Orphanet J Rare Dis. 2008; 33:16. As with the ZZ mutation, the deficiency of circulating AAT in subjects with the SZ mutation results in unregulated protease activity that degrades lung tissue over time and can result in emphysema, particularly in smokers.

[0008] The current standard of care for AAT deficient individuals who have or show signs of developing significant lung or liver disease is augmentation therapy (AAT replacement therapy). AATaugmentation therapy involves administration of a pooled, purified human plasma protein concentrate to augment the reduced circulating levels of AAT in subjects with severe AATD. Infusions of the plasma protein have been shown in randomized pbacebo controlled clinical studies to slow the rate of emphysema progression on CT scans. However, AAT augmentation therapy does not halt lung disease progression and also does not restore the AAT acute phase response which occurs in response to various insults in normal (PiMM) subjects. During the normal AAT acute phase response, plasma AAT levels increase -2 fold in response to an insult (such as a pulmonary exacerbation) leading to greater protection of the lung from the increased lung burden of PMN-derived serine proteinases which is associated with increased neutrophilic lung inflammation which occurs during a pulmonary exacerbation. Similarly, although AAT replacement therapy shows promise in slowing the progression of emphysema in subjects with severe AATD, only 2% of the administered drug reaches the lungs. In addition, replacement AAT therapy requires weekly visits for treatment which is burdensome to patients. Thus, there is a continuing need for new and more effective treatments for AATD.

[0009] The current standard of care for AAT deficient individuals who have or show signs of developing significant lung or liver disease is augmentation therapy (AAT replacement therapy). AAT augmentation therapy involves administration of a pooled, purified human plasma protein concentrate to augment the reduced circulating levels of AAT in subjects with severe AATD. Infusions of the plasma protein have been shown in randomized pbacebo controlled clinical studies to slow the rate of emphysema progression on CT scans. However, AAT augmentation therapy does not halt lung disease progression and also does not restore the AAT acute phase response which occurs in response to various insults in normal (PiMM) subjects. During the normal AAT acute phase response, plasma AAT levels increase ~2 fold in response to an insult (such as a pulmonary exacerbation) leading to greater protection of the lung from the increased lung burden of PMN-derived serine proteinases which is associated with increased neutrophilic lung inflammation which occurs during a pulmonary exacerbation. Similarly, although AAT replacement therapy shows promise in slowing the progression of emphysema in subjects with severe AATD, only 2% of the administered drug reaches the lungs. In addition, replacement AAT therapy requires weekly visits for treatment which is burdensome to patients. Thus, there is a continuing need for new and more effective treatments for AATD.

[0010] In some embodiments, the disclosure provides a compound capable of modulating alpha-1 antitypsin activity, 3-(5-(4-fluorophenyl)-6-isopropyl-l,5- dihydropyrrolo[2,3-f]indazol-7-yl)propanoic acid (Compound I) and pharmaceutically acceptable salts thereof. Compund I can be depicted as having the following structure:

[0011] In some embodiments, the disclosure provides pharmaceutical compositions comprising Compound I and/or at least one pharmaceutically acceptable salt thereof, which compositions may further include at least one additional active pharmaceutical ingredient and/or at least one carrier. In some embodiments, the disclosure provides methods of treating AATD comprising administering Compound I and/or at least one pharmaceutically acceptable salt thereof, optionally as part of a pharmaceutical composition comprising at least one additional component, to a subject in need thereof. In some embodiments, the disclosure provides processes of making Compound I and/or pharmaceutically acceptable salts thereof.

Definitions

[0012] “Compound I” as used throughout this disclosure refers to 3-(5-(4- fluorophenyl)-6-isopropyl-l,5-dihydropyrrolo[2,3-f]indazol-7-yl)propanoic acid, which can be depicted as having the following structure:

Compound I may be in the form of an isomeric mixture or enantioenriched (e.g., >90% ee, >95% ee, > 98% ee) isomers. Compound I may be in the form of a pharmaceutically acceptable salt.

[0013] As used herein, “AAT” means alpha- 1 antitypsin. As used herein, “AATD” means alpha- 1 antitrypsin deficiency.

[0014] As used herein, “mutations” can refer to mutations in the SERPINA1 gene (the gene encoding AAT) or the effect of alterations in the genesequence on the AAT protein. A “ SERPINA1 gene mutation” refers to a mutation in the SERPINA1 gene, and an “AAT protein mutation” refers to a mutation that results in an alteration in the amino acid sequence of the AAT protein. A genetic defect or mutation, or a change in the nucleotides in a gene in general, results in a mutation in the AAT protein translated from that gene. [0015] As used herein, a patient who is “homozygous” for a particular gene mutation has the same mutation on each allele.

[0016] As used herein, a patient who is “heterozygous” for a particular gene mutation has the particular mutation on one allele, and a different mutation on the other allele. [0017] As used herein, a patient who has the PiZZ genotype is a patient who is homozygous for the Z mutation in the A1AT protein.

[0018] As used herein, the term “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refers to a biologically active compound.

[0019] As used herein, the term “pharmaceutically acceptable salt” refers to a salt form of a compound of this disclosure wherein the salt is nontoxic. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in ./ Pharmaceutical Sciences , 1977, 66, 1-19.

[0020] As used herein, “ULN” means “upper limit of normal.”

[0021] Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts:

Table 1:

[0022] Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non- limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(Ci-4alkyl)4 salts. This disclosure also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts. [0023] The terms “patient” and “subject” are used interchangeably and refer to an animal including humans.

[0024] As used herein, the terms “treatment,” “treating,” and the like generally mean the improvement of AATD or its symptoms and/or lessening the severity of AATD or its symptoms in a subject.

[0025] As used herein, the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrently with, or subsequent to each other.

[0026] The terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. The terms “about” and “approximately” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values is measured or determined. In some embodiments, the terms “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

[0027] One of ordinary skill in the art would recognize that, when an amount of “a compound and/or a pharmaceutically acceptable salt thereof’ is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound. It is noted that the disclosed amounts of the compounds or their pharmaceutically acceptable salts thereof herein are based upon their free base form. For example, “100 mg of at least one compound chosen from Compound I and pharmaceutically acceptable salts thereof’ includes 100 mg of Compound I and a concentration of a pharmaceutically acceptable salt of Compound I equivalent to 100 mg of Compound I.

[0028] As used herein, administration of a “daily” amount of Compound I and/or a pharmaceutically acceptable salt thereof refers to the total amount that is administered in one day but does not limit the frequency of administration per day. The daily amount administered to a patient can be administered once or multiple times in a day, such as twice daily or three times daily (wherein each of multiple administrations comprises administering some amount of Compound I and/or a pharmaceutically acceptable salt thereof that is less than the “daily” amount, given that the “daily” amount refers to the total amount administered in one day). Each administration of Compound I and/or a pharmaceutically acceptable salt thereof can consist of administering Compound I and/or pharmaceutically acceptable salt thereof in the form of a single composition (e.g., a single dosage, such as a single tablet or a single capsule) or in the form of multiple compositions (e.g., multiple dosages, such as multiple (i.e., two or more) tablets and/or capsules).

