Modulators of alpha-1 antitrypsin

Abstract

Pyrano[4,3-b]indole derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD).

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 004,702, filed April 3, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[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.

[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 made 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-induced damage, especially during periods of inflammation.

[0004] The mutation most commonly associated with AATD involves a glutamic acid to lysine substitution (E342K) 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 approximately 15% of the mutant Z-AAT protein is correctly folded and secreted from cells. A further consequence of the Z mutation is that secreted Z-AAT has 40% to 80% reduced normal antiprotease activity compared to the wild-type protein (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 in hepatocytes leads to 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 over time degrades lung tissue, resulting in 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 further shortened lifespan (58 years) (Piitulainen and Tanash, COPD 2015;12(1):36-41). PiZZ individuals represent a large proportion of those with clinically relevant AATD lung disease. Therefore, there is a need for additional and effective treatments for AATD. 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 not 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. [Prior art documents] [Non-patent literature]

[0006] [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] Fregonese and Stolk,Orphanet J Rare Dis.2008;33:16 Summary of the Invention [Means for solving the problem]

[0007] The current standard of care for AAT-deficient individuals who have or show signs of developing significant lung or liver disease is augmentation therapy or protein replacement therapy. Augmentation therapy involves 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, making efficacy 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. DETAILED DESCRIPTION OF THE INVENTION

[0008] One aspect of the present disclosure relates to compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb ...IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) to (IIb-2), (IIb-1) The present invention provides compounds of formula (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives. For example, compound (Ia) or (Ib), a tautomer of these compounds, a deuterated derivative of these compounds or tautomers, or a pharmaceutically acceptable salt of any of the foregoing, can be prepared by the steps of: [ka] where: W 1 is absent or is a bond, -O-, or -CR D R D - and W 2 -O-, -(CR D R D ) p - or -C=O, However, W 1 and W 2 are not both -O-, R A and R B are each independently hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; or alternatively, R A and R B are each independently C1-C3 alkyl or C1-C3 alkoxy, and R A and R B together with the intervening C atoms form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl containing at least one oxygen atom, R C are independently hydrogen, —OH, C1-C3 alkyl, or C1-C3 haloalkyl R D is, independently for each occurrence, hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; or alternatively, R D is, independently for each occurrence, C1-C3 alkyl or C1-C3 alkoxy, and two R D groups, together with the intervening C atoms, form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl containing at least one oxygen atom; U 1 and U 2are each independently hydrogen, halogen, —NH2, —CH3, or —OH; However, U 1 and U 2 One of the groups is -OH or -NH2, but U 1 and U 2 are both -OH or -NH2, not U 1 and U 2 are not both hydrogen, Ring A is C3-C 12 carbocyclyl or 3- to 12-membered heterocyclyl; X does not exist, -(CR E R E ) q - or -CH2OCH2-, wherein R E is independently for each occurrence hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; Y is -COOH or [ka] and Ring B is C3-C 12 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R 1 and R 2 is, independently for each occurrence, halogen, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, or O—(C-C cycloalkyl); R 3 is independently for each occurrence halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -OH, -O(CR f R f ) r COOH, ═O, -COOH, -C(═O)NR f R f , -(CR f R f ) rCOOH, phenyl, or 5- or 6-membered heteroaryl, wherein R f is, independently for each occurrence, hydrogen, halogen, or —CH; R 3 wherein the phenyl or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -OH, and -COOH; R 4 is independently for each occurrence halogen, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, —COOH, —CHCOOH, or —OCHCOOH; k and n are each independently an integer selected from 0, 1, 2, and 3; j and m are each independently an integer selected from 0, 1, and 2; p and r are each independently an integer selected from 1 and 2; q is an integer selected from 1, 2, and 3.

[0009] Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formulas (Ia), (I Compounds (IIa-1)-(IIa-2), (IIb-1)-(IIb-2), (IIIa), (IIIb-1)-(IIIb-2), (IVa-1)-(IVa-3), (IVb-1)-(IVb-2), (Va-1)-(Va-2), (Vb-1)-(Vb-5), and (VIb-1)-(VIb-2)) are modulators of AAT activity. In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa) The compounds of formula (I) (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), and tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC50 activity of 2.0 μM or less when tested in an AAT functional assay. 50In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa) The compounds of formula (I) (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC50 activity of less than 0.5 μM when tested in an AAT functional assay. 50 It has.

[0010] In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), ( Compounds of formula IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), and tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an IC of 5.0 μM or less when tested in the Z-AAT elastase activity assay. 50In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), ( Compounds of formula IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an IC of less than 2.0 μM when tested in the Z-AAT elastase activity assay. 50 It has.

[0011] In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa) The compounds of formula (I) (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), and tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC50 activity of 2.0 μM or less when tested in an AAT functional assay. 50 and has an IC of 5.0 μM or less when tested in the Z-AAT elastase activity assay 50In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa) The compounds of formula (I) (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC50 activity of less than 0.5 μM when tested in an AAT functional assay. 50 and has an IC of 5.0 μM or less when tested in the Z-AAT elastase activity assay 50 In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa) The compounds of formula (I) (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), and tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, have an EC50 activity of 2.0 μM or less when tested in an AAT functional assay. 50 and has an IC of less than 2.0 μM when tested in the Z-AAT elastase activity assay 50In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa) The compounds of formula (I) (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives, have an EC50 activity of less than 0.5 μM when tested in an AAT functional assay. 50 and has an IC of less than 2.0 μM when tested in the Z-AAT elastase activity assay 50 It has.

[0012] In some embodiments, Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), ( Compounds of formula IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives are provided for use in treating AATD.

[0013] In one aspect of the disclosure, the compound of Formula (Ia) or (Ib) is selected from compounds 1-189 and 192-210, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD. In some embodiments, the compound is selected from compounds 1-210, tautomers of compounds 1-210, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in the treatment of AATD.

[0014] In some embodiments, the present disclosure provides compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb and (VIb-1) to (VIb-2)), 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 may include a compound selected from compounds 1 to 210, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0015] Another aspect of the present disclosure provides a method of treating AATD, the method comprising administering to a patient a compound of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., a compound of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-3) In some embodiments, the method comprises administering to a subject in need thereof at least one compound selected from compounds 1-210, tautomers of those compounds, deuterated derivatives of those 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 to a subject in need thereof at least one compound selected from compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0016] In some embodiments, the method of treatment includes administering to a patient of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), The method comprises administering to a subject in need thereof at least one active agent in the same pharmaceutical composition or as a separate composition: at least one compound selected from compounds (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), tautomers of those compounds, deuterated derivatives of those 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 active agent in the same pharmaceutical composition or as a separate composition: a compound selected from compounds 1-210, 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. 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.

[0017] In some embodiments, the method of treatment includes administering to a subject a compound of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), The method includes administering to a subject in need thereof at least one active agent, either in the same pharmaceutical composition or as a separate composition, at least one compound selected from compounds (IVb-1)-(IVb-2), (Va-1)-(Va-2), (Vb-1)-(Vb-5), and (VIb-1)-(VIb-2), 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 a healthy human donor. In some embodiments, the method includes administering to a subject in need thereof at least one active agent, either in the same pharmaceutical composition or as a separate composition, a compound selected from compounds 1-210, 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.

[0018] In some embodiments, the method of treatment includes administering to a subject a compound of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), The method includes administering to a subject in need thereof at least one active agent, either in the same pharmaceutical composition or as a separate composition, at least one compound selected from compounds (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), 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 recombinant AAT. In some embodiments, the method includes administering to a subject in need thereof at least one active agent, either in the same pharmaceutical composition or as a separate composition, a compound selected from compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with the at least one additional active agent, either in the same pharmaceutical composition or in a separate composition, wherein the additional active agent is recombinant AAT.

[0019] Also provided is a method for modulating AAT, the method comprising administering to a subject a compound of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., a compound of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2) (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt to a subject in need thereof. In some embodiments, the method for modulating AAT comprises administering to a subject in need thereof at least one compound selected from compounds 1-210, tautomers of those compounds, deuterated derivatives of those 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.

[0020] and (VIb-1) to (VIb-5) of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIa-1) to (IIa-5), or (IIb-1) to (VIb-5) for use in therapy. Also provided are compounds of Formula (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2), and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, provided are compounds selected from Compounds 1-210 (e.g., Compounds 1-189 and 192-210), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in therapy.

[0021] and (VIb-1) to (VIb-5) of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) Also provided are pharmaceutical compositions comprising a compound of Formula (IIb-1), (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, provided are pharmaceutical compositions comprising a compound selected from Compounds 1-210 (e.g., Compounds 1-189 and 192-210), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing for use in therapy.

[0022] I. Definition As used herein, the term "AAT" refers to alpha-1 antitrypsin or a variant thereof, including, but not limited to, an AAT gene variant such as the Z variant. As used herein, "Z-AAT" refers to an AAT variant having a Z variant.

[0023] 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.

[0024] As used herein, a patient who is "homozygous" for a particular genetic mutation has the same mutation in each allele.

[0025] As used herein, a patient with the PiZZ genotype is a patient who is homozygous for the Z mutation in the AAT protein.

[0026] As used herein, the term "AATD" means alpha-1 antitrypsin deficiency, an inherited disorder characterized by low circulating levels of AAT.

[0027] 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 contains lesser amounts of isotopic substitutions having hydrogen atoms 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 is 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 as a whole.

[0028] 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 may be substituted with more than one substituent selected from a specified group, the substituents may be 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.

[0029] The term "isotopically modified" refers to species whose chemical structure differs from specific compounds of the present disclosure only in their 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.

[0030] Unless otherwise indicated, structures depicted herein are also meant 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 compounds of the present disclosure are within the scope of the present disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0031] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule.

[0032] "Stereoisomer" refers to both enantiomers and diastereomers.

[0033] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ("D"). It will be recognized that some variation in natural isotopic abundance will occur in synthesized compounds depending on the source of the chemicals used in synthesis. Despite this variation, the concentration of naturally occurring 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 a "deuterated derivative" of a compound of the present disclosure is referred to, 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).

[0034] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0035] 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 units of saturation 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.

[0036] 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.

[0037] The term "alkenyl," as used herein, means a straight-chain (ie, linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more carbon-carbon double bonds.

[0038] "Cycloalkyl", "cyclic alkyl", "carbocyclyl", or "carbocycle" refers to a fused, spirocyclic, or bridged monocyclic C 3-9 hydrocarbons or fused, spirocyclic, bridged bicyclic or tricyclic C rings that are fully saturated or contain one or more unsaturated units, but are not fully aromatic; 8-14" refers to a hydrocarbon, and any individual ring within the 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.

[0039] 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.

[0040] 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 heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including in the case of N-substituted pyrrolidinyl) means one or more of:

[0041] The term "alkoxy" as used herein refers to an alkyl group as previously defined, where one carbon 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.

[0042] The terms "haloalkyl" and "haloalkoxy" refer to alkyl or alkoxy, optionally 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 perhaloalkyl, such as -CHF, -CHF, -CF, -CF-, or -CFCF.

[0043] As used herein, "=O" refers to an oxo group.

[0044] As used herein, a "cyano" or "nitrile" group refers to -C≡N.

[0045] As used herein, a "hydroxy" group refers to an --OH group.

[0046] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system with 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.

[0047] 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. A non-limiting example of an aryl group is a phenyl ring.

[0048] 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.

[0049] 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 (incorporated herein in its entirety by reference), and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999).

[0050] 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).

[0051] 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).

[0052] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds, which are formed between an acidic and a base group of the compound, such as an amino acid functional group, or a basic and an acidic group of the compound, such as a carboxyl functional group.

[0053] 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, 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.

[0054] Acids commonly utilized 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 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-dionate, hexyne-1,6-dionate, hexyne-1,6-diol ... Included are dionate, 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.

[0055] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4(Alkyl)4 salts are included. This disclosure also contemplates the quaternization of any basic nitrogen-containing group 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 halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0056] The terms "patient" and "subject" are used interchangeably and refer to animals including humans.

[0057] The terms "effective dose", "effective amount", "therapeutically effective dose", and "therapeutically effective amount" are used interchangeably herein and refer to the amount of a compound that produces the desired effect (e.g., improvement of AATD or symptoms of AATD, reduction in the severity of AATD or symptoms of AATD, and / or reduction in the incidence or prevalence of AATD or symptoms of AATD) when administered. The exact amount of the effective dose will depend on the purpose of the 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).

[0058] As used herein, the term "treatment" and its cognates (e.g., "treat," "treating") refer to the improvement of AATD or its symptoms in a subject, the delay in the onset of AATD or its symptoms in a subject, or the reduction in the severity of AATD or its symptoms in a subject. As used herein, "treatment" and its cognates include, but are not limited to, improving liver and / or spleen function, reducing jaundice, improving lung function, reducing lung disease and / or lung exacerbations (e.g., emphysema), reducing skin diseases (e.g., necrotizing panniculitis), increasing growth in children, improving appetite, and reducing fatigue. Improvement or reduction in the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0059] The terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, include a specific dose, amount, or weight percent value, or a range of doses, amounts, or weight percents, recognized by those of skill in the art, that provides the equivalent pharmacological effect as that provided by the specific 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.

[0060] Formula (Ia), (Ib), (IIa-1)~(IIa-2), (IIb-1)~(IIb-2), (IIIa), (IIIb-1)~(IIIb-2), (IVa-1)~(IVa-3), (IVb-1)~(IVb-2), (V a-1)~(Va-2), (Vb-1)~(Vb-5), and (VIb-1)~(VIb-5) (for example, formula (Ia), (Ib), (IIa-1)~(IIa-2), (IIb-1)~(IIb-2), (IIIa), (IIIb Any one or more of the compounds of Formulas 1-210, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered once daily, twice daily, or three times daily for the treatment of AATD. In some embodiments, any one or more compounds are selected from Compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compounds of Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb- At least one compound selected from the group consisting of compounds of Formula (II), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, are administered once daily.In some embodiments, a compound selected from Compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, a compound selected from Compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, a compound selected from Compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, a compound selected from Compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, at least one compound selected from compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily. In some embodiments, at least one compound selected from compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily.In some embodiments, the compounds of Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb- In some embodiments, at least one compound selected from compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily. In some embodiments, at least one compound selected from compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily.

[0061] Any one or more of the compounds of Formulae (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. In some embodiments, any one or more of the compounds is selected from Compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0062] 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. "AAT augmentation therapy" refers to the administration of recombinant AAT.

[0063] In some embodiments, 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 formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb

[0039] Compounds of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2)), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily, twice daily, or three times daily. In some embodiments, 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 1-210 is administered once daily, twice daily, or three times daily.

[0064] Those skilled in the art will recognize that when an amount of a compound is disclosed, the relative amount of a pharmaceutically acceptable salt form of the compound is an 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 the compounds of Formula (Ia) or Formula (Ib) and a pharmaceutically acceptable salt thereof" includes 10 mg of the compound of Formula (Ia) or Formula (Ib) and a concentration of a pharmaceutically acceptable salt of the compound of Formula (Ia) or Formula (Ib) equivalent to 10 mg of the compound of Formula (Ia) or Formula (Ib).

[0065] As used herein, the term "ambient conditions" means room temperature, outside air conditions, and uncontrolled humidity conditions.

[0066]

[0033] In the present specification, one or more compounds (e.g., (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2) A reference to a method of treatment (method of treating AATD) using a compound of formula (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds, is For example, one or more compounds (e.g., (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., compounds represented by Formula (Ia), (Ib), (IIa-1) (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2)), and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds), and / or In the manufacture of a medicament for treating AATD, one or more compounds (e.g., (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., compounds represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (I It should be understood that this reference should also be interpreted as a reference to the use of compounds of formula (Ib-1)-(IIb-2), (IIIa), (IIIb-1)-(IIIb-2), (IVa-1)-(IVa-3), (IVb-1)-(IVb-2), (Va-1)-(Va-2), (Vb-1)-(Vb-5), or (VIb-1)-(VIb-2), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds.