[0029] In some embodiments, the disclosure provides methods of treating AATD with Compound I and/or a pharmaceutically acceptable salt thereof. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered daily. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered once daily or multiple times daily, such as twice daily or three times daily. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered three times daily.

[0030] In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered as a single composition. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in multiple compositions (for example, as multiple tablets and/or multiple pills per single administration). Accordingly, in some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered once daily as a single composition. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered once daily as multiple compositions, which are administered contemporaneously. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount of 100 mg to 1600 mg. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg once daily. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered twice daily in a daily amount of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg, i.e.,

Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount (i.e., total amount per day) of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg in two portions (which may be equal or unequal) during a single day. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount (i.e., total amount per day) in two portions (which may be equal or unequal) during a single day, wherein one of the portions is 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, or 850 mg. Reference to administration of Compound I and/or a pharmaceutically acceptable salt thereof in an amount of “twice daily” refers to administering an amount of Compound I and/or a pharmaceutically acceptable salt thereof two times in one day, wherein each of the two administrations comprises administration of some amount of Compound I and/or a pharmaceutically acceptable salt thereof that is less than the daily amount, but where the total of these amounts administered in the one day equals the daily amount.

[0031] In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount of about 100 mg to about 1600 mg. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1200 mg, or about 1600 mg daily. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1200 mg, or about 1600 mg once daily. In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in a daily amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1200 mg, or about 1600 mg twice daily.

[0032] In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered every 8 hours (“q8h”), every 12 hours (“ql2h”), or every 24 hours (“q24h”). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered every 8 hours (q8h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered every 24 hours (q24h).

[0033] In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 100 mg, 200 mg, 300 mg, or 400 mg every 8 hours (q8h), in an amount of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg every 12 hours (ql2h), or in an amount of 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg every 24 hours (q24h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 100 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 200 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 300 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 400 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 600 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of 800 mg every 12 hours (ql2h).

[0034] In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, about 200 mg, about 300 mg, or about 400 mg every 8 hours (q8h), in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg every 12 hours (ql2h), or in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1200 mg, or about 1600 mg every 24 hours (q24h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of about 200 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of about 300 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of about 600 mg every 12 hours (ql2h). In some embodiments, Compound I and/or a pharmaceutically acceptable salt thereof is administered in an amount of about 800 mg every 12 hours (ql2h).

[0035] In some embodiments, the disclosure provides pharmaceutical compositions comprising Compound I and/or a pharmaceutically acceptable salt thereof, which compositions may further include at least one additional active pharmaceutical ingredient and/or at least one carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising at least one compound chosen from Compound I and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0036] Compound I and/or a pharmaceutically acceptable salt thereof can be administered in a single pharmaceutical composition or separate pharmaceutical compositions. Such pharmaceutical compositions can be administered once daily (i.e., every 24 hours (q24h)) or multiple times daily, such as twice daily. Multiple daily administrations can be administered at any time, such as every 8 hours (q8h) (i.e., three times per day), or every 12 hours (ql2h) (i.e., twice per day).

[0037] In some embodiments, the disclosure provides a pharmaceutical composition comprising 100 to 1600 mg of Compound I and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg of Compound I and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising 100 mg, 200 mg, 300 mg, 400 mg, or 600 mg of Compound I and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising 800 mg, 1200 mg, or 1600 mg of Compound I and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, or 850 mg of Compound I and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound I and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier that is administered every 12 hours (ql2h). [0038] In some embodiments, the patient to whom Compound I and/or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is administered is in the fasted state. As used herein, a patient who is in the “fasted state” has abstained from all food and drink (except water) for at least eight hours (such as for at least ten hours) before and four hours after administration of Compound I and/or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, wherein consumption of water is permitted until one hour before and may resume one hour after administration of Compound I and/or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0039] In some embodiments, the patient to whom Compound I and/or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same is administered is in the fed state. As used herein, a patient who is in the “fed state” has abstained from all food and drink (except water) for at least eight hours hours (such as for at least ten hours) before the start of a meal and consumption of the meal is started within 30 minutes of administration of Compound I and/or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same and the entire meal is consumed in 30 minutes or less. In some embodiments, additional food is not permitted for at least two hours (such as four hours) after administration of Compound I and/or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same. In some embodiments, water may be consumed without restriction beginning after administration of Compound I and/or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same. In some embodiments, water may be consumed without restriction beginning at least one hour after administration. In some embodiments, the meal is a high-fat meal, such as a meal containing about 800-1000 calories total and containing about 500-600 calories from fat and/or 55-65 grams of fat. In some embodiments, the meal is a low-fat meal, such as a meal containing about 500-600 calories total and containing about 100-125 calories from fat and/or 11-14 grams of fat. In some embodiments, the meal contains about 20 g of fat.

[0040] A pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, lubricants.

[0041] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as com starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

[0042] The pharmaceutical compositions described herein are useful for treating AATD.

[0043] Any suitable pharmaceutical compositions known in the art can be used for Compound I and/or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions employed in the therapies of the disclosure are tablets. In some embodiments, the tablets are suitable for oral administration. These compositions and combinations are useful for treating AATD.

[0044] In some embodiments, pharmaceutical compositions of the disclosure (including, but not limited to, tablets) comprise Compound I and/or a pharmaceutically acceptable salt thereof and cellulose. In some embodiments, pharmaceutical compositions of the disclosure (including, but not limited to, tablets) comprise Compound I and/or a pharmaceutically acceptable salt thereof and croscarmellose sodium. In some embodiments, pharmaceutical compositions of the disclosure (including, but not limited to, tablets) comprise Compound I and/or a pharmaceutically acceptable salt thereof and sodium stearyl fumarate. In some embodiments, pharmaceutical compositions of the disclosure (including, but not limited to, tablets) comprise Compound I and/or a pharmaceutically acceptable salt thereof, cellulose, and croscarmellose sodium. In some embodiments, pharmaceutical compositions of the disclosure (including, but not limited to, tablets) comprise Compound I and/or a pharmaceutically acceptable salt thereof, cellulose, croscarmellose sodium, and sodium stearyl fumarate.

[0045] An exemplary embodiment of a tablet containing 400 mg of Compound I is shown in Table 2.

Table 2. Exemplary Tablet Comprising 400 mg of Compound I.

[0046] An exemplary embodiment of a tablet containing 100 mg of Compound I is shown in Table 3.

Table 3. Exemplary Tablet Comprising 100 mg of Compound I.

[0047] In some embodiments, a tablet comprising Compound I further comprises a coating. In some embodiments, a tablet comprising Compound I further comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc, which is referred to herein as a “non-functional film coating.” An exemplary embodiment of a tablet comprising 100 mg of Compound I and further comprising a non-functional film coating is shown in Table 4. The non-functional film coating can be applied to the tablet comprising Compound I using traditional tablet film coating processes.

Table 4. Exemplary Tablet Comprising 100 mg of Compound I and a Non- Functional Film Coating.

[0048] In some embodiments, disclosed herein are methods of treating, lessening the severity of, or symptomatically treating AATD in a patient comprising administering an effective amount of a compound, pharmaceutically acceptable salt thereof, or a deuterated analog of any of the foregoing; or a pharmaceutical composition, of this disclosure to a patient, such as a human, wherein said patient has AATD. In some embodiments, said patient has the PiZZ genotype. In some embodiments, said patient has the SZ mutation. [0049] In some embodiments, the disclosure also is directed to methods of treatment using isotope-labelled compound of Compound I, which, in some embodiments, are referred to as Compound I’ or pharmaceutically acceptable salt(s) thereof, wherein the formula and variables of such compounds and salts are each and independently as described above or any other embodiments described above, provided that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled). Examples of isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶C1, respectively.

[0050] The isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and/or various types of assays, such as substrate tissue distribution assays. For example, tritium (¾)- and/or carbon-14 (¹⁴C)- labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability. For example, deuterium (²H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non-²H-labelled compounds. In general, deuterium (¾)- labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which could be desired. The isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

[0051] In some embodiments, the isotope-labelled compounds and salts are deuterium (²H)-labelled ones. In some specific embodiments, the isotope-labelled compounds and salts are deuterium (²H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium. In chemical structures, deuterium is represented as “D.”

[0052] The deuterium (²H)-labelled compounds and salts can manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of kM/kD = 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417, incorporated in its entirety herein by reference.

[0053] The concentration of the isotope(s) (e.g., deuterium) incorporated into the isotope-labelled compounds and salt of the disclosure may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, if a substituent in a compound of the disclosure is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), 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), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0054] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It may be reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.

[0055] Non-limiting embodiments of the disclosure include: la. A method of treating alpha-1 antitrypsin deficiency comprising administering to a patient in need thereof Compound I

a deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing in a daily amount of 100 mg to 1600 mg. lb. Compound I, a deuterated derivative thereof, and/or a pharmaceutically acceptable salt of the foregoing for use in treating alpha- 1 antitrypsin deficiency in a patient in need thereof in a daily amount of 100 mg to 1600 mg. lc. Use of Compound I, a deuterated derivative thereof, and/or a pharmaceutically acceptable salt of the foregoing in the manufacture of a medicament for treating alpha- 1 antitrypsin deficiency in a patient in need thereof in a daily amount of 100 mg to 1600 mg.

2. The method according to embodiment la, wherein the patient has the PiZZ genotype.

3. The method according to embodiment la, wherein the patient has an SZ mutation in alpha- 1 antitrypsin.

4. The method according to any one of embodiments la, 2, and 3, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered in a daily amount of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg.

5. The method according to any one of embodiments la and 2-4, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered multiple times daily.

6. The method according to any one of embodiments la and 2-4, wherein Compound I deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 8 hours (q8h) or every 12 hours (ql2h).

7. The method according to any one of embodiments la and 2-4, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered once daily.

8. The method according to any one of embodiments la, 2-4 and 7, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 24 hours (q24h).

9. The method according to any one of embodiments la and 2-6, wherein 100 mg, 200 mg, 400 mg, 300 mg, 600 mg, or 800 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

10. The method according to any one of embodiments la and 2-6, wherein 100 mg, 200 mg, 300 mg, or 400 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h). 11. The method according to any one of embodiments la and 2-6, wherein 100 mg, 200 mg, 400 mg, or 600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

12. The method according to any one of embodiments la and 2-6, wherein 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

13. The method according to any one of embodiments la and 2-6, wherein 100 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

14. The method according to any one of embodiments la and 2-6, wherein 200 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

15. The method according to any one of embodiments la and 2-6, wherein 400 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

16. The method according to any one of embodiments la and 2-6, wherein 600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

17. The method according to any one of embodiments la and 2-16, wherein the method comprises administering to a patient in need thereof Compound I.

18. The method according to any one of embodiments la and 2-16, wherein the method comprises administering to a patient in need thereof a pharmaceutically acceptable salt of Compound I.

19. The method according to any one of embodiments la and 2-4, wherein the method comprises administering to a patient in need thereof a pharmaceutical composition comprising Compound I and/or a pharmaceutically acceptable salt thereof.

20. The method according to embodiment 19, wherein the pharmaceutical composition is administered once daily.

21. The method according to embodiment 19, wherein the pharmaceutical composition is administered multiple times daily.

22. The method according to any one of embodiments 19-21, wherein the pharmaceutical composition is administered every 8 hours (q8h), every 12 hours (ql2h), or every 24 hours (q24h).

23. The method according to any one of embodiments 19-21, wherein the pharmaceutical composition comprises 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

24. The method according to embodiments 19-21, wherein the pharmaceutical composition comprises 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing in an amount of and is administered every 12 hours (ql2h).

25. The method according to embodiment 24, wherein the pharmaceutical composition comprises 100 mg, 200 mg, 300 mg, or 400 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

26. The method according to embodiment 24, wherein the pharmaceutical composition comprises 100 mg, 200 mg, 400 mg, or 600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

27. The method according to 22, wherein the pharmaceutical composition comprises 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing and is administered every 12 hours (ql2h).

28. The method according to embodiment 25, wherein the pharmaceutical composition comprises 100 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

29. The method according to embodiment 25, wherein the pharmaceutical composition comprises 200 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

30. The method according to embodiment 25, wherein the pharmaceutical composition comprises 400 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

31. The method according to embodiment 25, wherein the pharmaceutical composition comprises 600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing. 32. The method according to any one of embodiments 19-31, wherein the pharmaceutical composition comprises Compound I.

33. The method according to any one of embodiments 19-31, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound I.

34. The method according to any one of embodiments 19-33, wherein the pharmaceutical composition is a tablet.

35. The method according to embodiment 34, wherein the tablet is suitable for oral administration.

36. The method according to any one of embodiments 19-34, wherein the pharmaceutical composition comprises Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing, cellulose, croscarmellose sodium, and/or sodium stearyl fumarate.

37. The method according to embodiment 34 or embodiment 35, wherein the tablet comprises Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing, cellulose, croscarmellose sodium, and/or sodium stearyl fumarate.

38. The method according to any one of embodiments 34, 35, or 37, wherein the tablet comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc.

39. The method according to any one of embodiments la - and 2-38, wherein the patient is in the fasted state.

40. The method according to any one of embodiments la- and 2-38, wherein the patient is in the fed state.

41. A pharmaceutical composition comprising 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing for use in treating alpha- 1 antitrypsin deficiency in a patient in need thereof.

42. The pharmaceutical composition according to embodiment 41, wherein the pharmaceutical composition comprises 100 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

43. The pharmaceutical composition according to embodiment 41, wherein the pharmaceutical composition comprises 200 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing. 44. The pharmaceutical composition according to embodiment 41, wherein the pharmaceutical composition comprises 400 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

45. The pharmaceutical composition according to embodiment 41, wherein the pharmaceutical composition comprises 600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

46. The pharmaceutical composition according to any one of embodiments 41- 45, wherein the pharmaceutical composition comprises Compound 1.

47. The pharmaceutical composition according to any one of embodiments 41- 45, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound 1.

48. The pharmaceutical composition according to any one of embodiments 41- 47, wherein the pharmaceutical composition is a tablet.

49. The pharmaceutical composition according to embodiment 48, wherein the tablet is suitable for oral administration.

50. The pharmaceutical composition according to any one of embodiments 41- 49, wherein the pharmaceutical composition comprises Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing, cellulose, croscarmellose sodium, and/or sodium stearyl fumarate.