[0067] Exemplary embodiments: Some embodiments of the present disclosure include, but are not limited to, the following. 1. A compound represented by one of the following structural formulas: [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: W 1 is absent or is a bond, -O-, or -CR D R D - and W 2 -O-, -(CR D R D ) p - or -C=O, However, W 1 and W 2 are not both -O-, R A and R B are each independently hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; or alternatively, R A and R B are each independently C1-C3 alkyl or C1-C3 alkoxy, and R A and R B together with the intervening C atoms form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl containing at least one oxygen atom, R C are independently hydrogen, —OH, C1-C3 alkyl, or C1-C3 haloalkyl; R D is, independently for each occurrence, hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; or alternatively, R D is, independently for each occurrence, C1-C3 alkyl or C1-C3 alkoxy, and two R D groups, together with the intervening C atoms, form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl containing at least one oxygen atom; U 1 and U2 are each independently hydrogen, halogen, —NH2, —CH3, or —OH; However, U 1 and U 2 One of the groups is -OH or -NH2, but U 1 and U 2 are both -OH or -NH2, not U 1 and U 2 are not both hydrogen, Ring A is C3-C 12 carbocyclyl or 3- to 12-membered heterocyclyl; X does not exist, -(CR E R E ) q - or -CH2OCH2-, wherein R E is independently for each occurrence hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; Y is -COOH or [ka] and Ring B is C3-C 12 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R 1 and R 2 is, independently for each occurrence, halogen, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, or O—(C-C cycloalkyl); R 3 is independently for each occurrence halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -OH, -O(CR f R f ) r COOH, ═O, -COOH, -C(═O)NR f R f , -(CR f Rf ) r COOH, phenyl, or 5- or 6-membered heteroaryl, wherein R f is, independently for each occurrence, hydrogen, halogen, or —CH; R 3 wherein the phenyl or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -OH, and -COOH; R 4 is independently for each occurrence halogen, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, —COOH, —CHCOOH, or —OCHCOOH; k and n are each independently an integer selected from 0, 1, 2, and 3; j and m are each independently an integer selected from 0, 1, and 2; p and r are each independently an integer selected from 1 and 2; q is an integer selected from 1, 2, and 3; a compound, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. 2.R A and R B are each independently hydrogen, halogen, —OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; or alternatively, R A and R B are each independently C1-C3 alkyl, and R A and R B together with the intervening C atom form cyclopropyl or cyclobutyl, R D is, independently for each occurrence, hydrogen, halogen, —OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; or alternatively, R D is, independently for each occurrence, C1-C3 alkyl; and two R Dgroups, together with the intervening C atoms, form cyclopropyl or cyclobutyl, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all other variables not specifically defined in this embodiment are as defined in the preceding embodiment. 3. Represented by one of the following structural formulas: [ka] In the formula, R A and R B are each independently hydrogen or C1-C2 alkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 4.U 1 is -NH2 or -OH, U 2 is hydrogen, halogen, or -CH3, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-3, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 5. Represented by one of the following structural formulas: [ka] In the formula, U 2 is hydrogen, F, or Cl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 6. Ring A is R 3and ring A is 4-9 membered carbocyclyl or 5- or 6-membered heterocyclyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 7. Ring A is R 3 and ring A is optionally substituted with cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, tetrahydro-2H-pyranyl, piperidinyl, spiro[2.3]hexanyl, 1-iminohexahydro-1λ 6 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-6, wherein 2H-thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl 1,1-dioxide, or 2,3-dihydro-1H-indenyl, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 8. Ring A is R 3 and ring A is optionally substituted with [ka] and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 9.R 3 is independently for each occurrence halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, —OH, —O(CR f R f ) r COOH, =O, -COOH, -C(=O)NR f R f , -(CR f R f ) r COOH, phenyl, or 5-membered heteroaryl, wherein R f is, independently for each occurrence, hydrogen or —CH; R 3 wherein the phenyl or 5-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, C1-C2 alkyl, C1-C2 alkoxy, -OH, and -COOH; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-7, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 10. R 3 is independently for each occurrence F, -CH3, -CF3, -CHF2, - CH2F 、 -OH, -OCH3, -COOH, -CH2COOH, -CF2COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, =O, -OCH2COOH, -OCHCH3COOH, phenyl, pyrazolyl, or oxazolyl, wherein R 3 The phenyl is substituted with -COOH, R 3 wherein the pyrazolyl is substituted with -COOH and -CH3, R 3 is substituted with -COOH, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-9, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 11. Represented by one of the following structural formulas: [ka] 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-10, wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 12. Represented by one of the following structural formulas: [ka] In the formula, R 3 are F, -CH3, -CF3, -CHF2, - CH2F 、 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-11, wherein R is —OH, —OCH, or —OCH, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 13. Represented by one of the following structural formulas: [ka] During the ceremony, R A and R B are each independently hydrogen, halogen, —OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; R C are independently hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl; X does not exist, -(CR E R E ) q - or -CH2OCH2-, wherein R E is independently for each occurrence hydrogen, C1-C2 alkyl, or C1-C2 alkoxy; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1, wherein all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 14.R A and R B are each independently hydrogen or C1-C2 alkyl; U 1 is -NH2 or -OH, U 2 is hydrogen, halogen, or -CH3, X is absent, —CH—, —(CH)—, —(CH)—, or —CHOCH—; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of embodiment 1 or 13, wherein all other variables not specifically defined in this embodiment are as defined in embodiment 1 or 13. 15. Represented by one of the following structural formulas: [ka] During the ceremony, U 2 is hydrogen, F, or Cl, R C is hydrogen, -CH3, or -CF3, X is absent or -CH-; The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1, 13, and 14, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1, 13, and 14. 16. Represented by one of the following structural formulas: [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 and 13-15, wherein all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 13-15. 17. Ring B is R 4 and Ring B is C-C cycloalkyl, phenyl, or 5-membered heteroaryl, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 13-16. 18. Ring B is R 4 and ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 14-17. 19. Ring B is R 4 and ring B is [ka] and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 14-18. 20.R 4 is independently for each occurrence F, Cl, —CH, —OCH, —COOH, or —OCHCOOH, and all other variables not specifically defined in this embodiment are as defined in any one of embodiments 1 and 14-19, or a tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof. 21. Represented by one of the following structural formulas: [ka] [ka] The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 and 13-20, wherein j is an integer selected from 0, 1, and 2, and all other variables not specifically defined herein are as defined in any one of embodiments 1 and 13-20. 22. Represented by one of the following structural formulas: [ka] [ka] 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 and 13-21, wherein j is an integer selected from 0, 1, and 2, and all other variables not specifically defined herein are as defined in any one of embodiments 1 and 13-21. 23. X is -(CH2)2-, -(CH2)3-, or -CH2OCH2-; Y is -COOH, The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1, 13, and 14, wherein all other variables not specifically defined in this embodiment are as defined in embodiment 1, 13, or 14. 24.R 1 and R 2 is each independently for each occurrence halogen, C1-C2 alkyl, or C1-C2 alkoxy, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 25.R 1 is independently for each occurrence F, Cl, cyano, —CH3, or —OCH3, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 26.R 2 is F for each occurrence; m is an integer selected from 0 and 1; and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-26, wherein k is an integer selected from 1 and 2, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1 to 27, wherein m is 0, and all other variables not specifically defined in this embodiment are as defined in any one of the preceding embodiments. 29. A compound selected from compounds 1-210, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. 30. A pharmaceutical composition comprising at least one compound according to any one of embodiments 1-29, a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing. 31. A method for treating alpha-1 antitrypsin (AAT) deficiency, comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-29, or a therapeutically effective amount of the pharmaceutical composition of embodiment 30. 32. A method for modulating alpha-1 antitrypsin (AAT) activity, comprising contacting the AAT with a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of embodiments 1-29, or a therapeutically effective amount of the pharmaceutical composition of embodiment 30. 33. The method of embodiment 31 or 32, wherein the therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is administered in combination with AAT augmentation therapy and / or AAT replacement therapy.

[0068] II. Compounds and Compositions In some embodiments, the compound of the present disclosure is a compound of (Ia) or (Ib): [ka] a tautomer thereof, a deuterated derivative of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: W 1 is absent or is a bond, -O-, or -CR D R D - and W 2 -O-, -(CR D R D ) p - or -C=O, However, W 1 and W 2 are not both -O-, R A and R B are each independently hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; or alternatively, R A and R B are each independently C1-C3 alkyl or C1-C3 alkoxy, and R A and R B together with the intervening C atoms form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl containing at least one oxygen atom, R C are independently hydrogen, —OH, C1-C3 alkyl, or C1-C3 haloalkyl; R D is, independently for each occurrence, hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; or alternatively, R D is, independently for each occurrence, C1-C3 alkyl or C1-C3 alkoxy, and two R D groups, together with the intervening C atoms, form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl containing at least one oxygen atom; U1 and U 2 are each independently hydrogen, halogen, —NH2, —CH3, or —OH; However, U 1 and U 2 One of the groups is -OH or -NH2, but U 1 and U 2 are both -OH or -NH2, not U 1 and U 2 are not both hydrogen, Ring A is C3-C 12 carbocyclyl or 3- to 12-membered heterocyclyl; X does not exist, -(CR E R E ) q - or -CH2OCH2-, wherein R E is independently for each occurrence hydrogen, halogen, —OH, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; Y is -COOH or [ka] and Ring B is C3-C 12 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R 1 and R 2 is, independently for each occurrence, halogen, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, or O—(C-C cycloalkyl); R 3 is independently for each occurrence halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -OH, -O(CR f R f ) r COOH, ═O, -COOH, -C(═O)NR f R f , -(CR f Rf ) r COOH, phenyl, or 5- or 6-membered heteroaryl, wherein R f is, independently for each occurrence, hydrogen, halogen, or —CH; R 3 wherein the phenyl or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -OH, and -COOH; R 4 is independently for each occurrence halogen, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, —COOH, —CHCOOH, or —OCHCOOH; k and n are each independently an integer selected from 0, 1, 2, and 3; j and m are each independently an integer selected from 0, 1, and 2; p and r are each independently an integer selected from 1 and 2; q is an integer selected from 1, 2, and 3.

[0069] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R A and R B are each independently hydrogen, halogen, —OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; or alternatively, R A and R B are each independently C1-C3 alkyl, and R A and R B together with the intervening C atom form cyclopropyl or cyclobutyl, R D is, independently for each occurrence, hydrogen, halogen, —OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; or alternatively, R Dis, independently for each occurrence, C1-C3 alkyl, and two R D groups, together with the intervening C atoms, form cyclopropyl or cyclobutyl, All other variables not specifically defined in this paragraph are as defined in the preceding embodiments.

[0070] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (IIa-1) or Formula (IIa-2): [ka] In the formula, R A and R B are each independently hydrogen or C1-C2 alkyl, and all other variables not specifically defined in this paragraph are as defined in the preceding embodiments.

[0071] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, U 1 is -NH2 or -OH, U 2 is hydrogen, halogen, or -CH3, All other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0072] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by formula (IIIa): [ka] In the formula, U 2 is hydrogen, F, or Cl, and all other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0073] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A is a 4-9 membered carbocyclyl or a 5- or 6-membered heterocyclyl, and R 3 and all other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0074] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, Ring A is cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, tetrahydro-2H-pyranyl, piperidinyl, spiro[2.3]hexanyl, 1-iminohexahydro-1λ 6 -thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl 1,1-dioxide, or 2,3-dihydro-1H-indenyl; and ring A is selected from R 3 and all other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0075] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring A is: [ka] Selected from R 3 and all other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0076] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is independently for each occurrence halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -OH, -O(CR f R f ) r COOH, ═O, -COOH, -C(═O)NR f R f, -(CR f R f ) r COOH, phenyl, or 5-membered heteroaryl, wherein R f is, independently for each occurrence, hydrogen or —CH; R 3 wherein the phenyl or 5-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, C1-C2 alkyl, C1-C2 alkoxy, -OH, and -COOH; All other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0077] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 3 is independently for each occurrence F, -CH3, -CF3, -CHF2, - CH2F 、 -OH, -OCH3, -COOH, -CH2COOH, -CF2COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, =O, -OCH2COOH, -OCHCH3COOH, phenyl, pyrazolyl, or oxazolyl, wherein R 3 The phenyl is substituted with -COOH, R 3 wherein the pyrazolyl is substituted with -COOH and -CH3, R 3 is substituted with -COOH, All other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0078] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by formula (IVa-1), formula (IVa-2), or formula (IVa-3): [ka] wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0079] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by formula (Va-1) or formula (Va-2): [ka] In the formula, R 3 are F, -CH3, -CF3, -CHF2, - CH2F 、 -OH, or -OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0080] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (IIb-1) or Formula (IIb-2): [ka] During the ceremony, R A and R B are each independently hydrogen, halogen, —OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; R C are independently hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl; X does not exist, -(CR E R E ) q - or -CH2OCH2-, wherein R E is independently for each occurrence hydrogen, C1-C2 alkyl, or C1-C2 alkoxy; All other variables not specifically defined in this paragraph are as defined for formula (Ia) or (Ib).

[0081] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R A and R B are each independently hydrogen or C1-C2 alkyl; U 1 is -NH2 or -OH, U 2 is hydrogen, halogen, or -CH3, X is absent, —CH—, —(CH)—, —(CH)—, or —CHOCH—; All other variables not specifically defined in this paragraph are as defined for any one of formulas (Ia), (Ib), (Va-1), and (Va-2).

[0082] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (IIIb-1) or Formula (IIIb-2): [ka] During the ceremony, U 2 is hydrogen, F, or Cl, R C is hydrogen, -CH3, or -CF3, X is absent or -CH-; All other variables not specifically defined in this paragraph are as defined for any one of formulas (Ia), (Ib), (Va-1), (Va-2), (IIb-1), and (IIb-2).

[0083] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by formula (IVb-1) or (IVb-2): [ka] wherein all other variables not specifically defined in this paragraph are as defined for any one of formulas (Ia), (Ib), (Va-1), (Va-2), (IIb-1), (IIb-2), (IIIb-1), and (IIIb-2).

[0084] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring B is R 4 and Ring B is C-C cycloalkyl, phenyl, or 5-membered heteroaryl, and all other variables not specifically defined in this paragraph are as defined for any one of Formulas (Ia), (Ib), (Va-1), (Va-2), (IIb-1), (IIb-2), (IIIb-1), (IIIb-2), (IVb-1), and (IVb-2).

[0085] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring B is: [ka] Selected from R 4 and all other variables not specifically defined in this paragraph are as defined for any one of formulas (Ia), (Ib), (Va-1), (Va-2), (IIb-1), (IIb-2), (IIIb-1), (IIIb-2), (IVb-1), and (IVb-2).

[0086] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, ring B is: [ka] Selected from R 4and all other variables not specifically defined in this paragraph are as defined for any one of formulas (Ia), (Ib), (Va-1), (Va-2), (IIb-1), (IIb-2), (IIIb-1), (IIIb-2), (IVb-1), and (IVb-2).

[0087] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 4 is independently for each occurrence F, Cl, —CH 3 , —OCH 3 , —COOH, or —OCH 2 COOH, and all other variables are as defined for any one of the preceding embodiments.

[0088] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (Vb-1), Formula (Vb-2), Formula (Vb-3), Formula (Vb-4), or Formula (Vb-5): [ka] wherein j is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this paragraph are as defined for formula (Ia), (Ib), or any one of the preceding embodiments.

[0089] In some embodiments, the disclosed compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is represented by Formula (VIb-1), Formula (VIb-2), Formula (VIb-3), Formula (VIb-4), or Formula (VIb-5): [ka] wherein j is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this paragraph are as defined for formula (I) or any one of the preceding embodiments.

[0090] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula (IIb-1) or Formula (IIb-2), R A and R B are each independently hydrogen or C1-C2 alkyl; U 1 is -NH2 or -OH, U 2 is hydrogen, halogen, or -CH3, X is absent, —CH—, —(CH)—, —(CH)—, or —CHOCH—; All other variables not specifically defined in this paragraph are as defined for any one of formulas (Ia), (Ib), (IIb-1), and (IIb-2).

[0091] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of Formula (IIb-1) or Formula (IIb-2), X is —(CH)—, —(CH)—, or —CHOCH—; Y is -COOH, All other variables not specifically defined in this paragraph are as defined for any one of formulas (Ia), (Ib), (IIb-1), and (IIb-2).

[0092] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1 and R 2 is each independently for each occurrence halogen, C-C alkyl, or C-C alkoxy, and all other variables not specifically defined in this paragraph are as defined in any one of the preceding embodiments.

[0093] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 1is independently for each occurrence F, Cl, —CH 3 , or —OCH 3 , and all other variables are as defined in any one of the preceding embodiments.

[0094] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, R 2 for each occurrence, is F, m is an integer selected from 0 and 1, and all other variables are as defined in any one of the preceding embodiments.

[0095] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, k is an integer selected from 1 and 2, and all other variables are as defined in any one of the preceding embodiments.

[0096] In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, m is 0, and all other variables are as defined in any one of the preceding embodiments.

[0097] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure is selected from compounds 1-210 (Table A), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. [ka] [ka] [ka] [ka] [ka] [ka]

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[0098] Some embodiments of the present disclosure include compounds 1-210, or compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., For example, compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), or tautomeric derivatives thereof. In some embodiments, the derivative is a compound of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., formula (Ia), (Ib), (I The compound is a silicon derivative in which at least one carbon atom in a compound selected from the compounds of formulas Ia-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)) is replaced with silicon.In some embodiments, the derivative is a compound of Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1) to (IIa-2) and silicon derivatives in which at least one carbon atom in a compound selected from the group consisting of compounds (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), or a tautomer thereof, is replaced by boron. In other embodiments, the derivative is a compound of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., a compound of formula (Ia), (Ib), (IIa-1) to (IIa-2) and phosphate derivatives in which at least one carbon atom in a compound selected from the group consisting of compounds of formulas IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), or a tautomer thereof, is replaced by phosphorus. Because the general properties of silicon, boron, and phosphorus are similar to those of carbon, the replacement of carbon with silicon, boron, or phosphorus can result in compounds with biological activity similar to the original carbon-containing compound.

[0099] In some embodiments, the derivative is a compound of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., formula (Ia), (Ib), (IIa-1) (IIa-1) to (IIb-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), and tautomers thereof, are silicon derivatives in which one carbon atom is replaced by silicon. In other embodiments, two carbon atoms are replaced by silicon. The carbon replaced by silicon may be a non-aromatic carbon. In some embodiments, a quaternary carbon atom of a tert-butyl moiety may be replaced by silicon. In some embodiments, the silicon derivatives of the present disclosure may include one or more hydrogen atoms replaced by deuterium. For example, one or more hydrogen atoms of a tert-butyl moiety in which a carbon is replaced by silicon may be replaced by deuterium. Other embodiments include compounds 1-210, or compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa- The silicon derivatives of compounds selected from compounds of formulas (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2)), and their tautomeric forms, may have silicon incorporated into a heterocycle.

[0100] Another aspect of the present disclosure is directed to compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), a compound according to any one of formulas (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), a compound selected from compounds 1 to 210, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (I A pharmaceutical composition comprising at least one compound selected from Compounds IIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), and Compounds 1 to 210, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered to a patient in need thereof.

[0101] 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.

[0102] It is also understood that the pharmaceutical compositions of the present disclosure can be employed in combination therapy, i.e., the pharmaceutical compositions described herein can further comprise at least one other active agent. Alternatively, the compounds of Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formulas (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2) Pharmaceutical compositions comprising at least one compound selected from Compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered as separate compositions simultaneously with, prior to, or subsequent to a composition comprising at least one additional active agent. In some embodiments, pharmaceutical compositions comprising at least one compound selected from Compounds 1-210, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, may be administered as separate compositions simultaneously with, prior to, or subsequent to a composition comprising at least one additional active agent.

[0103] In some embodiments, a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb),

[0039] The compounds of Formula (IIIb-1) through (IIIb-2), (IVa-1) through (IVa-3), (IVb-1) through (IVb-2), (Va-1) through (Va-2), (Vb-1) through (Vb-5), or (VIb-1) through (VIb-2), 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 the use is simultaneous, the compound of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., the compound of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2) The compounds of Formula (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), 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 in separate pharmaceutical compositions.In some embodiments, when the use is simultaneous, the compound of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., the compound of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to ( In some embodiments, the compounds of Formula (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2), 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 together in the same pharmaceutical composition. In some embodiments, the compound is a compound selected from Compounds 1-210 (e.g., Compounds 1-189 and 192-210), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0104] In some embodiments, a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (I Compounds of Formula IIb-1) through (IIIb-2), (IVa-1) through (IVa-3), (IVb-1) through (IVb-2), (Va-1) through (Va-2), (Vb-1) through (Vb-5), or (VIb-1) through (VIb-2), 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 a method of treating AATD, the method 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 1-210 (e.g., compounds 1-189 and 192-210), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0105] In some embodiments, a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (II

[0013] Combinations of compounds of Formula Ia), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2), 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 1-210 (e.g., compounds 1-189 and 192-210), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0106] In some embodiments, an additional active agent is provided for use in a method of treating AATD, the method comprising combining the additional active agent with a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2), 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 1-210 (e.g., compounds 1-189 and 192-210), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0107] In some embodiments, a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIb), Compounds of Formula Ib-1) through (IIIb-2), (IVa-1) through (IVa-3), (IVb-1) through (IVb-2), (Va-1) through (Va-2), (Vb-1) through (Vb-5), or (VIb-1) through (VIb-2), 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 compound is 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 1-210 (e.g., compounds 1-189 and 192-210), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0108] In some embodiments, a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (II

[0013] Combinations of compounds of Formula Ia), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2), 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 1-210 (e.g., compounds 1-189 and 192-210), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0109] In some embodiments, an additional active agent is provided for use in the method of treating AATD, and the additional active agent is a compound represented by Formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-5) (e.g., Formula (Ia), (Ib), (IIa-1), (IIb-2), (IIa-1), (IIb-2), (IIa-1), (IIb-2), (IIa-1), (IIb-2), (IIIa), (IIIb-1), (IIIb-2), (IVa-1), (IVa-3), (IVb-1), (IVb-2), (Va-1), (Va-2), (Vb-1), (Vb-5), or (VIb-1), (VIb-5), (e.g., Formula (Ia), (Ib), (IIa-1), (IIa-2), (IIa-2), (IIb-1), (IIb-2), (IIa-2), (IIa-3), (IVa-1), (IVa-2), (IVa-1), (IVa-2), (IVa-2), (IVa-1), (IVb-2), (Va-1), (Va-2), (Vb-1), (Vb-5), or (VIb-1), (VIb-5), (e.g., Formula (Ia), (Ib), (IIa-2 ... In some embodiments, the compound of formula (I) is prepared for administration in combination with a compound of formula (I), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), or (VIb-1) to (VIb-2), 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 1-210 (e.g., compounds 1-189 and 192-210), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0110] In some embodiments, the additional active agent is selected from the group consisting of alpha-1 antitrypsin protein (AAT) derived from plasma of a healthy human donor and recombinant AAT. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) derived from plasma of a healthy human donor. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) derived from plasma of a healthy human donor.

[0111] 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, 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 appropriate for 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, 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.

[0112] 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 invention 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.

[0113] In some embodiments, the methods of the present disclosure include the use of compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., compounds of formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2) (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, to a patient in need thereof. In some embodiments, the compound of Formula (I) is selected from compounds 1-210, 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.

[0114] Another aspect of the present disclosure provides a method for modulating alpha-1 antitrypsin activity, the method comprising: modulating the alpha-1 antitrypsin with a compound represented by formula (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., formula (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb-2), (IIIa), (IIIb-1)-(IIIb-2), (IVa-1)-(IVa-3), (IVb-1)-(IVb-2), (Va-1)-(Va-2), (Vb-1)-(Vb-5), and (VIb-1)-(VIb-2), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a method of modulating alpha-1 antitrypsin activity comprises contacting the alpha-1 antitrypsin with at least one compound selected from Compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0115] 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.

[0116] III. Compound Preparation All generic, subgeneric, and specific compound formulas disclosed herein are considered part of the present invention.

[0117] A. Compounds of Formula I The compounds of the present disclosure can be made according to standard chemical practices or as described herein. Throughout the following synthetic schemes and in accordance with the compounds of formulae (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-5) (e.g., Formulae (Ia), (Ib), (IIa-1) to (IIa-2), (IIb-1) to (IIb-2), The following abbreviations are used in the description of preparing compounds (IIIa), (IIIb-1) to (IIIb-2), (IVa-1) to (IVa-3), (IVb-1) to (IVb-2), (Va-1) to (Va-2), (Vb-1) to (Vb-5), and (VIb-1) to (VIb-2), compounds 1 to 210, and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Abbreviation BrettPhos Pd G4 = Dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane; Methanesulfonic acid; N-methyl-2-phenylaniline; Palladium DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amine DMA = dimethylacetamide DMAP = dimethylaminopyridine DME = dimethoxyethane DMF = dimethylformamide DMSO = dimethyl sulfoxide EtOH = ethanol EtOAc = ethyl acetate HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphorus hexafluoride ion) MeOH = methanol MP-TMT scavenger resin = macroporous polystyrene-bound trimercaptotriazine, a resin-bound equivalent of 2,4,6-trimercaptotriazine (TMT). MTBE = methyl tert-butyl ether NMM = N-methylmorpholine NMP = N-methylpyrrolidine Pd(dppf)2Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2 = palladium(II) dichloride PdCl2(PPh3)2 = bis(triphenylphosphine) palladium(II) dichloride SFC = Supercritical Fluid Chromatography SPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TBAF = tetrabutylammonium fluoride tBuXPhos Pd G1 = chloro[2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) or t-BuXPhos palladium(II) phenethylamine chloride tBuXPhos Pd G3 = [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuXPhos Pd G4 = Ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane; Dichloromethane; Methanesulfonate; N-Methyl-2-phenyl-aniline palladium(II) TFA = trifluoroacetic acid THF = tetrahydrofuran XPhos Pd G1 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride or (XPhos)palladium(II) phenethylamine chloride

[0118] In some embodiments, the process for preparing a compound of Formula (Ia) or Formula (Ib), a tautomer thereof, a deuterated derivative of the compound and tautomer, or a pharmaceutically acceptable salt of any of the foregoing, comprises reacting a compound of Formula (Ia) or Formula (Ib), a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt thereof, with a deprotecting reagent, as depicted in Schemes 1-8 below, where all variables are as defined for Formula (Ia) or Formula (Ib) above. [ka]

[0119] Scheme 1 depicts a process for the preparation of intermediates of general formula 1-7, which can be used as intermediates in the preparation of compounds of formula Ia and 1b. 1 is any suitable alcohol protecting group, for example, PG 1 can be benzyl, methyl, or MOM. 2 PG 1 is any suitable alcohol protecting group that can be removed perpendicular to 2 can be a silicon-based protecting group such as TBS or TBDPS. 1 and Q 2is a halogen, such as Cl, Br, or I. Compounds of formula 1-3 can be prepared from 1-1 and 1-2 using any suitable conditions for the Sonogashira coupling reaction. For example, the reaction can be carried out in the presence of a catalyst such as Pd(PPh3)2Cl2 and CuI. A base such as diisopropylethylamine can be used. The reaction can be carried out in a solvent such as 1,4-dioxane with heating (e.g., 50°C). Compounds of formula 1-4 can be prepared from compounds of formula 1-3 using an appropriate reagent for the addition of an alcohol protecting group. In some embodiments, TBS chloride in the presence of imidazole in dichloromethane solvent can be used. Compounds of formula 1-5 can be prepared by amination of compounds of formula 1-4 using any suitable conditions for Buchwald amination. For example, in some embodiments, tBuXPhos Pd G3 catalyst in the presence of NaOtBu can be used. The reaction can be carried out in a solvent such as m-xylene. The reaction can be carried out at room temperature. In some embodiments, compounds of formula 1-7 are formed spontaneously during the reaction conditions of the amination. In some embodiments, compounds of formula 1-7 are formed from 1-6 using any suitable conditions for cyclizing an amine to an alkyne. For example, in some embodiments, treatment with a palladium catalyst, such as PdCl or PdCl(MeCN) may be used. The reaction may be carried out in the presence of heat. The reaction may be carried out in methanol and ethyl acetate solvents. In some embodiments, a base such as KOtBu may be used. Compounds of formula 1-8 may be prepared from compounds of formula 1-7 using suitable conditions for removing silicon protecting groups. For example, a reagent such as TBAF may be used. The reaction may be carried out in a solvent such as 2-methyl-THF at 70°C. [ka]

[0120] Scheme 2 depicts a process for the preparation of compounds of formula 2-8, which can be used as intermediates in the preparation of compounds of formula Ia and Ib. Compounds of formula 2-8 can be prepared from compounds of formula 2-1 using the methods described for the preparation of compounds of formula 1-8. [ka]

[0121] Scheme 3 shows a process for the preparation of compounds of formula 3-3 from compounds of formula 1-8. Compounds of formula 3-2 may be prepared from 1-8 by reductive alkylation, followed by intramolecular cyclization to the ketone for formula 3-1. In some embodiments, this reaction may be carried out in the presence of a reagent such as triethylsilane and an acid such as methanesulfonic acid. In alternative embodiments, an acid such as trifluoroacetic acid may be used. The reaction may be carried out in a solvent such as dichloroethane at room temperature. Compounds of formula 3-3 may be prepared by the reaction of PG 1 3-2 can be prepared from 3-2 using any method suitable for the removal of an alcohol protecting group suitable for PG 1 When is a benzyl group, transfer hydrogenation conditions can be used. For example, a compound of formula 3-2 can be treated with Pd on carbon and ammonium formate in a solvent such as ethanol and ethyl acetate to give a compound of formula 3-3. In some embodiments, a Pd(OH) catalyst can be used. In some instances, a dealkylating agent such as BBr in a solvent such as dichloromethane can be used to remove the benzyl protecting group. [ka]

[0122] Scheme 4 shows a method for the preparation of compounds of formula 4-3. Compounds of formula 4-3 can be prepared from compounds 2-8 using a similar process used to prepare compounds of formula 3-3. [ka]

[0123] Scheme 5 shows a process for preparing compounds of formula 5-3. Reductive alkylation and cyclization between compounds of formula 1-8 and ketones of formula 5-1 gives compounds of formula 5-2. The reaction can be carried out in the presence of triethylsilane and methanesulfonic acid. The reaction can be carried out in a solvent such as dichloroethane or dichloromethane. The reaction can also be carried out under heating, for example, up to 50°C. Compounds of formula 5-3 can be prepared from compounds of formula 5-2 using standard alcohol deprotection methods. [ka]

[0124] Scheme 6 shows a process for the preparation of compounds of formula 6-3 from compounds of formula 2-8. Compounds of formula 6-3 can be prepared from compounds of formula 2-8 using methods similar to those used to prepare compounds of formula 5-3. [ka]

[0125] Scheme 7 shows a method for the preparation of compounds of formula 7-3 from compounds of formula 7-1. 21 is any suitable alkyl group that forms an ester protecting group. For example, R 21 can be Me, Et, iPr, or tBu. Compounds of formula 7-2 can be prepared from 7-1 using any suitable method for deprotecting an ester group. For example, in some embodiments, hydrolysis with a base such as LiOH in a solvent such as THF and water can be used. In other examples, treatment with BBr3 can be performed. In some embodiments, R 21 When is a tert-butyl group, compounds of formula 7-1 can be treated with trifluoroacetic acid to give compounds of formula 7-2. [ka]

[0126] Scheme 8 shows a process for the preparation of compounds of formula 8-2 from compounds of formula 8-1. Conditions similar to those used to prepare compounds of formula 7-3 can be used. [Example]

[0127] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0128] Example 1 Synthesis of Compounds All specific and generic compounds, methods for making those compounds, and intermediates disclosed for making those compounds are considered to be part of this disclosure.

[0129] A. Synthesis of Starting Materials The preparation of S1-S22 illustrates synthetic routes to intermediates used in the synthesis of compounds 1-210.

[0130] Preparation of S1 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S1) [ka] Step 1. Synthesis of 1-benzyloxy-3-bromo-2-iodo-benzene (C2) A solution of 3-bromo-2-iodo-phenol C1 (129 g, 431.6 mmol) in acetone (1.5 L) was stirred for 5 min. K2CO3 (75 g, 542.7 mmol), NaI (21 g, 140.1 mmol), and bromomethylbenzene (55 mL, 462.4 mmol) were added. The reaction mixture was stirred at 55 °C for 7 h. The mixture was then cooled to room temperature, filtered, and washed with acetone (2 × 100 mL). The combined filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (1.5 L) and washed with water (2 × 100 mL) and brine (100 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (0–50% ethyl acetate in heptane) afforded the product C2 as a white solid (162 g, 96%). 1 H NMR (300 MHz, chloroform-d) δ 7.54-7.46 (m, 2H), 7.40 (ddd, J = 7.9, 7.0, 1.1 Hz, 2H), 7.37-7.31 (m, 1H), 7.28 (dd, J = 8.0, 1.3 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 6.76 (dd, J = 8.2, 1.3 Hz, 1H), 5.16 (s, 2H).

[0131] Step 2. Synthesis of 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol (C3) A 3 L three-necked round-bottom flask equipped with an overhead stirrer, temperature probe, reflux condenser, and nitrogen inlet was charged with 1-benzyloxy-3-bromo-2-iodo-benzene C2 (160 g, 411.3 mmol) and 2,2-dimethylbut-3-yn-1-ol (51 g, 519.6 mmol) in 1,4-dioxane (1.1 L) and stirred for 5 minutes. N-isopropylpropan-2-amine (370 mL, 2.64 mol) was then added. The reaction mixture was purged with nitrogen for approximately 15 minutes, and then copper iodide (3.7 g, 19.4 mmol) and PdCl2 (12.5 g, 17.8 mmol) were added. The resulting reaction mixture was warmed to 50 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature and poured into water (300 mL). Saturated aqueous NH4Cl (ca. 400 mL) was added, followed by ethyl acetate (ca. 2 L), and the mixture was stirred for 15 minutes. The organic layer was separated and washed with 1N HCl solution (2 x 200 mL), brine (200 mL), then dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (gradient: 0 to 50% ethyl acetate in heptane) afforded the product as a yellow solid. 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol (130 g, 88%). 1 H NMR (400MHz, chloroform-d) δ7.48(ddt,J=7.4,1.5,0.7Hz,2H), 7.44-7.37(m,2H), 7.36-7.29(m,1H), 7.19(dd,J=8.1,1.0Hz,1H ), 7.08(t,J=8.2Hz,1H), 6.86(dd,J=8.3,1.0Hz,1H), 5.13(s,2H), 3.48(d,J=7.2Hz,2H), 2.12(t,J=7.2Hz,1H), 1.33(s,6H). LCMS m / z 359.02[M+1] + .

[0132] Step 3. Synthesis of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane (C4) A 3 L three-necked round-bottom flask equipped with an overhead stirrer, temperature probe, reflux condenser, and nitrogen inlet was charged with 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol C3 (130 g, 361.9 mmol) in DMF (850 mL). The mixture was stirred at ambient temperature for 5 minutes, and then imidazole (64 g, 940.1 mmol) and TBSCl (64 g, 424.6 mmol) were added (observed Tmax = 31 °C). The reaction mixture was poured into ice water (approximately 1 L) and extracted with MTBE (2 × 1 L). The organic phase was washed with 1 N HCl (2 × 200 mL) and brine (200 mL), then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column: 1.5 kg Isco. Gradient, 0-50% ethyl acetate in heptane) to give the product C4 as a clear pale yellow oil: [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane (164 g, 96%). 1 H NMR (400MHz, chloroform-d) δ7.55-7.44(m,2H), 7.42-7.35(m,2H), 7.35-7.28(m,1H), 7.19(dd,J=8.1,1.0Hz,1H), 7. 04(t,J=8.2Hz,1H), 6.83(dd,J=8.4,1.0Hz,1H), 5.12(s,2H), 3.59(s,2H), 1.31(s,6H), 0.90(s,9H), 0.05(s,6H).