51. The pharmaceutical composition according to embodiment 48 or embodiment 49, wherein the tablet comprises Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing, cellulose, croscarmellose sodium, and/or sodium stearyl fumarate.

52. The pharmaceutical composition according to any one of embodiments 48, 49, or 51, wherein the tablet comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc.

53. Compound I, a deuterated derivative thereof, and/or a pharmaceutically acceptable salt of the foregoing for the use according to embodiment lb, wherein the use is further defined in any one of the limitations recited in embodiments 2-52.

54. The use of Compound I, a deuterated derivative thereof, and/or a pharmaceutically acceptable salt of the foregoing according to embodiment lc, wherein the use is further defined in any one of the limitations recited in embodiments 2-52. Example 1: Synthesis of Compound I Part A: Synthesis of Starting Materials

[0056] Preparations of C2, SI, and S2 describe synthetic routes to intermediates used in the synthesis of Compound I.

Preparation C2

5-chloro-6-(3-methylbut-l-yn-l-yl)-lH-indazole ( C2)

[0057] Pd(PPh3)2Cl2 (1.7 g, 2.4 mmol) was added to a nitrogen purged solution of 3- methylbut-l-yne (10.7 mL, 104.6 mmol), 6-bromo-5-chloro-li/-indazole Cl (10.4 g, 44.9 mmol) and Cul (497 mg, 2.6 mmol) in Et3N (100 mL) and 1,4-dioxane (100 mL). The solution was stirred at 90°C overnight in a Parr botle, whereupon Celite® and methanol were added, and the mixture concentrated in vacuo. Purification of the Celite® adsorbed mixture by silica gel chromatography (Gradient: 0-100% EtOAc in heptanes) afforded the product. Yield: 7.0 g, 71%. LCMS m/z 219.04 [M+H]⁺. 'HNMR (300 MHz, Chloroform- d) d 10.17 (s, 1H), 8.02 (d, J= 1.1 Hz, 1H), 7.80 (d, J = 0.7 Hz, 1H), 7.62 (t, J = 0.9 Hz, 1H), 2.88 (hept, J = 6.9 Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H).

Preparation SI

Step 1. Synthesis ofN-(4-fluorophenyl)-6-(3-methylbut-l-yn-l-yl)-\H-indazol-5-amine (C3)

[0058] t-Butanol (11 mL) was added to a vial containing 5-chloro-6-(3-methylbut-l- ynyl)-li/-indazole C2 (744 mg, 3.3 mmol), 4-fluoroaniline (600 mg, 5.4 mmol), sodium t- butoxide (1.3 g, 13.0 mmol), and BretPhos Pd G4 catalyst (79 mg, 0.09 mmol). The mixture was degassed with nitrogen and stirred at 120 °C overnight. The mixture was diluted with dichloromethane (75mL) and washed with 50% saturated sodium bicarbonate solution (mL40mL). The organic layer was dried by passing through a phase separator. Celite® was added to the solution, and the mixture was concentrated to dryness under reduced pressure. Purification by silica gel chromatography (Gradient: 0-100% EtOAc in heptanes) afforded the product. Yield: 812 mg, 80%. LCMS m/z 294.3 [M+H]⁺ confirmed the product C3 together with the cyclized SI as a minor component (4.6:1). The crude mixture was progressed to step 2 without further purification.

Step 2. Synthesis of 5-(4-fluorophenyl)-6-isopropyl-l,5-dihydropyrrolo[2,3-Jindazole (SI)

[0059] A solution of iV-(4-fluorophenyl)-6-(3-methylbut- 1 -ynyl)- 1 H-inda/ol-5-amine C4 (812 mg, 2.7 mmol) in DMSO (3.5 mL) was heated in a sealed vial at 150 °C for 90 min. 50% saturated sodium bicarbonate (25 mL) was added and the resulting mixture was extracted with EtOAc (2 x lOOmL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. Yield: 778 mg, 92%. LCMS m/z 294.3 [M+H]⁺ 'H NMR (300 MHz, DMSO-d6) d 12.59 (s, 1H), 7.96 (d, J = 1.0 Hz, 1H), 7.57 - 7.41 (m, 5H), 7.15 (t , J = 1.0 Hz, 1H), 6.48 (d, = 0.8 Hz, 1H), 2.98 - 2.84 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H).

Preparation S2 benzyl 5-(4-fluorophenyl)-6-isopropylpyrrolo[2, 3-Jindazole-l (5H)-carboxylate (S2)

[0060] To a suspension of 5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f]indazole SI (14.6 g, 49.1 mmol) in THF (288 mL) cooled to 1 °C on an ice-water bath, was added KOtBu (7.2 g, 64.2 mmol). After approx. 30 min, Cbz-Cl (21.5 mL of 3 M, 64.5 mmol) was added and the mixture stirred for an additional 1 h in a cooling bath. The reaction was quenched with water (300 mL), stirred for 5 min, then partitioned between EtOAc (400 mL) and water (100 mL). The organic layer was washed with brine (400 mL), dried over magnesium sulfate, and then concentrated in vacuo. The residue was treated with MTBE (40 mL) resulting in the formation of an orange/brown slurry. The slurry was poured into a filter funnel and the solid washed with MTBE until the material was a consistent pale yellow color. The solid was dried in a vacuum oven to afford the product. Yield: 17.04 g, 80%. LCMS m/z 428.25 [M+l]⁺. ¾ NMR (300 MHz, DMSO-d6) d 8.39 - 8.33 (m, 1H), 8.29 - 8.23 (m, 1H), 7.62 - 7.36 (m, 9H), 7.36 - 7.31 (m, 1H), 6.68 - 6.61 (m, 1H), 5.55 - 5.49 (m, 2H), 2.94 (m, 1H), 1.20 (dd, J = 6.8, 1.7 Hz, 6H).

Alternative Preparations of SI and S2

5-(4-fluorophenyl)-6-isopropyl-l , 5-dihydropyrrolo [2, 3-f]indazole (SI) & benzyl 5-(4- fluorophenyl)-6-isopropylpyrrolo[ 2, 3-f]indazole-l( 5 H) -car boxy late (S2)

Step 1. Synthesis of 4-bromo-5-iodo-2-methylaniline (C5)

[0061] To a solution of 5-iodo-2-methylaniline C4 (600 g, 2.6 mol) in DMF (3 L) at -6 °C was added /V-bromosuccinimide (460 g, 2.58 mol) in 5 portions over ~45 min (maintaining the temperature between -3 to -7 °C). The mixture was stirred at -5 to -8 °C for 55 min. The mixture was quenched by addition of 0.5M Na2S203 (200 mL) then added to ice/water (4.8 kg) over 4 min. A slurry formed, and an exotherm to +10°C was observed. The mixture was diluted with additional cold water (1 L), stirred for one hour at ~10 °C, filtered and washed with water (1.5 L). The solids were dried at 45 °C under vacuum to afford the product as an off-white solid. Yield: 779 g, 97%. 'H NMR (500 MHz, Chloroform-d) d 7.25 (s, 1H), 7.14 (s, 1H), 3.60 (2H, s), 2.05 (3H, s).