[0133] Step 4. Synthesis of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(4-fluoro-3-methyl-phenyl)aniline (C5) A solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane C4 (2 g, 4.224 mmol), 4-fluoro-2-methyl-aniline (600 mg, 4.794 mmol) in dioxane (8 mL) was bubbled with nitrogen for 5 minutes. To the mixture was added sodium t-butoxide (5 mL of 2 M, 10.00 mmol), followed by tBuXphos palladacycle (150 mg, 0.2184 mmol). The reaction was monitored by LC-MS. The reaction was run for 30 minutes. After stirring overnight at room temperature, water and dichloromethane were added, and the layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane, the layers were again separated through a phase separator, and the combined organics were concentrated. Purification by column chromatography (40 g column; 0-20% EtOAc in heptane) gave the product C5 as a straw-colored oil (2.1 g, 96%). 1 H NMR (400MHz, chloroform-d) δ7.49(dtd,J=6.9,1.5,0.8Hz,2H), 7.43-7.26(m,2H), 7.05-6.87(m,3H), 6.65-6.58(m,1H), 6.39-6 .31(m,2H), 5.10(s,2H), 3.54(s,2H), 2.23(dd,J=2.0,0.7Hz,2H), 1.53(s,3H), 1.29(s,6H),0.96-0.85(m,9H), 0.00(s,6H).

[0134] Step 5. Synthesis of [2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-propoxy]-tert-butyl-dimethyl-silane (C6) To a mixture of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(4-fluoro-3-methyl-phenyl)aniline C5 (2.1 g, 96%) in CH-CN (20 mL) was added PdCl2 (150 mg, 0.846 mmol) and stirred for 20 min. The reaction mixture was concentrated and then purified on a 40 g silica gel cartridge eluting with 0-30% EtOAc / heptane to give the product (1.3 g, 59%).1 H NMR (400MHz, chloroform-d) δ7.66-7.55(m,3H), 7.51-7.35(m,3H), 7.28-7.11(m,2H), 7.04-6.91(m,1H), 6.68(d,J=0.8Hz,1H), 6.61(dd,J=7.8,0.7Hz ,1H), 6.34(dt,J=8.2,0.7Hz,1H), 5.28(s,2H), 3.56(s,2H), 2.36(d,J=2 .0Hz,3H), 1.60(s,2H), 1.25(d,J=11.6Hz,6H), 0.88(s,9H), 0.00(s,6H).

[0135] Step 6. Synthesis of 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-propan-1-ol (S1) To a solution of C6 (1.6 g, 3.09 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (1 M in THF, 4 mmol) at room temperature. At 8:47 AM, TLC showed approximately 50% conversion to the product (confirmed by LCMS). After 90 min, an additional 2 mL of TBAF was added at room temperature. After 2 h, the reaction was concentrated and purified by column chromatography (80 g column; 0-100% EtOAc in heptane) to give the product S1 as an off-white solid. 1 H NMR(400MHz,chloroform-d)δ 7.45-7.41(m,2H), 7.35-7.22(m,3H), 7.11-7.00(m,3H), 6.90-6.84(m,1H), 6.49(dd,J=7.8,0.6Hz,1H ), 6.21(dt,J=8.2,0.7Hz,1H), 5.13(s,2H), 3.40(d,J=6.1Hz,2H), 2.23(d,J=2.0Hz,3H), 1.14(s,6H). LCMS m / z 404.23[M+1] +

[0136] Preparation of S2 2-(4-(benzyloxy)-1-(3-chloro-4-fluorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S2) [ka] Step 1. Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(3-chloro-4-fluorophenyl)aniline (C7) To a solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane C7 (1.94 g, 4.10 mmol) and 3-chloro-4-fluoro-aniline (650 mg, 4.47 mmol) in xylene (50 mL) under nitrogen, NaOtBu (1.18 g, 12.3 mmol) was added, followed by tBuXPhos Pd G3 (145 mg, 0.183 mmol). The reaction mixture was stirred at room temperature for 4 h, then diluted with water, saturated aqueous NH4Cl, and extracted with EtOAc (twice). The combined organics were concentrated to dryness and purified by silica gel chromatography (eluting with 0–50% EtOAc in heptane). Pure fractions were combined and concentrated to give a light brown oil (2.21 g, 100%).

[0137] Step 2. Synthesis of 4-(benzyloxy)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-1-(3-chloro-4-fluorophenyl)-1H-indole (C8) To a solution of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(3-chloro-4-fluorophenyl)aniline C7 in 2-MeTHF (5 mL) was added potassium 2-methylpropane-2-oleate (1 M, 5 mL, 5 mmol) at room temperature. After 5 h, the reaction was quenched with saturated aqueous NH4Cl and extracted twice with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated to give the product (2.21 g, 100%), which was taken on to the next reaction without further purification. LCMS m / z 538.36 [M+1] + .

[0138] Step 3. Synthesis of 2-(4-(benzyloxy)-1-(3-chloro-4-fluorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S2) To a solution of 4-(benzyloxy)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-1-(3-chloro-4-fluorophenyl)-1H-indole C8 (2.21 g, 4.10 mmol) in 2-MeTHF (5 mL) was added TBAF (1 M solution in THF, 8 mL, 8 mmol). After 4 days, an additional 10 mL of TBAF solution was added, and the mixture was heated at 70 °C overnight. The reaction mixture was concentrated. Purification by column chromatography (120 g column; 0 to 75% EtOAc in heptane) afforded the product as a straw-colored oil (625 mg, 36%). 1 H NMR(400MHz,chloroform-d)δ 7.57-7.30(m,8H), 7.02(t,J=8.0Hz,1H), 6.74(d,J=0.8Hz,1H), 6.63(d,J=7.8Hz,1H), 6.3 3(d,J=8.3Hz,1H), 5.26(s,2H), 3.53(d,J=6.3Hz,2H), 1.28(s,3H), 1.27(d,J=1.8Hz,3H). LCMS m / z 424.21[M+1] +

[0139] Preparation of S3 2-(4-(benzyloxy)-1-(3-fluoro-4-methylphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S3) [ka] Step 1. Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(3-fluoro-4-methylphenyl)aniline (C9). [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane C4 (4 g, 8.45 mmol), 3-fluoro-4-methyl-aniline (1.5 g, 12.0 mmol), and sodium 2-methylpropane-2-oleate (2 g, 20.8 mmol) were charged to a flask, followed by THF (25 mL). The mixture was stirred for 5 minutes and then degassed with nitrogen for approximately 10 minutes. tBuXPhos Pd G1 (0.2 g, 0.3071 mmol) was added, and the reaction mixture was degassed for an additional few minutes. The resulting reaction mixture was warmed to 60 °C and stirred at this temperature for 3 hours. The solvent was evaporated. Purification by column chromatography (20 g column; elution with 0 to 100% ethyl acetate in heptane) gave the product (3.58 g, 75%). LCMS m / z 518.51[M+1] +

[0140] Step 2. Synthesis of 2-(4-(benzyloxy)-1-(3-fluoro-4-methylphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S3) 3-(Benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(3-fluoro-4-methylphenyl)aniline C9 (3.50 g, 6.19 mmol) was charged in nitrogen-degassed methanol (15 mL) / ethyl acetate (15 mL) and then PdCl2(CH3CN)2 (320 mg, 1.23 mmol) was added. The reaction was heated at 60 °C for 4 h and then the solvent was evaporated. Purification by column chromatography (80 g column, eluting with 0 to 100% ethyl acetate in heptane) gave 2-[4-benzyloxy-1-(3-fluoro-4-methyl-phenyl)indol-2-yl]-2-methyl-propan-1-ol (2.3 g, 84%). 1H NMR(400MHz, methanol-d4)δ 7.53-7.46(m,2H), 7.44-7.34(m,3H), 7.34-7.27(m,1H), 7.17-7.09(m,2H), 6.87(t,J=8.0Hz,1H), 6.59(d,J=0.8Hz,1H) , 6.58-6.54(m,1H), 6.21(dt,J=8.3,0.7Hz,1H), 5.19(s,2H), 3.48(s,2H), 2.38(d,J=1.9Hz,3H), 1.22(d,J=7.2Hz,6H). LCMS m / z 404.36[M+1] +

[0141] Preparation of S4 2-(4-(benzyloxy)-1-(3,4-difluorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S4) [ka] Step 1. Synthesis of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(3,4-difluorophenyl)aniline (C10) To a solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane C4 (11 g, 23.2 mmol) and 3,4-difluoroaniline (3.27 g, 25.33 mmol) in xylene (60 mL) under nitrogen, NaOtBu (6 g, 62.4 mmol) was added, followed by tBuXPhos Pd G3 (315 mg, 0.40 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and saturated aqueous NH4Cl and extracted with EtOAc (×2). The combined organics were concentrated to dryness and purified by silica gel chromatography (column: 220 g silica, gradient: 0–50% EtOAc in heptane) to give the product as a yellow oil (11.6 g, 96%). 1H NMR (400MHz, chloroform-d) δ7.49(ddt,J=7.4,1.3,0.7Hz,2H), 7.38-7.32(m,2H), 7.31-7.25(m,1H), 7.10-6.96(m,3H), 6.86-6 .80(m,1H), 6.70(dd,J=8.3,0.8Hz,1H), 6.43-6.39(m,2H), 5.11(s,2H), 3.53(s,2H), 1.28(s,6H), 0.84(s,9H), 0.00(s,6H). LCMS m / z 522.52[M+1] + .

[0142] Step 2. Synthesis of 2-[4-benzyloxy-1-(3,4-difluorophenyl)indol-2-yl]-2-methyl-propan-1-ol (C24) A solution of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(3,4-difluorophenyl)aniline C10 (11.6 g, 22.2 mmol) in MeOH (100 mL) and EtOAc (51 mL) was purged with nitrogen for 1 h. PdCl2(CH3CN)2 (336 mg, 1.30 mmol) was added, and the mixture was heated to 60 °C overnight. The reaction was concentrated under reduced pressure and then purified by silica gel chromatography (gradient: 0 to 75% EtOAc in heptane) to give the product as a white solid (8.2 g, 91%). 1 H NMR (400MHz, chloroform-d) δ7.55(dt,J=6.3,1.4Hz,2H), 7.48-7.41(m,2H), 7.41-7.31(m,2H), 7.31-7.24(m,3H), 7.22-7.15(m,1H), 7.02(t,J=8.0 Hz,1H), 6.74(d,J=0.8Hz,1H), 6.63(d,J=7.8Hz,1H), 6.33(d,J=8.2Hz,1H), 5.26(s,2H), 3.53(dd,J=6.0,1.6Hz,2H), 1.28(s,3H), 1.27(s,3H). LCMS m / z 408.37[M+1] +

[0143] Preparation of S5 2-(4-(benzyloxy)-1-(3,4-difluorophenyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (S5) [ka] Step 1. Synthesis of 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol (C12) 1-Benzyloxy-3-bromo-5-fluoro-2-iodo-benzene in 1,4-dioxane (40 mL) and EtN (40 mL) C11 A solution of 2,2-dimethylbut-3-yn-1-ol (1.8 g, 18.3 mmol) (5 g, 12.3 mmol) was purged with nitrogen for 10 minutes, followed by the addition of CuI (157 mg, 0.82 mmol) and PdCl(PPh) (500 mg, 0.71 mmol). The resulting reaction mixture was warmed to 50 °C and stirred overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and partitioned between saturated aqueous NHCl (approximately 50 mL) and ethyl acetate (approximately 150 mL). After stirring for 10 minutes, the organic layer was separated and washed with 1 N HCl solution (2 × 50 mL), water (30 mL), brine (30 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 0–70% ethyl acetate in heptane) to give the product as a clear, yellow, viscous oil. 4-(2-Benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol C12 (4.23 g, 90%). 1 H NMR (400MHz, chloroform-d) δ7.49(dtd,J=6.9,1.4,0.7Hz,2H), 7.46-7.32(m,3H), 6.98(dd,J=8. 0,2.4Hz,1H), 6.65(dd,J=10.2,2.4Hz,1H), 5.12(s,2H), 3.49(d,J=7.1Hz,2H), 1.34(s,6H). LCMS m / z 377.01[M+1] + .

[0144] Step 2. Synthesis of ((4-(2-(benzyloxy)-6-bromo-4-fluorophenyl)-2,2-dimethylbut-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane (C13) To a mixture of 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol C12 (2.05 g, 5.43 mmol) and TBSCl (1.41 g, 9.36 mmol) in dichloromethane (20 mL) was added imidazole (561 mg, 8.24 mmol) in one portion at room temperature. After 40 min, water and dichloromethane were added. The layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane, the layers were again separated through a phase separator, and the combined organics were concentrated. Purification by column chromatography (80 g column; 0-40% EtOAc in heptane) gave the product C13. 1 H NMR (400 MHz, chloroform-d) δ 7.45-7.40 (m, 2H), 7.37-7.25 (m, 3H), 6.90 (dd, J = 8.1, 2.4 Hz, 1H), 6.55 (dd, J = 10.3, 2.4 Hz, 1H), 5.05 (s, 2H), 3.52 (s, 2H), 1.25 (s, 6H), 0.85 (s, 9H), 0.00 (s, 6H).

[0145] Step 3. Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(3,4-difluorophenyl)-5-fluoroaniline (C14) To a solution of [4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane C13 (2.35 g, 4.78 mmol) and 3,4-difluoroaniline (540 μL, 5.45 mmol) in xylene (20 mL) under nitrogen, NaOtBu (1.2 g, 12.5 mmol) was added. Nitrogen was bubbled through the mixture for 10 minutes. tBuXPhos Pd G3 (48 mg, 60.4 μmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted 2× with EtOAc. The combined organics were dried (NaSO), filtered, and concentrated. Purification by silica gel chromatography (80 g) eluting with 0–50% EtOAc in heptane gave product C14 (2.56 g, 99%). 1 H NMR(300MHz,chloroform-d)δ 7.50-7.44(m,2H), 7.40-7.26(m,3H), 7.10(dt,J=10.0,8.8Hz,1H), 7.00(ddd,J=11.6,6.9,2.6Hz,1H), 6.86(dt,J=8.3,4.1Hz,1H), 6. 52(s,1H), 6.34(dd,J=11.0,2.3Hz,1H), 6.14(dd,J=10.5,2.3Hz,1H), 5.08(s,2H), 3.53(s,2H), 1.28(s,6H), 0.84(s,9H), 0.00(s,6H). LCMS m / z 540.52[M+1] + .

[0146] Step 4. Synthesis of 2-(4-(benzyloxy)-1-(3,4-difluorophenyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (S5) A flask was charged with 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(3,4-difluorophenyl)-5-fluoro-aniline C14 (2.56 g, 4.74 mmol), methanol (30 mL), and ethyl acetate (15 mL) and degassed with nitrogen for 30 minutes. PdCl2(CH3CN)2 (100 mg, 0.386 mmol) was added, and the mixture was heated to 60 °C overnight. The reaction was concentrated under reduced pressure and then purified by column chromatography (80 g column; 0 to 30% EtOAc in heptane) to give the product S5 as an orange solid (1.75 g, 87%). 1 H NMR(400MHz,chloroform-d)δ 7.56-7.51(m,2H), 7.48-7.43(m,2H), 7.42-7.36(m,1H), 7.36-7.32(m,1H), 7.28-7.23(m,1H), 7.21-7.14(m,1H), 6.67(d,J=0.8Hz ,1H), 6.43(dd,J=11.5,2.0Hz,1H), 6.02(ddd,J=9.4,2.0,0.8Hz,1H), 5.21(s,2H), 3.51(d,J=5.6Hz,2H), 1.26(s,3H), 1.25(s,3H). LCMS m / z 426.37[M+1] + .

[0147] Preparation of S6 2-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S6) [ka] Step 1. 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(4-fluorophenyl)aniline (C15) A solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane C4 (40.3 g, 85.1 mmol) and 4-fluoroaniline (12.1 mL, 128 mmol) in m-xylene (400 mL) was purged with nitrogen for 10 minutes. NaOtBu (24.5 g, 255 mmol) and tBuXPhos Pd G3 (2.03 g, 2.56 mmol) were then added in one portion, and the reaction mixture was stirred at 35 °C for 4 hours and then filtered through Celite®. The filtered solid was rinsed with xylene, and the filtrate was concentrated. The filtered solid was washed with 1:1 EtOAc and water, and the organic layer of the filtrate was combined and concentrated along with the xylene filtrate to give a dark brown oil. Purification by silica gel chromatography (gradient: 0-20% EtOAc in heptane) gave the product C15 as a pale yellow oil (40.3 g, 94%). 1 H NMR(400MHz,chloroform-d)δ 7.53(ddt,J=7.4,1.3,0.7Hz,2H), 7.41-7.35(m,2H), 7.34-7.28(m,1H), 7.18-7.13(m,2H), 7.06-6.99(m,3H), 6.63(dd,J= 8.3,0.8Hz,1H), 6.42(s,1H), 6.39(dd,J=8.3,0.8Hz,1H), 5.14(s,2H), 3.57(s,2H), 1.32(s,6H), 0.87(s,9H), 0.03(s,6H). LCMS m / z 504.0[M+H] + .

[0148] Step 2. Synthesis of [2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-propoxy]-tert-butyl-dimethyl-silane (C16) To a solution of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(4-fluorophenyl)aniline C15 (40.3 g, 80.0 mmol) in MeCN (400 mL) was added PdCl2 (567 mg, 3.2 mmol). The reaction mixture was stirred at 60 °C overnight and then filtered. The filtrate was concentrated to dryness, triturated with MeCN, and filtered again. The process was repeated 3-4 times, and all solids were combined and dried under vacuum to give the product C16 as a tan solid (38.1 g, 95%). 1 H NMR(400MHz,chloroform-d)δ 7.60-7.55(m,2H), 7.48-7.43(m,2H), 7.42-7.35(m,3H), 7.25-7.18(m,2H), 6.98(t,J=8.0Hz,1H), 6.69(d,J=0.8Hz, 1H), 6.64-6.59(m,1H), 6.32(dt,J=8.3,0.7Hz,1H), 5.28(s,2H), 3.54(s,2H), 1.24(s,6H), 0.88(s,9H), 0.00(s,6H). LCMS m / z 504.0[M+H] + .

[0149] Step 3. Synthesis of [2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-propan-1-ol (S6) To a solution of [2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-propoxy]-tert-butyl-dimethyl-silane C16 (4.8 g, 9.53 mmol) in THF (40 mL) was added TBAF (40 mL of 1 M, 40.0 mmol). The mixture was stirred at 55 °C for 4 h, then concentrated and purified by silica gel chromatography (gradient: 0 to 50% EtOAc in heptane) to give the product 2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-propan-1-ol S6 (3.15 g, 85%) as an off-white solid. 1H NMR(400MHz,chloroform-d)δ 7.51-7.17(m,7H), 7.08(q,J=8.3,7.9Hz,2H), 6.88(t,J=7.9Hz,1H), 6.62(s,1H), 6 .50(d,J=7.8Hz,1H), 6.21(d,J=8.3Hz,1H), 5.13(s,2H), 3.35(s,2H), 1.12(s,6H). LCMS m / z 390.0[M+H] + .

[0150] Preparation of S7 2-(4-(benzyloxy)-6-fluoro-1-(4-fluorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S7) [ka] Step 1. Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluoro-N-(4-fluorophenyl)aniline (C17) To a solution of [4-(2-benzyloxy-6-bromo-4-fluorophenyl)-2,2-dimethylbut-3-ynoxy]-tert-butyl-dimethylsilane C13 (2.76 g, 5.62 mmol) and 4-fluoroaniline (600 μL, 6.33 mmol) in xylene (50 mL) under nitrogen, NaOtBu (1.35 g, 14.1 mmol) was added and nitrogen was bubbled through the mixture for 10 minutes. tBuXPhos Pd G3 (130 mg, 0.164 mmol) was then added and the reaction mixture was stirred overnight at room temperature. The reaction was diluted with water and brine and extracted twice with EtOAc. The combined organics were dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (120 g) eluting with 0-20% EtOAc in heptane to give the product C17 as a pale yellow oil that solidified on standing to give an off-white solid (2.76 g, 94%). 1H NMR(400MHz,chloroform-d)δ 7.50-7.46(m,2H), 7.40-7.34(m,2H), 7.33-7.28(m,1H), 7.14(dd,J=8.9,4.8Hz,2H), 7.06-7.00(m,2H), 6.50(s,1H), 6.2 5(dd,J=11.3,2.3Hz,1H), 6.09(dd,J=10.5,2.3Hz,1H), 5.08(s,2H), 3.54(s,2H), 1.29(s,6H), 0.84(s,9H), 0.00(s,6H). LCMS m / z 522.43[M+H] + .

[0151] Step 2. Synthesis of 2-(4-(benzyloxy)-6-fluoro-1-(4-fluorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S7) A flask was charged with 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-5-fluoro-N-(4-fluorophenyl)aniline C17 (2.76 g, 5.29 mmol), methanol (32 mL), and ethyl acetate (16 mL) and degassed with nitrogen for 35 minutes. PdCl2(CH3CN)2 (220 mg, 0.8480 mmol) was added, and the mixture was heated at 60 °C. A precipitate appeared, so an additional portion of EtOAc (20 mL) was added. The reaction was concentrated under reduced pressure after 2 months and then purified by column chromatography (80 g column; 50-100% EtOAc in heptane) to give the product S7 as a tan solid (2 g, 93%). LCMS m / z 408.14 [M+H] + .

[0152] Preparation of S8 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S8) [ka] Step 1. Synthesis of 4-(benzyloxy)-1-bromo-2-iodobenzene (C19) 1-Benzyloxy-3-iodo-benzene (30 g, 96.7 mmol) was dissolved in HOAc (300 mL) and cooled to 5 °C in an ice bath. Bromine (5 mL, 97.1 mmol) was added via an addition funnel. During the addition, the temperature rose to 15 °C. After stirring overnight, the reaction was poured into 1 L of water, forming a milky suspension, which was extracted with dichloromethane (3 × 100 mL). The extract was washed with saturated aqueous NaHCO3, and the organic layer was dried (Na2SO4), filtered, and concentrated. The crude oil was purified by flash chromatography (Combiflash® ISCO, 330 g gold column) eluting with 0–20% EtOAc / hex to give the product C19 (18 g, 47%). 1 H NMR (400 MHz, chloroform-d) δ 7.54-7.31 (m, 7H), 6.83-6.81 (s, 1H), 5.00 (s, 2H).

[0153] Step 2. Synthesis of 4-(5-(benzyloxy)-2-bromophenyl)-2,2-dimethylbut-3-yn-1-ol (C20) 4-Benzyloxy-1-bromo-2-iodo-benzene C19 (13.3 g, 34.2 mmol) and 2,2-dimethylbut-3-yn-1-ol (4 g, 40.8 mmol) were dissolved in dioxane (75 mL) and DIEA (15 mL, 86.1 mmol), and the solution was purged with nitrogen for 5–10 minutes. Bistriphenylphosphine Pd chloride (1.2 g, 1.71 mmol) was added, followed by CuI (710 mg, 3.73 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen and foil. The reaction mixture was filtered with EtOAc and then concentrated. Purification by column chromatography (330 g column; 0–100% EtOAc in heptane) afforded the product C20 (10 g, 81%) as a pale yellow oil. 4-(5-benzyloxy-2-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol (10g, 81%) 1H NMR(400MHz,chloroform-d)δ 7.45(d,J=8.9Hz,1H), 7.44-7.34(m,5H), 7.09(d,J=3.0Hz,1H), 6.82(dd,J=8.9,3 .0Hz,1H), 5.05(s,2H), 3.55(d,J=7.2Hz,2H), 2.10(d,J=7.1Hz,1H), 1.35(s,6H). LCMS m / z 359.17[M+H] + .

[0154] Step 3. Synthesis of ((4-(5-(benzyloxy)-2-bromophenyl)-2,2-dimethylbut-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane (C21) To a solution of 4-(5-benzyloxy-2-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol C20 (4.08 g, 11.4 mmol) in DMF (15 mL) was added tert-butyl-chloro-diphenyl-silane (3 mL, 11.5 mmol), followed by imidazole (1.93 g, 28.4 mmol), and the mixture was stirred at room temperature overnight. An additional portion of tert-butyl-chloro-diphenyl-silane (3 mL, 11.5 mmol) was added, and the mixture was heated at 80 °C for 30 min. Water and heptane were added. The extract was dried (NaSO), filtered, and concentrated. Purification by column chromatography (120 g GOLD column; 0-10% EtOAc in heptane) gave product C21 (2 g, 31%). 1 H NMR(400MHz,chloroform-d)δ 7.78-7.72(m,4H), 7.48-7.32(m,12H), 7.06(d,J=3.0Hz,1H), 6.79(dd,J=8.9,3.0Hz,1H), 5.00(s,2H), 3.66(s,2H), 1.40(s,6H), 1.12(s,9H).

[0155] Step 4. Synthesis of 4-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(4-fluoro-3-methylphenyl)aniline (C22) (4-(5-(benzyloxy)-2-bromophenyl)-2,2-dimethylbut-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane C21 (2.1 g, 3.51 mmol) and 4-fluoro-3-methyl-aniline (500 mg, 4.00 mmol) were dissolved in dioxane (6 mL) and t-BuOH (6 mL). Sodium t-butoxide (767 mg, 7.98 mmol) and tBuXphos palladacycle (154 mg, 0.224 mmol) [tBuXPhosPd Gen I] were added, and the reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was filtered through Celite® with EtOAc and then concentrated. Purification by column chromatography (80 g GOLD column, heptane) gave the product C22 as a straw-colored oil (1.22 g, 54%). 1 H NMR(400MHz,chloroform-d)δ 7.73(m,3H), 7.47-7.31(m,11H), 7.06-6.99(m,2H), 6.94-6.76(m,3H), 5.97(s,1H), 5 .04(s,1H), 5.00(s,2H), 3.62(s,2H), 2.22(s,3H), 1.36(s,6H), 1.09(d,J=1.2Hz,9H).

[0156] Step 5. Synthesis of 5-(benzyloxy)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-1-(4-fluoro-3-methylphenyl)-1H-indole (C23) To a solution of 4-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(4-fluoro-3-methylphenyl)aniline C22 (2.19 g, 4.22 mmol) in 2-MeTHF (10 mL) was added potassium 2-methylpropane-2-oleate (1 M in THF, 5.1 mL, 5.1 mmol) at room temperature. After 4 h, the reaction was diluted with water and saturated ammonium chloride and extracted twice with EtOAc. The combined organics were dried (NaSO), filtered, and concentrated to give the product C23 (2.19 g, 100%), which was taken on to the next reaction without further characterization.

[0157] Step 6. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S8) To a solution of 5-(benzyloxy)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-1-(4-fluoro-3-methylphenyl)-1H-indole C23 (2.19 g, 4.23 mmol) in THF (10 mL) was added TBAF (1 M in THF, 5.5 mL, 5.5 mmol) at room temperature. After 1 h, an additional 2.5 mL of TBAF solution was added at room temperature, and the mixture was stirred overnight. The reaction was diluted with water and saturated ammonium chloride and extracted twice with EtOAc. The combined organics were dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (80 g silica column; 0 to 100% ethyl acetate in heptane) to give the product S8 as an off-white solid (970 mg, 57%). 1 H NMR(400MHz,chloroform-d)δ 7.51-7.31(m,6H), 7.23-7.12(m,4H), 6.84(dd,J=8.8,2.4Hz,1H), 6.60(d,J=8.9Hz,1H), 6.49(d,J=0.8Hz,1H), 5. 13(s,2H), 3.52(d,J=6.3Hz,2H), 2.35(d,J=2.0Hz,3H), 1.39(t,J=6.4Hz,1H), 1.33(d,J=1.2Hz,1H), 1.26(s,6H). LCMS m / z 404.14[M+H] + .

[0158] Preparation of S9 2-(5-fluoro-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S9) [ka] Step 1. Synthesis of 4-(2-bromo-5-fluorophenyl)-2,2-dimethylbut-3-yn-1-ol (C25) 1-Bromo-4-fluoro-2-iodo-benzene C24 (1.7 mL, 13.0 mmol) and 2,2-dimethylbut-3-yn-1-ol (1.5 g, 15.3 mmol) were dissolved in dioxane (15 mL) and DIEA (5.6 mL, 32.2 mmol), and the solution was purged with nitrogen for 5–10 minutes. Bistriphenylphosphine Pd chloride (456 mg, 0.648 mmol) was added, followed by CuI (270 mg, 1.42 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen and foil. The reaction mixture was filtered with EtOAc and then concentrated. Purification by column chromatography (80 g column; 0–100% EtOAc in heptane) gave the product C25 (2.73 g, 78%). 1 H NMR(400MHz,chloroform-d)δ 7.54(dd,J=8.9,5.3Hz,1H), 7.18(dd,J=8.9,3.0Hz,1H), 6.91(ddd,J=8.9, 7.9,3.0Hz,1H), 3.55(d,J=5.6Hz,2H), 2.03(t,J=6.6Hz,1H), 1.35(s,6H). LCMS m / z 271.1[M+H] + .

[0159] Step 2. Synthesis of ((4-(2-bromo-5-fluorophenyl)-2,2-dimethylbut-3-yn-1-yl)oxy)(tert-butyl)diphenylsilane (C26) To a solution of 4-(2-bromo-5-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol C25 (2.73 g, 10.1 mmol) in DMF (8 mL), tert-butyl-chloro-diphenyl-silane (2.66 mL, 10.2 mmol) was added, followed by imidazole (1.5 g, 22.0 mmol), and the mixture was stirred for 4 h. Column chromatography (C18 AQ 275 g column, aqueous TFA / MeCN) afforded pure compound C26 as a colorless oil (4.25 g, 83%). 1H NMR(400MHz,chloroform-d)δ 7.70-7.64(m,4H), 7.46(dd,J=8.8,5.3Hz,1H), 7.42-7.31(m,6H), 7.06(dd,J=9.0,3 .0Hz,1H), 6.82(ddd,J=8.9,7.9,3.1Hz,1H), 3.58(s,2H), 1.33(s,6H), 1.06(s,9H).

[0160] Step 3. Synthesis of 2-(4-((tert-butyldiphenylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-4-fluoro-N-(4-fluoro-3-methylphenyl)aniline (C27). C26 (2.06 g, 4.04 mmol), 4-fluoro-3-methyl-aniline (610 mg, 4.874 mmol), and sodium t-butoxide (880 mg, 9.16 mmol) were suspended / dissolved in dioxane (8 mL) and t-BuOH (8 mL), and the reaction was purged with nitrogen for several minutes. While purging, tBuXphos palladacycle (139 mg, 0.202 mmol) was added, and the reaction mixture was stirred at 45 °C for 4 h. The reaction mixture was diluted with water and dichloromethane. The layers were separated using a phase separator, and the combined organics were concentrated. Purification by column chromatography (80 g gold column, heptane) gave the product C27 as a straw-colored oil (2.24 g, 100%). 1 H NMR(400MHz,chloroform-d)δ 7.75-7.67(m,4H), 7.50-7.34(m,6H), 7.04(dd,J=9.0,2.9Hz,1H), 6.98-6.82(m ,5H), 6.06(s,1H), 3.62(s,2H), 2.23(d,J=2.0Hz,3H), 1.36(s,6H), 1.08(s,9H).

[0161] Step 4. Synthesis of 2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)-5-fluoro-1-(4-fluoro-3-methylphenyl)-1H-indole (C28) To a solution of C27 (2.24 g, 4.05 mmol) in 2-MeTHF (5 mL) was added potassium 2-methylpropane-2-oleate (4.1 mL of 1 M, 4.100 mmol) at room temperature. After 2 h, the reaction was added to brine and EtOAc. The layers were separated, and the organics were dried (NaSO), filtered, and concentrated. Purification by column chromatography (80 g gold column, heptane) gave the product C28 as a straw-colored oil (1.394 g, 62%). 1 H NMR(400MHz,chloroform-d)δ 7.72-7.68(m,1H), 7.48(m,3H), 7.45-7.38(m,4H), 7.27-7.21(m,3H), 6.92-6.84(m,3H), 6.79(td, J=9.1,2.5Hz,1H), 6.54-6.46(m,2H), 3.61(s,3H), 2.16(d,J=2.0Hz,3H), 1.29(s,6H), 1.01(s,9H).

[0162] Step 5. Synthesis of 2-(5-fluoro-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S9) To a solution of tert-butyl-[2-[5-fluoro-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-propoxy]-diphenyl-silane C28 (750 mg, 1.35 mmol) in 2-MeTHF (10 mL) was added TBAF (1 M in THF, 3 mL, 3 mmol) at room temperature, and the mixture was heated at 70 °C overnight. Water and dichloromethane were added, the layers were separated, and the organics were dried (Na SO ), filtered, and concentrated. Purification by column chromatography (40 g column; 0-75% EtOAc in heptane) afforded the product S9 as a straw-colored oil (350 mg, 82%). LCMS m / z 316.13 [M+H] + .

[0163] Preparation of S10 4-(benzyloxy)-1-(4-fluorophenyl)-1H-indole (S10) [ka] Step 1. Synthesis of 4-(benzyloxy)-1-(4-fluorophenyl)-1H-indole (S10) Nitrogen was bubbled through a mixture of 4-benzyloxy-1H-indole C29 (20 g, 89.6 mmol), 1-fluoro-4-iodo-benzene (15 mL, 130 mmol), CuI (1 g, 5.25 mmol), and cesium carbonate (50 g, 154 mmol) in DMF (125 mL) and then stirred at 120 °C for 48 h. The reaction mixture was diluted with water (1 L) and EtOAc (500 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated to give a brown solid. The solid was triturated with ether and filtered to give the product S10 (19 g, 64%) as a gray solid. 1 H NMR(400MHz,DMSO-d6)δ 7.66-7.58(m,2H), 7.55-7.50(m,4H), 7.45-7.37(m,5H), 7.36-7.27(m,1H), 7.09(d,J=6.0Hz,2H), 6.73(q,J=2.7,2.2Hz,2H), 5.28(s,2H). LCMS m / z 318.16[M+H] + .

[0164] Preparation of S11 4-Benzyloxy-6-fluoro-1-(4-fluorophenyl)indole (S11) [ka] Step 1. Synthesis of 4-bromo-6-fluoro-1-(4-fluorophenyl)indole (C31) To a mixture of 4-bromo-6-fluoro-1H-indole C30 (5 g, 23.4 mmol), (4-fluorophenyl)boronic acid (6.54 g, 46.74 mmol), and copper(II) acetate (8.5 g, 46.8 mmol) in dichloromethane (100 mL), triethylamine (6.5 mL, 46.6 mmol) was added, and the mixture was vigorously stirred in air. Additional dichloromethane (100 mL), 4-fluorophenylboronic acid (5.7 g), Cu(OAc)2, and NEt3 (6 mL) were added, and the mixture was vigorously stirred. The reaction mixture was filtered through Celite® with EtOAc and then concentrated. Purification by column chromatography (gradient: 0 to 50% EtOAc in heptane) afforded the product C31 as a white solid (2.84 g, 39%). 1 H NMR(400MHz,DMSO-d6)δ7.78(d,J=3.3Hz,1H), 7.69-7.62(m,2H), 7.47-7.40(m,2H), 7.3 8(dd,J=9.1,2.1Hz,1H), 7.31(ddd,J=9.9,2.1,0.9Hz,1H), 6.66(dd,J=3.4,0.8Hz,1H). LCMS m / z 308.02[M+1] + .