Step 2. Synthesis of 5-bromo-6-iodo-\H-indazole (C6)

[0062] To a solution of C5 (791 g, 2.5 mol) in AcOH (4.2 L) at 44 °C was added isopentyl nitrite (333 g, 2.8 mol) over 1 h. The reaction was allowed to exotherm to 55 °C, then held between 55-64 °C. The mixture was stirred at 55 °C for 30 min, then cooled to 50 °C. Ice-cold water (4.2 L) was added over 15 min while continuing to cool to 20 °C.

The slurry was stirred for 25 min at 20 °C, filtered and washed with water (2 L). The crude orange solid was dried at 50°C under vacuum. The solid was then triturated at room temperature in MeCN (2.25 L) for 30 minutes, filtered, and washed with MeCN (-750 mL) to afford the product as an orange solid. Yield: 679 g, 83%. 'H NMR (500 MHz, DMSO-d6) d 13.25 (1H, s), 8.22 (1H, s), 8.20 (lH,s), 8.05 (1H, s).

Step 3. Synthesis of 5-bromo-6-(3-methylbut-l-yn-l-yl)-\H-indazole (C7)

[0063] A solution of C6 (2738 g, 8.5 mol) in DMF (10 L) was de-oxygenated with 4 x vacuum/ nitrogen cycles. The mixture was cooled to 6 °C and then diethylamine (1.54 kg, 21.1 mol) and 3-methyl-l-butyne (652 g, 9.57 mol) were added. The mixture was transferred using nitrogen pressure to an inert 20-L autoclave containing copper (I) iodide (32 g, 168 mmol) and PdCh(PPh3)2 (115 g, 164 mmol). The autoclave was sealed, pressurized to 5 psi using nitrogen and then heated to 85 °C for 15 h. The pressure increased to 23 psi initially and then gradually decreased to 15 psi as the 3-methyl-l- butyne was consumed (the pressure stopped dropping after about 8 h, presumably indicating complete reaction). The mixture was cooled to 20 °C and then added to a mixture of 37% hydrochloric acid (1.5 kg, 14.9 mol), water (13.7 L) and MTBE (8.7 L) at 5 °C [exotherm to 26°]. The layers were separated, and the organic layer was washed with a mixture of water (8 L) and saturated brine (2 L), and then with saturated brine (3 L). The aqueous layers were sequentially re-extracted with MTBE (5 L then 3 L). The combined organics were dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The residue was triturated in dichloromethane (2 L) at 35 °C, gradually diluted with hexane (2 L) and cooled to 20°C. The slurry was filtered, washed with 1:1 dichloromethane:hexane (1.5 L) and dried under vacuum at 40 °C to afford the product as a pale tan solid. Yield: 1492 g, 67%. ¾ NMR (500 MHz, Chloroform-d) d 10.6 (s, 1H), 8.01 (s, 1H), 7.98 (s,lH), 2.85 (m, 1H), 1.32 (d, 9H). Steps 4 and 5. Synthesis of C3 and 5-(4-fluorophenyl)-6-isopropyl-\H-pyrrolo[2,3- Jindazole (SI)

[0064] To a 50 L glass reactor was added C7 (2973 g, 11.3 mol), 4-fluoroaniline (1419 g, 12.8 mol) and THF (29 L). The solution was vacuum purged with nitrogen (5 x) and cooled to 3 °C. Sodium /-butoxide (3473 g, 36 mol) was added in 1 kg portions over 20 minutes with a resulting heat rise to 16 °C. The solution was vacuum purged with nitrogen (5 x) and cooled to 11 °C. /BuXPhos Pd G1 MTBE catalyst (200 g, 0.2 mol) was added in 3 portions over 1 hour. An exotherm to 33 °C over 2 h was observed. The contents were stirred overnight - cooling to room temperature. HPLC analysis indicated conversion to C3. The solution was diluted with hexanes (4 L) and cooled to 3 °C. Acetic acid was added over 1 h (exotherm to 20 °C). Water (8 L) was added and the contents stirred, then settled. The lower layer was removed, and the upper layer concentrated by vacuum distillation to approx. 10 L. The solution was diluted with methanol (25 L) and heated overnight to about 55 °C. The solution was concentrated by vacuum distillation to about 10 L and cooled to 16 °C. The solids were collected by filtration and washed with cool methanol (4 L) and dried in a vacuum oven to provide the product SI as a brown solid. Yield: 2.52 kg, 76% yield.

Step 6. Synthesis of benzyl 5-(4-fluorophenyl)-6-isopropylpyrrolo[2,3f]indazole- 1 (5H)-carboxylate (S2)

[0065] A solution of SI (132 g, 450 mmol) in THF (2 L) in a 5 L round-bottomed flask equipped with overhead stirrer was cooled to 12 °C. KOtBu (70 g, 625 mmol, 1.4 eq) was added. The mixture warmed to 18 °C over 10 min, and was allowed to stir for a further 30 min. Thick cotton-like needles resulted. An additional 200 mL of THF was added. Cbz- C1 (107 g, 90 mL 635 mmol) was added over 1 h, while cooling the flask in a water bath. The contents were maintained between 16 °C and 22 °C during and after the addition. The resulting slurry was diluted with MTBE (1 L) and washed with water (1 L). The organic layer was concentrated in vacuo to give a light yellow slurry. The material was slurried in methanol (0.5 L) and cooled overnight to about 0 °C. The material was collected by filtration and washed with MeOH (0.2 L) followed by acetonitrile (0.1 L) then dried to afford the product as a light yellow solid. Yield: 145 g, 76% yield. Part B: Synthesis of Compound I

Compound I

3-[ 5-( 4-fluorophenyl)-6-isopropyl- \H-pyrrolo[ 2, 3-fJindazol- 7-yl Jpropanoic acid

Step 1. Synthesis of benzyl 5-(4-fluorophenyl)-6-isopropyl-7-[(E)-3-methoxy-3-oxo- prop-l-enyl ]pyrrolo[ 2, 3-fJindazole-l-carboxylate ( C8)

[0066] To a solution of benzyl 5-(4-fluorophenyl)-6-isopropyl-pyrrolo[2,3-f]indazole- 1-carboxylate (122g, 282 mmol) was dissolved in dichloromethane (1 L) was added methyl 3,3-dimethoxypropanoate (42 mL, 296 mmol) and trifluoroacetic acid (140 mL,

1.8 mol). The reaction was stirred overnight at 50 °C. An additional 0.1 equivalents of methyl 3,3-dimethoxypropanoate were then added and the mixture stirred for an additional 6h at 50 °C. The reaction mixture was concentrated to an oil, and then diluted with dichloromethane. The mixture was washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as yellow oil, which was progressed to the next step without further purification. Yield: 140 g, 81%. LCMS m/z 512.3 [M+H]⁺. Step 2. Synthesis of methyl 3-[5-(4-fluorophenyl)-6-isopropyl-\H-pyrrolo[2,3- fjindazol- 7-yl Jpropanoate ( C9)

[0067] A solution of benzyl 5-(4-fluorophenyl)-6-isopropyl-7-[(E)-3-methoxy-3-oxo- prop-l-enyl]pyrrolo[2,3-f]in(iazole-l-carboxylate C8 (140 g) in methanol (1.5 L) and EtOAc (1.5 L) was divided equally into 3 batches. A slurry of 10 % Palladium on carbon (18 g, 16.9 mmol) in EtOAc was added to each batch. The mixtures were degassed (by evacuation) and then placed under an atmosphere of hydrogen gas using a hydrogen balloon (2 balloons per reaction). After 4h, the hydrogen balloons were replenished, and the mixtures stirred at room temperature overnight. Hydrogen balloons were replenished again, and the reactions stirred for a further overnight period. The mixtures were purged with nitrogen, and then filtered through Celite®, washing with methanol and EtOAc. The combined organic filtrate was concentrated in vacuo. Dilution with EtOAc resulted in the formation of a precipitate, which was filtered off and dried at 40°C under vacuum to afford the product. Yield: 79 g, 72%. LCMS m/z 380.2 [M+H]⁺.