[0165] Step 2. Synthesis of 4-benzyloxy-6-fluoro-1-(4-fluorophenyl)indole (S11) A vial was charged with 4-bromo-6-fluoro-1-(4-fluorophenyl)indole C31 (2.14 g, 6.95 mmol), palladium allyl chloride (38 mg, 0.21 mmol), di-tert-butyl-[6-methoxy-3-methyl-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (293 mg, 0.63 mmol), CsCO (4.2 g, 12.9 mmol), followed by toluene (14 mL) and benzyl alcohol (1.4 mL, 13.5 mmol). The mixture was stirred at 90-100 °C under nitrogen. The mixture was filtered through Celite®, and the filtrate was concentrated. EtOAc was added, and the mixture was sonicated and filtered to give the product S11 as a white solid (1.8 g, 77%). 1H NMR (400MHz, DMSO-d6) δ7.65-7.58(m,2H), 7.55-7.49(m,3H), 7.46-7.32(m,5H), 6.85(ddd,J=10.0,2.0,0.8Hz,1H), 6.73-6.67(m,2H), 5.29(s,2H).

[0166] Preparation of S12 3-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-3-methylbutan-1-ol (S12) [ka] Step 1. Synthesis of 5-(2-benzyloxy-6-bromo-phenyl)-3,3-dimethyl-pent-4-yn-1-ol (C32) A solution of 1-benzyloxy-3-bromo-2-iodo-benzene C2 (60 g, 154.2 mmol), 3,3-dimethylpent-4-yn-1-ol (23 g, 205.0 mmol), and N-isopropylpropan-2-amine (140 mL, 998.9 mmol) in 1,4-dioxane (400 mL) was purged with nitrogen for 10 minutes, and then CuI (1.38 g, 7.25 mmol) and Pd(PPh3)2Cl2 (4.65 g, 6.63 mmol) were added. The reaction mixture was stirred at 50 °C for 4 hours, then cooled to room temperature and filtered to remove a light tan solid. The filtrate was concentrated to dryness and then partitioned between water and EtOAc. The mixture was filtered through Celite® to aid in separation of the layers. The organic layer was concentrated to dryness and purified by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) to give the product C32 as an orange oil (47 g, 82%). 1H NMR(400MHz,chloroform-d)δ 7.52-7.48(m,2H), 7.44-7.39(m,2H), 7.38-7.32(m,1H), 7.20(dd,J=8.1,1.0Hz,1H), 7.07(t,J=8.2Hz,1H), 6.85(d d,J=8.4,0.9Hz,1H), 5.15(s,2H), 3.89(q,J=6.1Hz,2H), 2.23(t,J=5.9Hz,1H), 1.82(t,J=6.3Hz,2H), 1.39(s,6H). LCMS m / z 373.0[M+H] + .

[0167] Step 2. Synthesis of [5-(2-benzyloxy-6-bromo-phenyl)-3,3-dimethyl-pent-4-ynoxy]-tert-butyl-dimethyl-silane (C33) To a solution of 5-(2-benzyloxy-6-bromo-phenyl)-3,3-dimethyl-pent-4-yn-1-ol C32 (47 g, 125.9 mmol) in dichloromethane (500 mL) was added TBS-Cl (19.9 g, 132.0 mmol) and imidazole (9.0 g, 132.2 mmol). The reaction mixture was stirred at room temperature over the weekend. The tan precipitate was removed by filtration, and the filtrate was washed with water (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the product C33 as a pale yellow oil (59.3 g, 97%). 1 H NMR(400MHz,chloroform-d)δ 7.50(ddq,J=6.8,1.5,0.7Hz,2H), 7.41-7.36(m,2H), 7.35-7.30(m,1H), 7.19(dd,J=8.1,1.0Hz,1H), 7.05(t,J=8.2Hz,1H ), 6.84(dd,J=8.3,1.0Hz,1H), 5.13(s,2H), 3.98-3.90(m,2H), 1.85-1.77(m,2H), 1.36(s,6H), 0.89(s,9H), 0.05(s,6H). LCMS m / z 487.0[M+H] + .

[0168] Step 3. Synthesis of 3-benzyloxy-2-[5-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-pent-1-ynyl]-N-(4-fluorophenyl)aniline (C34) A solution of C33 (59.3 g, 121.7 mmol) and 4-fluoroaniline (17.3 mL, 182.6 mmol) in m-xylene (500 mL) was degassed with nitrogen for 10 minutes, then NaOtBu (35.1 g, 365.2 mmol) and tBuXPhos Pd G3 (2.9 g, 3.65 mmol) were added in one portion. The reaction mixture was stirred at 35 °C for 1 hour and then filtered through Celite®. The filter pad was washed with 1:1 EtOAc / water, and the organic layer of the filtrate was then combined with xylene and concentrated to dryness. The resulting brown oil was purified by silica gel chromatography (gradient: 0 to 25% EtOAc in heptane) to give the desired product C34 as an amber oil (56.1 g, 89%). 1 H NMR(400MHz,chloroform-d)δ 7.52(ddq,J=7.0,1.5,0.8Hz,2H), 7.42-7.37(m,2H), 7.34-7.29(m,1H), 7.19-7.14(m,2H), 7.07-7.00(m,3H), 6.68(dd,J=8.3,0.8Hz,1 H), 6.40(dd,J=8.3,0.8Hz,1H), 6.38(s,1H), 5.15(s,2H), 3.94-3.86(m,2H), 1.85-1.77(m,2H), 1.38(s,6H), 0.86(s,9H), 0.00(s,6H). LCMS m / z 518.0[M+H] + .

[0169] Step 4. Synthesis of [3-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-3-methyl-butoxy]-tert-butyl-dimethyl-silane (C35) To a solution of C34 (56.1 g, 108.4 mmol) in MeCN (500 mL) was added PdCl (965 mg, 5.44 mmol). The reaction mixture was stirred at 65 °C overnight, then cooled to room temperature and filtered. The filtrate was concentrated to dryness, triturated with MeCN, and filtered again. The solids were combined, rinsed with cold MeCN, and then dried under vacuum to give the product C35 as a white solid (48.7 g, 87%). 1 H NMR(400MHz,chloroform-d)δ 7.54(ddt,J=7.5,1.4,0.7Hz,2H), 7.45-7.39(m,2H), 7.35(tdd,J=5.8,3.9,2.6Hz,3H), 7.21-7.14(m,2H), 6.94(t,J=8.0Hz,1H), 6.61 -6.56(m,2H), 6.27(dt,J=8.2,0.7Hz,1H), 5.24(s,2H), 3.57-3.49(m,2H), 1.76-1.66(m,2H), 1.27(s,6H), 0.83(s,9H), -0.04(s,6H). LCMS m / z 518.0[M+H] + .

[0170] Step 5. Synthesis of 3-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-3-methylbutan-1-ol (S12) To a solution of [3-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-3-methyl-butoxy]-tert-butyl-dimethyl-silane (1.0 g, 1.67 mmol) in THF (24 mL) was added a solution of TBAF (1 M in THF, 24 mL, 24 mmol). The mixture was stirred at 60° C. for 2 hours and then concentrated. Purification by silica gel chromatography (gradient: 0-50% EtOAc in heptane) gave S12 (540 mg, 71%). LCMS m / z 404.32 [M+H] + .

[0171] Preparation of S13 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indole (S13) [ka] Step 1. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indole (S13) Nitrogen was bubbled through a mixture of 5-benzyloxy-1H-indole C36 (2 g, 8.96 mmol), 1-fluoro-4-iodo-2-methyl-benzene (2.1 g, 8.90 mmol), CuI (100 mg, 0.525 mmol), and cesium carbonate (5.2 g, 16.0 mmol) in DMF (10 mL), and the mixture was stirred at 120 °C overnight. The reaction mixture was diluted with water and EtOAc. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography (gradient: 0 to 15% EtOAc in heptane) gave S13 (2.4 g, 81%). 1 H NMR(400MHz,chloroform-d)δ 7.58-7.46(m,3H), 7.15(t,J=8.8Hz,1H), 6.98(dd,J=9.0,2.5Hz,1H), 6.59(dd,J=3.3,0.9Hz,1H), 5.16(s,2H), 2.38(d,J=2.1Hz,3H).

[0172] Preparation of S14 2-(4-(benzyloxy)-1-(4-fluoro-3-methoxyphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S14) [ka] Step 1. Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(4-fluoro-3-methoxyphenyl)aniline (C37) To a solution of C4 (3.39 g, 7.16 mmol) and 4-fluoro-3-methoxy-aniline (1.10 g, 7.794 mmol) in xylene (30 mL) under nitrogen, NaOtBu (1.75 g, 18.2 mmol) was added, followed by tBuXPhos Pd G3 (240 mg, 0.302 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The reaction was quenched with water and saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organics were concentrated to dryness and purified by silica gel chromatography (80 g column) eluting with 0–50% EtOAc in heptane. Pure fractions were combined and concentrated to give the product C37 as a yellow oil (3.65 g, 96%). 1 H NMR(400MHz,chloroform-d)δ 7.52-7.47(m,2H), 7.38-7.32(m,2H), 7.31-7.25(m,1H), 7.04-6.96(m,2H), 6.80(dd,J=7.6,2.5Hz,1H), 6.68(ddd,J=8.7,3.8,2.6H z,1H), 6.63(dd,J=8.3,0.8Hz,1H), 6.40-6.33(m,2H), 5.11(s,2H), 3.83(s,3H), 3.54(s,2H), 1.53(s,6H), 1.29(s,6H), 0.84(s,9H). LCMS m / z 534.33[M+H] + .

[0173] Step 2. Synthesis of 2-(4-(benzyloxy)-1-(4-fluoro-3-methoxyphenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S14) Nitrogen was bubbled through a mixture of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(4-fluoro-3-methoxy-phenyl)aniline C37 (3.65 g, 6.84 mmol) in methanol (50 mL) and ethyl acetate (25 mL) for 20 min, then PdCl(CHCN) (75 mg, 0.289 mmol) was added, and the mixture was stirred overnight and then concentrated. Purification by column chromatography (80 g column; 0 to 75% EtOAc in heptane) gave product S14 (1 g, 35%).1 H NMR(400MHz,chloroform-d)δ 7.57-7.50(m,2H), 7.46-7.39(m,2H), 7.39-7.33(m,1H), 7.24-7.17(m,1H), 7.03-6.93(m,3H), 6.72(d,J=0.8Hz,1H), 6.6 1(dd,J=7.8,0.6Hz,1H), 6.36(dt,J=8.2,0.7Hz,1H), 5.25(s,2H), 3.86(s,3H), 3.52(dd,J=6.3,3.0Hz,2H), 1.27(s,6H). LCMS m / z 420.39[M+H] + .

[0174] Preparation of S15 2-(4-(benzyloxy)-1-(4-chloro-3-fluorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S15) [ka] Step 1. Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(4-chloro-3-fluorophenyl)aniline (C38) A reaction vessel was charged with [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane C4 (4 g, 8.45 mmol), 4-chloro-3-fluoro-aniline (2 g, 13.7 mmol), and sodium 2-methylpropane-2-oleate (2 g, 20.8 mmol) in THF (25 mL). Nitrogen was bubbled through the mixture for 10 min. tBuXPhos Pd G1 (0.2 g, 0.307 mmol) was added, and nitrogen was bubbled through the mixture for an additional 5 min. The reaction mixture was heated at 60 °C for 3 h. LCMS showed partial conversion, so an additional amount of tBuXPhos Pd G1 (0.2 g, 0.307 mmol) was added, and heating was continued at 100 °C overnight. The solvent was evaporated. Purification by column chromatography (80 g column; 0-100% EtOAc in heptane) gave product C38 (840 mg, 43% purity, 8%). LCMS m / z 538.45 [M+H] + .

[0175] Step 2. Synthesis of 2-(4-(benzyloxy)-1-(4-chloro-3-fluorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S15). Nitrogen was bubbled through a mixture of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(4-chloro-3-fluoro-phenyl)aniline C38 (840 mg, 1.56 mmol) in methanol (15 mL) and ethyl acetate (15 mL) for 10 min, then PdCl(CHCN) (50 mg, 0.193 mmol) was added, and the mixture was stirred at 60 °C overnight and then concentrated. Purification by column chromatography (80 g column; 0-100% EtOAc in heptane) gave product S15 (210 mg, 92% pure, 29%). LCMS m / z 424.3 [M+H] + .

[0176] Preparation of S16 2-(4-(benzyloxy)-1-(4-chlorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S16) [ka] Step 1. Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(4-chlorophenyl)aniline (C39) A reaction vessel was charged with [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane C4 (4 g, 8.45 mmol), 4-chloroaniline (1.5 g, 11.8 mmol), and sodium 2-methylpropane-2-oleate (2 g, 20.8 mmol) in THF (25 mL). Nitrogen was bubbled through the mixture for 10 min. tBuXPhos Pd G1 (0.2 g, 0.307 mmol) was added, and nitrogen was bubbled through the mixture for an additional 5 min. The reaction mixture was heated at 60 °C for 3 h. LCMS showed partial conversion, so an additional amount of tBuXPhos Pd G1 (0.2 g, 0.307 mmol) was added, and heating was continued at 100 °C overnight. The solvent was evaporated. Purification by column chromatography (80 g column; 0-100% EtOAc in heptane) gave product C39 (3.47 g, 72% purity, 57%). LCMS m / z 520.49 [M+H] + .

[0177] Step 2. Synthesis of 2-(4-(benzyloxy)-1-(4-chlorophenyl)-1H-indol-2-yl)-2-methylpropan-1-ol (S16) Nitrogen was bubbled through a mixture of C39 (1.75 g, 3.36 mmol) in methanol (15 mL) and ethyl acetate (15 mL) for 10 min, then PdCl(CHCN) (100 mg, 0.386 mmol) was added, and the mixture was stirred at 60 °C overnight and then concentrated. Purification by column chromatography (80 g column; 0-100% EtOAc in heptane) gave product S16 (370 mg, 92% purity, 25%). LCMS m / z 406.34 [M+H] + .

[0178] Preparation of S17 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethan-1-ol (S17) [ka] Step 1: Synthesis of 4-(2-(benzyloxy)-6-bromophenyl)but-3-yn-1-ol (C40) A 20 mL drum vial with a red pressure-release cap was sequentially charged with 1-benzyloxy-3-bromo-2-iodo-benzene C2 (10.2 g, 26.2 mmol), but-3-yn-1-ol (2.02 g, 28.8 mmol), and then DMF (35 mL). Nitrogen gas was bubbled through the mixture for 15–20 min. To this solution was added Pd(PPh3)2Cl2 (1.2 g, 1.71 mmol). CuI (500 mg, 2.63 mmol) was added, followed by diethylamine (4.1 mL, 39.6 mmol). The mixture was allowed to stir at room temperature for 15 min and then heated to 40 °C for 65 h. The reaction was purified by reverse-phase column chromatography (C18 275 g column; 5–95% MeCN in aqueous TFA). The combined fractions were partially concentrated under reduced pressure. The mixture was extracted with two approximately 100 mL portions of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-(2-benzyloxy-6-bromo-phenyl)but-3-yn-1-ol C40 (6.09 g, 70%). 1H NMR(400MHz,chloroform-d)δ 7.49-7.29(m,5H), 7.19(dd,J=8.1,1.0Hz,1H), 7.06(t,J=8.2Hz,1H), 6.85(dd,J=8. 4,1.0Hz,1H), 5.15(s,2H), 3.80(t,J=5.9Hz,2H), 2.78(t,J=6.0Hz,2H), 2.14(s,1H).

[0179] Step 2: Synthesis of ((4-(2-(benzyloxy)-6-bromophenyl)but-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane (C41) To a mixture of 4-(2-benzyloxy-6-bromo-phenyl)but-3-yn-1-ol C40 (6.09 g, 18.4 mmol) and TBSCl (4.5 mL, 24.18 mmol) in dichloromethane (70 mL) was added imidazole (1.9 g, 27.91 mmol) in one portion at room temperature. The reaction was allowed to stir overnight. Water was added to the reaction mixture, and the mixture was re-extracted with dichloromethane. The layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane, and the layers were again separated through a phase separator, and the combined organics were concentrated. Purification by column chromatography (120 g column; 0 to 100% EtOAc in heptane) gave 4-(2-benzyloxy-6-bromo-phenyl)but-3-ynoxy-tert-butyl-dimethyl-silane C41 (7.65 g, 93%). 1 H NMR(400MHz,chloroform-d)δ 7.40-7.19(m,5H), 7.10(dd,J=8.1,1.0Hz,1H), 6.95(t,J=8.2Hz,1H), 6.74(dd,J=8.3,1.0H z,1H), 5.07(s,z2H), 3.78(t,J=7.5Hz,2H), 2.67(t,J=7.5Hz,2H), 0.82(s,9H), 0.00(s,6H).