Alternative Synthesis of methyl 3-[5-(4-fluorophenyl)-6-isopropyl-\H-pyrrolo[2,3- fjindazol- 7-yl Jpropanoate ( C9)

[0068] To a solution of benzyl 5-(4-fluorophenyl)-6-isopropyl-7-[(E)-3-methoxy-3- oxo-prop-l-enyl]pyrrolo[2,3-f]indazole-l-carboxylate C8 (49.2 g, 96.1 mmol) in EtOH (1 L) in a 2L three-necked round-bottomed flask equipped with a magnetic stirbar, dropping funnel, and reflux condenser was added 10% Pd on carbon (10 g, 9.397 mmol) catalyst. Triethylsilane (155 mL, 970.4 mmol) was then added dropwise at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was filtered over a Celite® plug. The celite plug was washed with EtOH and the filtrate was evaporated in vacuo to afford a slightly yellow oil. The oil was dissolved in dichloromethane and filtered over a plug of silica gel. The plug was eluted with dichloromethane to elute residual silyl by products, and then 50% EtOAc in dichloromethane to elute the product. The filtrate was evaporated in vacuo to afford the product as a white solid (30.9 g, 85%). 'H NMR (400 MHz, Chloroform-d) d 9.93 (s, 1H), 8.04 (d, J = 1.3 Hz, 1H), 7.55 (t, .7 = 1.1 Hz, 1H),

7.39 - 7.33 (m, 2H), 7.31 - 7.26 (m, 2H), 7.13 (t, J = 0.8 Hz, 1H), 3.77 (s, 3H), 3.37 - 3.21 (m, 2H), 3.09 (m, J = 7.2 Hz, 1H), 2.87 - 2.64 (m, 2H), 1.33 (d, J = 12 Hz, 6H). ¹⁹F NMR (376 MHz, Chloroform-d) d -112.83. Step 3. Synthesis of 3-[5-(4-fluorophenyl)-6-isopropyl-\H-pyrrolo[2,3-f]indazol-7- yl Jpropanoic acid ( Compound I)

[0069] An aqueous solution of LiOH (183 mL of 2.5 M, 458 mmol) was added to a solution of C9 (35.8 g, 91.4 mmol) in THF (336 mL) and methanol (336 mL). The reaction was stirred at room temperature for 1 h. The mixture was the concentrated in vacuo reducing the volume to ~ 400 mL. 1M NaOH (400 mL) was added and the aqueous layer washed with dichloromethane (2 x 500 mL). The aqueous layer was then acidified to -pH 3-4 by the addition of 6M HC1 solution, then extracted with EtOAc (2 x 800 mL).

The EtOAc layers were combined and dried over sodium sulfate, and concentrated in vacuo. Purification in 4 batches by silica gel chromatography (Gradient: 0-10% methanol in dichloromethane) then concentration in vacuo gave the product as a foam. Addition of minimal EtOAc resulted in the formation of a precipitate which was filtered and dried under vacuum to afford the product. Yield: 40.2 g, 66%. LCMS m/z 366.2 [M+H]⁺. 'H NMR (300 MHz, DMSO-d6) d 12.57 (s, 1H), 12.22 (s, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.52 - 7.39 (m, 5H), 7.00 (d, J = 1.1 Hz, 1H), 3.13 (dd, .7 = 9.5, 6.6 Hz, 2H), 3.02 (m, .7 = 7.2 Hz, 1H), 2.63 - 2.53 (m, 2H), 1.25 (d, J = 12 Hz, 6H).

Alternative Preparation for 3-[5-(4-fluorophenyl)-6-isopropyl-\H-pyrrolo[2,3- ]indazol-7 -yljpropanoic acid (Compound I)

[0070] To a slurry of C9 (1237 g, 3.3 mol) in methanol (5 L) at 27 °C was added a mixture of 45% KOH (760 mL, 8.9 mol) in water (2.7 L) over 1 min [exotherm to 40 °C]. The mixture was heated to 46-49 °C for 3 h. The mixture was then cooled to 14 °C, and then treated with acetic acid (560 mL, 9.8 mol) over 3 min. The resulting slurry was diluted with water (1.4 L) and then stirred at ~20 °C overnight before filtering. The solids were washed with water (2 L) and dried under vacuum oven at 50 °C to afford the product. (1173 g, 3.2 mol, 98%).

Example 2: Preparation of a Tablet Containing 400 mg of Compound I [0071] The following materials were used in this exemplary preparation of a tablet containing 400 mg of Compound I.

[0072] In this exemplary preparation, Compound I, microcrystalline cellulose, and croscarmellose sodium were sieved, combined in a bin blender, and blended. Sieved sodium stearyl fumarate was added to the bin blender, and the mixture was blended. The mixture was then dry granulated and milled to form milled granules. These milled granules were added to a bin blender, to which was added sieved microcrystalline cellulose and sieved croscarmellose sodium. The mixture was blended. Sieved sodium stearyl fumarate was added to the bin blender, and the mixture was blended. The resulting blend was discharged and then charged to a tablet press. The blend was compressed into tablets, which were discharged.

Example 3: Preparation of a Tablet Containing 100 mg of Compound I [0073] The method of Example 2 can be used to prepare a tablet containing 100 mg of Compound I. The method is performed as in Example 2, except using the following quantities of materials:

Example 4: Preparation of a Coated Tablet Comprising 100 mg of Compound I [0074] The method of Example 2 can be used to prepare a tablet comprising 100 mg of Compound I, which is coated with the non-functional film coating described elsewhere herein. The method is performed as in Example 2, except using the following quantities of materials:

[0075] The non-functional film coating is applied to the tablet comprising Compound I using traditional tablet film coating processes. Accordingly, the composition of the resulting coated tablet is as follows:

Example 5: Prophetic Safety and Efficacy Study of Compound I

[0076] This will be a Phase 2, randomized, double-blind, placebo-controlled study of

Compound I.

[0077] Inclusion Criteria will include

1. Subjects will be 18 through 80 years of age, and females will have a negative pregnancy test at screening and Day 1.

2. Plasma antigenic AAT level < 8 pm at screening (if applicable, as determined > more than 42 days after last dose of augmentation therapy).

3. Subjects will have a PiZZ genotype.

[0078] Exclusion Criteria will include

1. Subjects meeting any of the following criteria:

• Subjects who have undergone solid organ, lung, or hematological transplantation or is currently on a transplant list.