[0180] Step 3: Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-N-(4-fluoro-3-methylphenyl)aniline (C42) Nitrogen was passed through a solution of 4-(2-benzyloxy-6-bromo-phenyl)but-3-ynoxy-tert-butyl-dimethyl-silane C41 (7.65 g, 17.17 mmol) and 4-fluoro-2-methyl-aniline (2.6 g, 20.78 mmol) in dioxane (7 mL) for 4 minutes. To this solution was added t-BuOH (8 mL), followed by sodium t-butoxide (2.5 g, 26.01 mmol), and then tBuXphos palladacycle G1 (590 mg, 0.859 mmol). Bubbling was continued for an additional 3 minutes, and then the vial was placed in a heating block set at 45 °C. After 16 hours, water and ethyl acetate were added. The aqueous layer was re-extracted with ethyl acetate, and the organic layer was separated and dried over sodium sulfate. The combined organic layers were concentrated under reduced pressure and redissolved in dichloroethane. Purification by column chromatography (80 g column; 0-20% EtOAc in heptane) gave C42 (5.85 g, 70%). 1 H NMR (400 MHz, chloroform-d) δ 7.50-7.21 (m, 5H), 7.14-6.86 (m, 4H), 6.61-6.51 (m, 1H), 6.34-6.25 (m, 1H), 5.10 (s, 1H), 3.79 (t, J = 7.2 Hz, 1H), 2.71 (t, J = 7.1 Hz, 1H), 2.20 (d, J = 2.0 Hz, 2H), 0.80 (d, J = 13.9 Hz, 6H), −0.09 (s, 1H).

[0181] Step 4: Synthesis of 4-(benzyloxy)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-fluoro-3-methylphenyl)-1H-indole (C43) To a solution of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxybut-1-ynyl]-N-(4-fluoro-3-methyl-phenyl)aniline C42 (5.85 g, 11.9 mmol) in 2-MeTHF (74 mL) was added potassium 2-methylpropane-2-oleate (1 M, 12 mL, 12 mmol) at room temperature, and the reaction mixture was stirred overnight. EtOAc, brine, and saturated ammonium chloride were added, the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give C43 (5.85 g, 100%).

[0182] Step 5: Synthesis of 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethan-1-ol (S17) To a solution of 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]ethoxy-tert-butyl-dimethyl-silane C43 (5.85 g, 11.95 mmol) in THF (70 mL) was added TBAF (1 M in THF, 12 mL, 12 mmol) and the reaction was allowed to stir overnight. Water was added and the product was extracted with two portions of ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (0 to 100% ethyl acetate in heptane) to give 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]ethanol S17 (310 mg, 7%). 1 H NMR(400MHz,chloroform-d)δ 7.57-7.53(m,2H), 7.47-7.34(m,3H), 7.21-7.14(m,3H), 7.04(t,J=8.1Hz,1H), 6.71-6.67(m,2H), 6.64(d,J=8 .0Hz,1H), 5.27(s,2H), 3.82(q,J=6.2Hz,2H), 2.91(td,J=6.5,0.8Hz,2H), 2.37(d,J=1.9Hz,3H), 1.60(s,2H). LCMS m / z 376.42[M+H] + .

[0183] Preparation of S18 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethan-1-ol (S18) [ka] Step 1: Synthesis of isopropyl 1-(hydroxymethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C45) To a solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate C44 (3.5 g, 12.1 mmol) in THF (10 mL) at −78° C. was added lithium tri-tert-butoxyaluminum hydride solution (28 mL of 1 M, 28 mmol). The mixture was stirred at room temperature overnight and heated at 50° C. for 2 hours. The reaction was quenched with NH4Cl solution at room temperature, extracted with dichloromethane, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (80 g column; 0–40% EtOAc in heptane) gave 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethan-1-ol (C45) (1.6 g, 57%). 1 H NMR(400MHz,chloroform-d)δ 5.08(hept,J=6.3Hz,1H), 3.83(d,J=6.5Hz,2H), 3.18(d,J=2.9Hz,6H), 2.62-2. 48(m,2H), 2.42(td,J=6.5,0.9Hz,1H), 2.28-2.15(m,2H), 1.29(d,J=6.3Hz,6H).

[0184] Step 2: Synthesis of isopropyl 1-(fluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C46) A solution of isopropyl 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylate (C45) (2.6 g, 11.19 mmol) in dichloromethane (20 mL) was cooled to −78 °C. To the solution was added 2,6-lutidine (2.2 mL, 19 mmol) and TfO (2.6 mL, 15.45 mmol). The mixture was allowed to warm slowly to room temperature overnight and then quenched with water. The mixture was extracted with dichloromethane and washed with saturated aqueous NaHCO, saturated aqueous NHCl, and then brine. Drying over NaSO, filtration, and concentration gave the triflate intermediate, which was dissolved in THF (20 mL) and cooled to −78 °C. To the solution was added tetrabutylammonium fluoride solution (1 M, 22 mL, 22 mmol), stirred, and allowed to warm slowly to room temperature for 1 hour. The reaction was quenched with water at room temperature, extracted with EtOAc, washed with brine, dried over NaSO, filtered, and concentrated. Purification by column chromatography (40 g column; 0 to 30% EtOAc in heptane) afforded isopropyl-1-(fluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C46) (2.4 g, 92%). 1 H NMR (400 MHz, chloroform-d) δ 5.08 (p, J = 6.3 Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H), 3.18 (d, J = 0.6 Hz, 7H), 2.67-2.51 (m, 3H), 2.28-2.17 (m, 2H), 1.28 (d, J = 6.2 Hz, 6H).

[0185] Step 3: Synthesis of 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethan-1-ol (S18) To a solution of isopropyl 1-(fluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C46) in MeOH (10 mL) was added NaOH (3 M, 4 mL, 12 mmol) and the mixture was stirred at 55 °C overnight. The reaction was concentrated and neutralized to pH 3 with HCl. The mixture was extracted with dichloromethane, dried over NaSO, filtered, and concentrated to give product S18 (550 mg, 45%). 1H NMR (400 MHz, chloroform-d) δ 4.87 (s, 1H), 4.75 (d, J = 1.0 Hz, 2H), 4.64 (s, 1H), 3.68-3.57 (m, 2H), 3.32-3.23 (m, 2H), 3.19 (d, J = 3.0 Hz, 5H), 2.69-2.61 (m, 2H), 2.36-2.25 (m, 2H).

[0186] Preparation of S19 Ethyl 1-(difluoromethyl)-4-oxocyclohexane-1-carboxylate (S19) [ka] Step 1. Synthesis of ethyl 8-(difluoromethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (C48) To a solution of ethyl 8-formyl-1,4-dioxaspiro[4.5]decane-8-carboxylate C47 (0.9 g, 3.72 mmol) in dichloromethane (15 mL) was added DAST (1.1 mL, 8.33 mmol) and stirred overnight. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Purification by column chromatography (12 g column; 0-30% EtOAc in heptane) gave ethyl 8-(difluoromethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate C48 (800 mg, 81%). 1 H NMR (400 MHz, chloroform-d) δ 5.79 (t, J = 56.3 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.96 (d, J = 2.2 Hz, 4H), 2.26-2.14 (m, 2H), 1.91-1.64 (m, 7H), 1.31 (t, J = 7.1 Hz, 3H).

[0187] Step 2. Synthesis of ethyl 1-(difluoromethyl)-4-oxocyclohexane-1-carboxylate (S19) To the product, ethyl 8-(difluoromethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate C48 (800 mg, 3.03 mmol) in acetone (15 mL), HCl (18 mL of a 2 M solution, 36 mmol) was added, and the mixture was stirred at room temperature overnight. After concentration, the residue was extracted with dichloromethane, dried over NaSO, filtered, and concentrated to give ethyl 1-(difluoromethyl)-4-oxocyclohexane-1-carboxylate (S19) (640 mg, 78%). 1 H NMR (400 MHz, chloroform-d) δ 5.98 (t, J = 56.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.61-2.31 (m, 6H), 2.09-1.91 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0188] Preparation of S20 1-(Difluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylic acid (S20) [ka] Step 1: Synthesis of isopropyl 1-formyl-3,3-dimethoxycyclobutane-1-carboxylate (C49) A solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate C44 (7.5 g, 26.0 mmol) in THF (50 mL) was cooled to -78 °C. To the solution was added DIBAL (50 mL of a 1 M solution, 50 mmol) and stirred at -78 °C for 2 h. The reaction was quenched with NH4Cl. 200 mL of saturated Rochelle's salt was added and the mixture was stirred for 2 h. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (40 g column; 0-30% EtOAc in heptane) gave C49 (3.2 g, 53%). 1 H NMR (400 MHz, chloroform-d) δ 9.69 (d, J = 2.1 Hz, 1H), 5.38-4.65 (m, 1H), 3.38-2.81 (m, 6H), 2.84-2.38 (m, 4H), 1.55-0.97 (m, 6H).

[0189] Step 2: Synthesis of isopropyl 1-(difluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C50) To a solution of triethylamine trihydrofluoride (2.8 mL, 17.2 mmol) and TEA (1.25 mL, 8.97 mmol) in dichloromethane (25 mL) at 0 °C, XtalFluor-M (3.2 g, 13.17 mmol) and isopropyl 1-formyl-3,3-dimethoxy-cyclobutanecarboxylate C49 (2.0 g, 8.69 mmol) were added. The mixture was warmed to 25 °C and then allowed to stir at that temperature for 16 h. The reaction was quenched with saturated NaHCO3 and extracted with dichloromethane. The organic layer was dried (Na2SO4) and concentrated to give the product C50 (2.18 g, 100%). 1 H NMR(400MHz,chloroform-d)δ 6.05(t,J=56.6Hz,1H), 5.29-4.92(m,1H), 3.18(d,J=3.9Hz,6H), 2.73-2.56(m,2H), 2.57-2.29(m,2H), 1.28(dd,J=13.0,6.3Hz,6H).

[0190] Step 3: Synthesis of 1-(difluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylic acid (S20) To a solution of isopropyl 1-(difluoromethyl)-3,3-dimethoxy-cyclobutanecarboxylate C50 (2.20 g, 8.72 mmol) in MeOH (10 mL), THF (10 mL), and water (5 mL), LiOH.HO (1.46 g, 34.9 mmol) was added, and the mixture was microwaved for 4 h. The reaction mixture was concentrated, neutralized with HCl (17 mL of 2 M, 34 mmol), and back-extracted with dichloromethane (3 × 40 ml). The organic layer was dried (NaSO) and concentrated to give product S20 (400 mg, 22%). The product was taken on to the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 6.13 (t, J = 56.3 Hz, 1H), 3.20 (d, J = 7.8 Hz, 6H), 2.78-2.36 (m, 4H).

[0191] Preparation of S21 1-(Difluoromethyl)-4-oxocyclohexane-1-carboxylic acid (S21) [ka] To a solution of S19 (500 mg, 2.27 mmol) in THF (2 mL) and EtOH (2 mL) was added NaOH (3 M, 1.5 mL, 4.5 mmol) and stirred overnight. The reaction was neutralized to pH 3 with aqueous HCl and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated. Purification by column chromatography (40 g column; 0-40% EtOAc in heptane) gave S21 (380 mg, 87%). 1 H NMR (400 MHz, chloroform-d) δ 6.03 (t, J = 55.9 Hz, 1H), 2.66-2.39 (m, 4H), 2.16-1.98 (m, 2H), 1.93-1.83 (m, 2H).

[0192] Preparation of S22 Methyl 3-fluoro-4-(2-methyloxiran-2-yl)benzoate (S22) [ka] A flame-dried flask was charged with trimethylsulfonium iodide (850 mg, 4.17 mmol) and sodium hydride (170 mg, 4.25 mmol). After keeping the flask under nitrogen, DMSO (3 mL) and THF (3 mL) were introduced. The mixture was allowed to stir at 25 °C for 30 min. The reaction was cooled to 0 °C, and methyl 4-acetyl-3-fluorobenzoate C51 (400 mg, 2.04 mmol) in THF (2 mL) was added, and the reaction was gradually warmed to 25 °C and stirred at that temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl and ethyl acetate, the layers were separated, and the organics were concentrated and purified using column chromatography (12 g gold column) to give product S22 (240 mg, 56%). LCMS m / z 211.13 [M+H] + .

[0193] compound 1 (1R,3R)-5'-(4-Fluoro-3-methylphenyl)-9'-hydroxy-3-methyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (1) [ka] Standard Procedure A Step 1: Synthesis of (1R,3R)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3-methyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (C52) and (1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3-methyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (C53) To a mixture of 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]ethanol S17 (207 mg, 0.551 mmol) and 1-methyl-3-oxo-cyclobutanecarboxylic acid (230 mg, 1.795 mmol) in DCE (1.75 mL) was added methanesulfonic acid (61 μL, 0.94 mmol) followed by triethylsilane (89 μL, 0.557 mmol), and the resulting dark solution was stirred at room temperature. After 15 min, the reaction was directly purified by column chromatography (24 g gold column; 5-40% EtOAc in heptane).

[0194] The first to elute was 9-benzyloxy-5-(4-fluoro-3-methyl-phenyl)-1′-methyl-spiro[3,4-dihydropyrano[4,3-b]indole-1,3′-cyclobutane]-1′-carboxylic acid C52 (88 mg, 32%). 1H NMR(400MHz,chloroform-d)δ 7.45-7.41(m,2H), 7.37-7.32(m,2H), 7.24(d,J=7.3Hz,1H), 7.17-7.10(m,3H), 6.87(t,J=8.1Hz,1H), 6.71(dd,J=8.2,0.7Hz,1H), 6.4 1(dd,J=8.0,0.8Hz,1H), 5.35(s,2H), 3.94(t,J=5.4Hz,2H), 3.62-3.54(m,2H), 2.61(t,J=5.3Hz,2H), 2.40-2.29(m,5H), 1.67(s,3H). LCMS m / z 486.29[M+H] + X-ray crystallography confirmed this stereoisomer as trans. Diagnostics associated with this characterized stereoisomer 1 H NMR chemical shifts were used to structurally assign other compounds in this series.

[0195] The second elution was (1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3-methyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (C53) (88 mg, 30%). 1 H NMR (400 MHz, chloroform-d) δ 7.41-7.36(m,2H), 7.31(ddd,J=7.6,6.8,1.4Hz,2H), 7.27-7.22(m,1H), 7.10-7.00(m,3H), 6.88(t,J=8.1Hz,1H), 6.67(dd,J=8.2,0.7Hz,1H), 6.5 0-6.47(m,1H), 5.39(s,2H), 3.92(t,J=5.4Hz,2H), 3.16-3.09(m,2H), 2.7 8-2.69(m,2H), 2.57(t,J=5.4Hz,2H), 2.26(d,J=2.0Hz,3H), 1.31(s,3H). LCMS m / z 486.29[M+H] + .

[0196] Standard Procedure B Step 2: Synthesis of (1R,3R)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-3-methyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (1) A mixture of 9-benzyloxy-5-(4-fluoro-3-methyl-phenyl)-1'-methyl-spiro[3,4-dihydropyrano[4,3-b]indole-1,3'-cyclobutane]-1'-carboxylic acid C52 (88 mg, 0.179 mmol), 10% Pd / C (50 mg, Degussa wet), and NH4CO2H (150 mg) in EtOH (5 mL) and EtOAc (2 mL) was stirred at room temperature. The reaction mixture was filtered through Celite® with the aid of EtOH and then concentrated. Water and dichloromethane were added, the layers were again separated through a phase separator, and the organics were concentrated. Purification by column chromatography (12 g column; 0–10% MeOH in dichloromethane) gave (1R,3R)-5′-(4-fluoro-3-methylphenyl)-9′-hydroxy-3-methyl-4′,5′-dihydro-3′H-spiro[cyclobutane-1,1′-pyrano[4,3-b]indole]-3-carboxylic acid (1) (12.6 mg, 17%). 1 H NMR(400MHz, methanol-d4)δ 7.26-7.12(m,3H), 6.85(t,J=7.9Hz,1H), 6.57(dd,J=8.2,0.8Hz,1H), 6.43(dd,J=7.7,0.8Hz,1H), 3.89(t,J =5.4Hz,2H), 3.52-3.42(m,2H), 2.55(t,J=5.3Hz,2H), 2.33(d,J=2.0Hz,3H), 2.22-2.13(m,2H), 1.66(s,3H). LCMS m / z 396.21[M+H] + .

[0197] compound 2 (1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3-methyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (2) [ka] (1S,3S)-5'-(4-Fluoro-3-methylphenyl)-9'-hydroxy-3-methyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (2) was prepared from C53 (25.5 mg, 37%) according to standard procedure B. 1 H NMR(400MHz, methanol-d4)δ 7.24-7.12(m,3H), 6.91-6.84(m,1H), 6.58(dd,J=8.2,0.8Hz,1H), 6.46(dd,J=7.7,0.8Hz,1H), 3.85(t,J=5 .4Hz,2H), 3.13-3.03(m,2H), 2.77-2.69(m,2H), 2.54(t,J=5.4Hz,2H), 2.33(d,J=2.0Hz,3H), 1.57(s,3H). LCMS m / z 396.17[M+H] + .

[0198] Compound 3 and Compound 4 2-((1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (3) and 2-((1R,3R)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (4). [ka] Step 1: Synthesis of methyl 2-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetate (C54) A reaction vial was charged with 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-propan-1-ol S1 (90 mg, 0.223 mmol), 2-(3-oxocyclobutyl)methyl acetate (45 mg, 0.317 mmol), and dichloromethane (900 μL). To the mixture was added methanesulfonic acid (36 mg, 0.375 mmol) and EtSiH (6 μL, 0.0376 mmol). The mixture was stirred at room temperature for 30 minutes. Direct purification on a 12 g silica gel cartridge eluting with 0-50% EtOAc / heptane gave methyl 2-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetate (C54) (90 mg, 76%) as a mixture of cis and trans isomers. LCMS m / z 528.6 [M+H] + .