• Subjects who have undergone gastrectomy or other gastrointestinal tract surgery, except appendectomy, cholecystectomy, and hemorrhoid surgery.

• Subjects who have cancer, except for squamous cell skin cancer, basal cell skin cancer, Stage 0 and Stage 1 melanoma and Stage 0 cervical carcinoma in situ. 2. Subjects who have a history of use of gene therapy or RNAi therapy.

3. Subjects who have used oral corticosteroids (at any dose) for a duration of greater than 3 months within the 3 months before screening.

4. A post-bronchodilator forced expiratory volume in 1 second (FEVi) value <30% of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI]) during screening. [NOTE: historical FEVi results within 1 year before Day 1 can be used to determine eligibility]

5. Subjects who have clinically important pulmonary disease other than AATD-related COPD.

6. Subjects who have a history of chronic liver disease or a history of clinically important liver disease within the previous 12 months before screening.

7. Subjects who have any of the following abnormal laboratory values at screening:

• Hemoglobin <10 g/dL

• Total bilirubin >ULN

• Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) >2 ^c ULN

• Estimated glomerular filtration rate <30 mL/min/1.73 m² (calculated by the Modification of Diet in Renal Disease Study Equation)

8. Subjects who have risk factors for Torsade de Pointes or concomitant medications that prolong the QT/QTc interval or any history of cardiac disorders.

9. Subjects who have a history of Gilbert’s Syndrome.

10. Subjects who show any clinically significant ECG abnormality at the Screening Visit and at the Screening Safety Visit (as applicable).

11. Subjects who have a median QTcF of triplicate standard 12-lead ECGs >450 msec at screening.

12. Subjects who are positive for HBsAg, HCV antibody, or HIV-1 and HIV-2 antibodies during screening.

13. Subjects who show hypersensitivity to any component of the investigational drug product or placebo (e.g., lactose).

14. Subjects for whom discontinuation of augmentation therapy is not considered to be in their best interest, based on the clinical judgment of the treating physician.

[0079] Schematics of the study design are shown in Tables 5 and 6. As depicted therein, the study will include a screening period, a treatment period, a washout visit, and a follow-up visit. In Tables 5 and 6, N equals the number of subjects, and these subject numbers include subjects who have never been on augmentation therapy and subjects who have been on augmentation therapy at any time.

[0080] For subjects who have never been on augmentation therapy, the Screening Period (Day -35 through Day -1) will occur up to 35 days before the first dose of Compound I. In some cases, a subject may have the Screening Period window extended for an additional 2 weeks (total of 4 weeks extension) with medical monitor approval. [0081] In Part A1 of this study, approximately 15 subjects in total with the PiZZ genotype and antigenic AAT levels < 8 mM at screening will be randomized (2: 1 : 1 : 1) to one of three Compound I groups (100 mg ql2h, 200 mg ql2h, and 400 mg ql2h )or the placebo group.

[0082] In Part A2 of this study, approximately 8 subjects in total with the PiZZ genotype and antigenic AAT levels < 8 mM at screening will be randomized (3: 1) to the Compound I group (400 mg ql2h) or the placebo group.

[0083] In Part B of this study, approximately 20 subjects in total with the PiZZ genotype and antigenic AAT levels < 8 pM at screening will be randomized (3:1) (600 mg ql2h) to one Compound I group or the placebo group.

[0084] Randomization will be stratified by percent predicted forced expiratory volume in 1 second FEVi (ppFEVi) obtained either during the Screening Period or from a historical ppFEVi value (<50% versus >50%).

[0085] For subjects who have never been on augmentation therapy, the Screening Period (Day -35 through Day -1) will occur up to 35 days before the first dose of Compound I. Subjects will have a Compound I Washout Visit 7 days after the last dose of augmentation therapy. In Part A1 of this study on subjects who have never been on augmentation therapy, 3 dose levels of Compound I will be evaluated (100 mg ql2h, 200 mg ql2h, and 400 mg ql2h). Specifically, subjects (approximately 15 in total) will be randomized to receive Compound I 400 mg every 12 hours (ql2h; n = 6), Compound I 200 mg ql2h (n = 3), Compound I 100 mg ql2h (n = 3), or placebo (n = 3). In Part A2 of this study on subjects who have never been on augmentation therapy, a single dose level of Compound I will be evaluated (400 mg ql2h). Specifically, subjects (approximately 8 in total) will be randomized to receive Compound I 400 mg every 12 hours (ql2h; n = 6) or placebo (n = 2). In Part B of this study on subjects who have never been on augmentation therapy, a single dose level of Compound I will be evaluated (600 mg ql2h). Specifically, subjects (approximately 20 in total) will be randomized to receive Compound I 600 mg every 12 hours (ql2h; n = 15) or placebo (n = 5).

[0086] For subjects who have been on augmentation therapy at any time, the Screening Period (Day -70 through Day -1) will occur up to 70 days before the first dose of Compound I. The last dose of augmentation therapy must be given more than 42 days before Day 1. To establish eligibility, an antigenic AAT level must be drawn (and results reviewed to confirm eligibility) more than 42 days after the last dose of augmentation therapy. Results must be confirmed to be < 8 pm before randomization. Subjects will remain off augmentation therapy thereafter until after the last Safety Follow Visit has been conducted. Subjects must discontinue augmentation therapy more than 42 days before the first dose of study drug. Subjects can resume augmentation therapy after completion of assessments at the Safety Follow-up Visit.

[0087] For subjects who have never been on augmentation therapy, the Screening Period (Day -35 through Day -1) will occur up to 35 days before the first dose of Compound I. Subjects will have a Compound I Washout Visit 7 days after the last dose of augmentation therapy. In Part A1 of this study on subjects who have never been on augmentation therapy, 3 dose levels of Compound I will be evaluated (100 mg ql2h, 200 mg ql2h, and 400 mg ql2h). Specifically, subjects (approximately 15 in total) will be randomized to receive Compound I 400 mg every 12 hours (ql2h; n = 6), Compound I 200 mg ql2h (n = 3), Compound I 100 mg ql2h (n = 3), or placebo (n = 3). In Part A2 of this study on subjects who have never been on augmentation therapy, a single dose level of Compound I will be evaluated (400 mg ql2h). Specifically, subjects (approximately 8 in total) will be randomized to receive Compound I 400 mg every 12 hours (ql2h; n = 6) or placebo (n = 2). In Part B of this study on subjects who have never been on augmentation therapy, a single dose level of Compound I will be evaluated (600 mg ql2h). Specifically, subjects (approximately 20 in total) will be randomized to receive Compound I 600 mg every 12 hours (ql2h; n = 15) or placebo (n = 5). Assuming 10% of the randomized subjects will have a missing value at Day 28, this sample size provides adequate power for the primary comparison and adequate precision to estimate the plasma functional AAT levels at Day 28 for the Compound I 600 mg ql2h group in Part B. Table 5: Schematic of Study Design for Subjects Who Have Never Been on Augmentation Therapy Part Al:

Part A2:

Part B:

1. N: number of subjects; ql2h: every 12 hours

2. Note: Table are not drawn to scale.

3. Subject numbers include subjects who have never been on augmentation therapy and subjects who have been on augmentation therapy at any time.

4. Antigenic AAT levels must be drawn to confirm eligibility and sent to the central laboratory; results must be obtained and confirmed to be <8 mM before randomization. Once antigenic AAT levels have been confirmed to meet this eligibility criterion, randomization and Day 1 can occur any time within the remaining screening window. Sites should allow at least 14 days for sample processing and antigenic AAT level result reporting.

Table 6: Schematic of Study Design for Subjects Who Have Been on Augmentation Therapy at Any Time Part Al:

Part A2:

Part B:

1. N: number of subjects; ql2h: every 12 hours

2. Tables are not drawn to scale.

3. Subject numbers include subjects who have never been on augmentation therapy and subjects who have been on augmentation therapy at any time. Subjects must discontinue augmentation therapy >42 days before antigenic AAT levels are drawn and sent to the central laboratory to confirm eligibility; results must be confirmed to be <8 mM before randomization. Once antigenic AAT levels have been confirmed to meet this eligibility criterion, randomization and Day 1 can occur any time within the remaining screening window. Sites should allow at least 14 days for sample processing and antigenic AAT level result reporting. Subjects can resume augmentation therapy after completion of assessments at the last Safety Follow-up Visit.

4. Blood samples will be obtained for antigenic and functional AAT levels at the same time that the other screening laboratory assessments are performed. If the subject received the last dose of augmentation therapy >42 days prior, this sample can be used to measure antigenic AAT level for eligibility. If samples are obtained <42 days after the last dose of augmentation therapy, another sample must be drawn >42 days after the last dose of augmentation therapy and sent to the central laboratory to confirm eligibility.

[0088] As noted above, the study population will be comprised of male and female subjects with a diagnosis of COPD and AATD with a confirmed PiZZ genotype. A total of 4 doses of Compound I will be evaluated in this study: 100 mg ql2h, 200 mg ql2h, 400 mg ql2h, and 600 mg ql2h. Compound I will be administered orally, 2 times a day, approximately 12 hours apart, with a regular meal.

[0089] The primary endpoint to assess the effect on circulating AAT will be the change from baseline in plasma functional AAT levels at Day 28. The primary comparison consists of pairwise comparison between the dose of Compound I 400 mg ql2h, Compound I 600 mg ql2h and placebo on the primary endpoint. As used herein, “baseline value” will be the most recent non-missing measurement (scheduled or unscheduled) collected before the first dose of study drug. For ECGs, the baseline value will be defined as the average of the non-missing pretreatment measurements (triplicate) before the first dose of Compound I. As used herein, “change (absolute change) from baseline” will be calculated as Post-baseline value - Baseline value. As used herein, “relative change from baseline” will be calculated and expressed in percentage as 100% ^c (post-baseline value - Baseline value)/Baseline value. The primary analysis will be based on a mixed- effects model for repeated measures (MMRM) with change from baseline at Days 7, 14 and 28 as the dependent variable.

[0090] Plasma samples will be collected to evaluate the effect of Compound I on AAT function and antigenic level in subjects with the PiZZ genotype based on the mechanism of action of Compound I. All safety and PK assessments to be performed are standard measurements for clinical studies in drug development. Furthermore, blood samples are also used for assessing serum chemistry at study visits on treatment and on Day 7, Day 14 and 28 after the last dose.

[0091] The overall safety profile of Compound I will be assessed in terms safety endpoints, including:

• Incidence of treatment emergent adverse events (TEAEs)

• Clinical laboratory values (i.e., hematology, serum chemistry, coagulation, and urinalysis)

• Standard 12-lead ECG outcomes

• Vital signs

• Pulse oximetry

Other Embodiments

[0092] The foregoing discussion discloses and describes merely exemplary embodiments of this disclosure. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications and variations can be made therein without departing from the spirit and scope of this disclosure as defined in the following claims.

Claims

Claims

1. A method of treating alpha- 1 antitrypsin deficiency comprising administering to a patient in need thereof Compound I

deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing in a daily amount of 100 mg to 1600 mg.

2. The method according to claim 1, wherein the patient has the PiZZ genotype.

3. The method according to claim 1, wherein the patient has an SZ mutation in alpha- 1 antitrypsin.

4. The method according to any one of claims 1-3, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered in a daily amount of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg.

5. The method according to any one of claims 1-4, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered multiple times daily.

6. The method according to any one of claims 1-4, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 8 hours (q8h) or every 12 hours (ql2h).

7. The method according to any one of claims 1-4, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered once daily.

8. The method according to any one of claims 1-4 or 7, wherein Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 24 hours (q24h).

9. The method according to any one of claims 1-6, wherein 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

10. The method according to any one of claims 1-6, wherein 100 mg, 200 mg, 300 mg, or 400 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

11. The method according to any one of claims 1-6, wherein 100 mg, 200 mg, 400 mg, or 600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

12. The method according to any one of claims 1-6, wherein 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing is administered every 12 hours (ql2h).

13. The method according to any one of claims 1-12, wherein the method comprises administering to a patient in need thereof Compound I.

14. The method according to any one of claims 1-12, wherein the method comprises administering to a patient in need thereof a pharmaceutically acceptable salt of Compound I.

15. The method according to any one of claims 1-4, wherein the method comprises administering to a patient in need thereof a pharmaceutical composition comprising Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

16. The method according to claim 15, wherein the pharmaceutical composition is administered once daily.

17. The method according to claim 15, wherein the pharmaceutical composition is administered multiple times daily.

18. The method according to any one of claims 15-17, wherein the pharmaceutical composition is administered every 8 hours (q8h), every 12 hours (ql2h), or every 24 hours (q24h).

19. The method according to any one of claims 15-17, wherein the pharmaceutical composition comprises 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1200 mg, or 1600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

20. The method according to claim 15 or claim 17, wherein the pharmaceutical composition comprises 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing in an amount of and is administered every 12 hours (ql2h).

21. The method according to claim 20, wherein the pharmaceutical composition comprises 100 mg, 200 mg, 300 mg, or 400 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

22. The method according to claim 20, wherein the pharmaceutical composition comprises 100 mg, 200 mg, 400 mg, or 600 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing.

23. The method according to 18, wherein the pharmaceutical composition comprises 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, or 800 mg of Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing and is administered every 12 hours (ql2h).

24. The method according to any one of claims 15-23, wherein the pharmaceutical composition comprises Compound I.

25. The method according to any one of claims 15-23, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound I.

26. The method according to any one of claims 15-25, wherein the pharmaceutical composition is a tablet.

27. The method according to claim 26, wherein the tablet is suitable for oral administration.

28. The method according to any one of claims 15-27, wherein the pharmaceutical composition comprises Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing, cellulose, croscarmellose sodium, and/or sodium stearyl fumarate.

29. The method according to claim 26 or 27, wherein the tablet comprises Compound I, deuterated derivative thereof, and/or a pharmaceutically acceptable salt of any of the foregoing, cellulose, croscarmellose sodium, and/or sodium stearyl fumarate.

30. The method according to claim 26, claim 27, or claim 29, wherein the tablet comprises a coating comprising polyvinyl alcohol (PVA), polyethylene glycol (PEG), titanium dioxide, and talc.

31. The method according to any one of claims 1-30, wherein the patient is in the fasted state.

32. The method according to any one of claims 1-30, wherein the patient is in the fed state.