[0199] Step 2: Synthesis of 2-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (C55) To methyl 2-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetate (C54) (90 mg, 0.171 mmol) in MeOH (5 mL) was added NaOH (2 M, 1 mL, 2 mmol), and the mixture was stirred at 50° C. for 3 h, then neutralized with HCl to pH 3. The mixture was concentrated, then extracted with EtOAc, dried (NaSO), filtered, and concentrated. Purification by column chromatography (0-30% EtOAc / heptane) gave 2-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (C55) (45 mg, 39%). LCMS m / z 514.6 [M+H] + .

[0200] Step 3: Synthesis of 2-((1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (3) and 2-((1R,3R)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (4) A mixture of 2-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (C55) (45 mg, 0.0876 mmol) and Pd(OH) (20 mg, 0.142 mmol) in EtOAc (10 mL) and MeOH (1 mL) was stirred under a hydrogen balloon for 1 h. The reaction was filtered through a layer of Celite® and concentrated. Purification by reverse phase chromatography gave 2-((1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (3) (16.1 mg, 41%). 1 H NMR(400MHz,chloroform-d)δ 7.25-7.12(m,3H), 6.91(t,J=7.9Hz,1H), 6.46(d,J=7.5Hz,1H), 6.42-6.31(m,1H), 3.50(s,2H), 3.05(q,J=8.1H) z,1H), 2.91(s,3H), 2.76(d,J=7.6Hz,2H), 2.53(t,J=10.3Hz,3H), 2.35(d,J=2.0Hz,3H), 1.09(d,J=3.6Hz,6H). LCMS m / z 424.6[M+H] + .

[0201] Chromatography also afforded 2-((1R,3R)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)acetic acid (4) (7.8 mg, 20%). 1H NMR(400MHz,chloroform-d)δ 7.26-7.07(m,3H), 6.90(t,J=7.9Hz,1H), 6.46(d,J=7.6Hz,1H), 6.37(d,J=8.2Hz,1H), 3.47(s,2H) ), 3.28(s,2H), 2.87(s,3H), 2.34(d,J=1.9Hz,3H), 2.14(d,J=12.7Hz,2H), 1.07(d,J=3.5Hz,6H). LCMS m / z 424.6[M+H] +

[0202] Compound 5 and Compound 6 (1S,3S)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (5) and (1R,3R)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (6). [ka] Step 1. Synthesis of 9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (C48) To a mixture of 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-propan-1-ol S1 (110 mg, 0.272 mmol) and 1-methyl-3-oxo-cyclobutanecarboxylic acid (87 mg, 0.679 mmol) in DCE (500 μL) was added methanesulfonic acid (30 μL, 0.462 mmol) followed by triethylsilane (109 μL, 0.682 mmol) and the resulting deep red solution was stirred at 45 °C. After 2 hours, the reaction was directly purified by column chromatography (24 g gold column, 0-20% MeOH in dichloromethane) to give 9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (C56) (140 mg, 100%). LCMS m / z 514.28 [M+H] + .

[0203] Step 2. Synthesis of (1S,3S)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (5) and (1R,3R)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (6) To a solution of 9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (C56) (140 mg, 0.273 mmol) in dichloromethane (5 mL) at 0-5 °C, BBr3 (1 M in heptane, 730 μL, 0.73 mmol) was added over 10 min. Saturated aqueous NH4Cl was added at the same temperature for 20 min, and the cold bath was removed. The layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane, the layers were again separated through a phase separator, and the combined organics were concentrated. Purification by column chromatography (24 g gold column; 0–10% MeOH in dichloromethane) gave (1S,3S)-5′-(4-fluoro-3-methylphenyl)-9′-hydroxy-3,4′,4′-trimethyl-4′,5′-dihydro-3′H-spiro[cyclobutane-1,1′-pyrano[4,3-b]indole]-3-carboxylic acid 5 (11.5 mg, 9%). 1 H NMR(400MHz,DMSO-d6)δ 11.89(s,1H), 9.89(s,1H), 7.38-7.23(m,3H), 6.80(t,J=7.9Hz,1H), 6.46(dd,J=7.7,0.9Hz,1H), 6.10(dd,J=8.1,0.8H z,1H), 3.35(s,2H), 2.98-2.89(m,2H), 2.69-2.59(m,2H), 2.29(d,J=1.9Hz,3H), 1.49(s,3H), 0.97(s,3H), 0.96(s,3H). LCMS m / z 424.26[M+H] + .

[0204] Chromatography also afforded (1R,3R)-5′-(4-fluoro-3-methylphenyl)-9′-hydroxy-3,4′,4′-trimethyl-4′,5′-dihydro-3′H-spiro[cyclobutane-1,1′-pyrano[4,3-b]indole]-3-carboxylic acid 6 (18.3 mg, 14%). 1H NMR(400MHz,DMSO-d6)δ 11.69(br s,1H), 9.65(br s,1H), 7.41-7.24(m,3H), 6.77(t,J=7.9Hz,1H), 6.50-6.45(m,1H), 6.08(dd,J=8.2,0.8Hz,1H), 2 .55-2.45(m,2H), 2.29(d,J=1.9Hz,3H), 2.12-2.05(m,2H), 1.59(s,3H), 0.99(s,3H), 0.98(s,3H). LCMS m / z 424.26[M+H] + .

[0205] Compound 7 and Compound 8 2-((1S,3S)-5'-(4-Fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (7) and 2-((1R,3R)-5'-(4-Fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (8). [ka] Step 1. Synthesis of tert-butyl-2-(3-benzyloxycyclobutoxy)acetate (C58) To a solution of 3-benzyloxycyclobutanol (C57) (22 g, 123 mmol) in toluene (200 mL) at 0 °C was added potassium hydroxide (180 mL of 35 w / v%, 1.123 mol). The mixture was stirred at 0 °C for 30 minutes, followed by the addition of tert-butyl 2-bromoacetate (45 mL, 305 mmol) and tetrabutylammonium hydrogen sulfate (4.5 g, 13.3 mmol). The reaction was allowed to stir at room temperature for 16 hours. The layers were separated, the aqueous layer was extracted with ether, and the combined organic layers were dried and concentrated to give tert-butyl-2-(3-benzyloxycyclobutoxy)acetate (C58) (32.2 g, 89%).

[0206] Step 2. Synthesis of tert-butyl-2-(3-hydroxycyclobutoxy)acetate (C59) Pd / C (5 g) was added to tert-butyl 2-(3-benzyloxycyclobutoxy)acetate (C58) (32.1 g, 110 mmol) in MeOH (500 mL), and the mixture was exposed to a hydrogen atmosphere and stirred overnight. The reaction was filtered through Celite® and the filtrate was evaporated to dryness to give tert-butyl-2-(3-hydroxycyclobutoxy)acetate (C59) (22.2 g, 100%). 1 H NMR (400 MHz, chloroform-d) δ 3.91-3.79 (m, 1H), 3.83 (s, 2H), 3.67-3.56 (m, 1H), 2.67 (dtd, J = 9.5, 6.6, 3.0 Hz, 2H), 1.93 (dtd, J = 9.4, 7.6, 2.9 Hz, 2H), 1.43 (s, 9H).

[0207] Step 3. Synthesis of tert-butyl-2-(3-oxocyclobutoxy)acetate (C60) To a solution of tert-butyl-2-(3-hydroxycyclobutoxy)acetate (C59) (5 g, 24.7 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (15 g, 35.4 mmol) in five portions. Water (500 μL, 27.7 mmol) was added slowly over 10 min. The reaction was stirred at room temperature for 2 h, then diluted with ether and washed with 10% NaSO and saturated aqueous NaHCO (1:1), then brine. The organic layer was dried (NaSO), filtered, and evaporated to dryness. Purification by column chromatography (220 g, eluting with 0–100% ethyl acetate in heptane) gave tert-butyl-2-(3-oxocyclobutoxy)acetate (C60) (3.70 g, 75%). 1 H NMR (400 MHz, chloroform-d) δ 4.36 (tt, J = 6.5, 4.7 Hz, 1H), 3.91 (s, 2H), 3.23-3.03 (m, 4H), 1.40 (s, 9H).

[0208] Step 4. 2-((1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (C61) and 2-((1r,3r)-9'(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (C62) A flask was charged with 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-propan-1-ol (S1) (600 mg, 1.49 mmol), tert-butyl-2-(3-oxocyclobutoxy)acetate (C60) (500 mg, 2.50 mmol) in dichloromethane (4 mL). Methanesulfonic acid (120 μL, 1.85 mmol) and triethylsilane (50 μL, 0.313 mmol) were added, and the mixture was stirred for 2 hours. TFA (1 mL, 13.0 mmol) was added to the reaction, which was stirred for 10 minutes, and then the solvent was evaporated. Purification by column chromatography (80 g gold column, eluting with 0-100% ethyl acetate in heptane) gave 2-(((1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy acid (C61) (138 mg, 14%). LCMS m / z 530.44 [M+H] + .

[0209] Chromatography also afforded 2-(((1R,3R)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (C62) (185 mg, 20%). LCMS m / z 530.44 [M+H] + .

[0210] Step 5. Synthesis of 2-((1S,3S)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (7) The product 7 was prepared from 2-(((1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (C61) according to standard procedure B by replacing ammonium formate with hydrogen gas at room temperature and using EtOH and THF as solvents. (64.5 mg, 73%) 1 H NMR(400MHz, methanol-d4)δ 7.25-7.12(m,3H), 6.81(t,J=7.9Hz,1H), 6.42(d,J=7.6Hz,1H), 6.18(d,J=8.1Hz,1H), 4.47(dq,J=7.1,4.2,3.4H z,1H), 4.08(s,2H), 3.44(s,2H), 3.28-3.18(m,2H), 2.46-2.37(m,2H), 2.33(d,J=2.1Hz,3H), 1.08-1.03(m,6H). LCMS m / z 440.37[M+H] + .

[0211] Step 6. Synthesis of 2-((1R,3R)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (8) The product 8 was prepared from 2-(((1s,3s)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)acetic acid (C62) according to standard procedure B by replacing ammonium formate with hydrogen gas at room temperature and using EtOH and THF as solvents. (74.6 mg, 59%)1 H NMR(400MHz, methanol-d4)δ 7.21-7.05(m,3H), 6.76(t,J=7.9Hz,1H), 6.42(dd,J=7.6,0.9Hz,1H), 6.14(dd,J=8.3,0.9Hz,1H), 4.44(p,J=7.4Hz,1H), 4.09(s,2H), 3.37(s,2H), 3.29(s,1H), 3.27(dd,J=7.1,4.1Hz,1H), 2.55(ddd,J=9.4,6.9,3.0Hz,2H), 2.30(d,J=2.0Hz,3H), 1.01(d,J=3.1Hz,6H). LCMS m / z 440.37[M+H] + .

[0212] compound 9 (1R,4R)-4-Fluoro-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indole]-4-carboxylic acid (9) [ka] Step 1. Synthesis of ethyl 4,4-diethoxy-1-fluorocyclohexane-1-carboxylate (S64) LDA (2 M, 14 mL, 28 mmol) was added to a stirred solution of ethyl 4,4-diethoxycyclohexanecarboxylate C63 (3.2 g, 13.1 mmol) in THF (50 mL) at −10° C. The resulting brown solution was stirred at −10° C. for 30 min. The reaction was cooled to −78° C., and N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (6.4 g, 20.3 mmol) in THF (20 mL) was added. The resulting solution was allowed to warm gradually to room temperature over 2 h, quenched with saturated NH4Cl, extracted with ether, and washed with brine. The organic layer was dried over Na2SO4 and concentrated to give a semi-solid. Purification by column chromatography (Combiflash® ISCO Lumen with ELSD, 80 g gold column, eluting with 0-100% ethyl acetate in heptane) gave ethyl 4,4-diethoxy-1-fluoro-cyclohexanecarboxylate (S64) (1.75 g, 51%) as an oil. 1 H NMR(400MHz,chloroform-d)δ 4.23(q,J=7.1Hz,2H), 3.50(q,J=6.9Hz,2H), 3.42(q,J=7.1Hz,2H), 2.15-1.99(m,1H), 1 .99-1.90(m,5H), 1.83-1.65(m,2H), 1.29(t,J=7.1Hz,3H), 1.17(dt,J=7.9,7.1Hz,6H).

[0213] Step 2. Synthesis of ethyl (1R,4R)-9'-(benzyloxy)-4-fluoro-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indole]-4-carboxylate (C65) Prepared according to standard procedure A using intermediate S1 and ethyl 4,4-diethoxy-1-fluoro-cyclohexanecarboxylate (C64) instead of the ketone. The reaction was carried out in dichloromethane instead of DCE to give C65 (227 mg, 61%). LCMS m / z 574.2 [M+H] + .

[0214] Step 3. Synthesis of (1R,4R)-9'-(benzyloxy)-4-fluoro-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indole]-4-carboxylic acid (C66) To a solution of ethyl 9-benzyloxy-1′-fluoro-5-(4-fluoro-3-methyl-phenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,4′-cyclohexane]-1′-carboxylate (C65) (227 mg, 0.242 mmol) in MeOH (1.5 mL) and dichloromethane (2 mL), lithium hydroxide (110 mg, 2.62 mmol) was added and the mixture was stirred for 2 h at 25° C. The reaction was neutralized with HCl (2 M, 1.3 mL, 2.6 mmol), the layers were separated, the aqueous layer was extracted with dichloromethane, and the combined organics were concentrated. Purification by column chromatography (80 g gold column, eluting with 0–60% ethyl acetate in heptane) gave (1R,4R)-9′-(benzyloxy)-4-fluoro-5′-(4-fluoro-3-methylphenyl)-4′,4′-dimethyl-4′,5′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[4,3-b]indole]-4-carboxylic acid (C66) (120 mg, 91%). 1 H NMR (400 MHz, chloroform-d) δ 7.51-7.37 (m, 2H), 7.37-7.29 (m, 2H), 7.28 (t, J = 1.4 Hz, 1H), 7.21-7.06 (m, 3H), 6.86 (t, J = 8.1 Hz, 1H), 6.44 (dd, J = 7.9, 0.8 Hz, 1H), 6.35 (dd, J = 8.2, 0.7 Hz, 1H), 5.39(s,2H), 3.51(s,2H), 3.08(t,J=14.0Hz,2H), 2.45(dt,J=41.6,12.2 Hz,2H), 2.33(d,J=1.9Hz,3H), 1.94(t,J=12.4Hz,4H), 1.07(d,J=2.3Hz,6H).

[0215] Step 4. Synthesis of (1R,4R)-4-fluoro-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indole]-4-carboxylic acid (9) Prepared according to standard procedure B starting from C66 to give product 9 (68.5 mg, 65%). The reaction was carried out in EtOH and THF at 50 °C. 1 H NMR(400MHz,DMSO-d6)δ 13.07(s,1H), 9.77(s,1H), 7.47-7.15(m,3H), 6.78(t,J=7.9Hz,1H), 6.49-6.23(m,1H), 6.10(dd,J=8.2,0.9Hz,1H), 4.11(q,J=5. 3Hz,1H), 3,3.17(d,J=5.1Hz,2H), 2.94(t,J=13.5Hz,1H), 2.41-2.12(m,5H), 1.76(dd,J=33.4,13.4Hz,4H), 1.01(d,J=2.3Hz,6H). LCMS m / z 456.23[M+H] + .

[0216] compound 10 1-(5'-(4-Fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (21) [ka] Step 1. Synthesis of ethyl 3,5-dimethyl-1-(3-oxocyclobutyl)-1H-pyrazole-4-carboxylate (C68) To a solution of 3-bromocyclobutanone (300 mg, 2.014 mmol) in trichloro(deuterio)methane (10 mL), triethylamine (310 μL, 2.22 mmol) was added and the mixture was allowed to stir for 30 minutes. NMR showed conversion to cyclobutenone. Ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate C67 (340 mg, 2.02 mmol) was added and the mixture was stirred for 2 hours. The reaction was quenched with saturated NH4Cl, extracted with dichloromethane, and then concentrated to give the product C68 (416 mg, 87%). 1 H NMR(400MHz,chloroform-d)δ 4.92(tt,J=8.0,6.2Hz,1H), 4.46-4.05(m,2H), 3.99-3.63(m,2H), 3.61-3.28(m ,2H), 2.54(d,J=1.3Hz,3H), 2.40(d,J=1.4Hz,3H), 1.34(td,J=7.1,1.3Hz,3H).

[0217] Step 2. Synthesis of ethyl 1-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (C69) Standard procedure A was used starting from C68 but using dichloromethane instead of DCE. This gave the product (C69). LCMS m / z 622.48 [M+H] + .

[0218] Step 3. Synthesis of 1-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (C70) To a solution of ethyl 1-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (C69) (109 mg, 0.175 mmol) in MeOH (800 μL), THF (1 mL), and water (500 μL) was added lithium hydroxide hydrate (75 mg, 1.79 mmol), and the mixture was microwaved at 100° C. for 2 h. The mixture was evaporated, neutralized with HCl (2 M, 1 mL, 2 mmol), and extracted three times with dichloromethane. The organic layer was dried, concentrated, and purified using reverse-phase chromatography (TFA modifier, 15.5 g column) to afford 1-(9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (C70) (35 mg, 33%) as a mixture of isomers, which was taken on to the next step without further purification. LCMS m / z 594.49 [M+H] + .

[0219] Step 4. Synthesis of 1-(5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (10) Standard procedure B starting from C70 was used, which was modified by using MeOH and THF as solvents and also heating at 50° C. This gave product (10). 1H NMR (400 MHz, chloroform-d) δ 7.19-7.03(m,3H), 6.84(dt,J=16.0,7.9Hz,1H), 6.45(dd,J=29.1,7.6Hz,1 H), 6.23(t,J=8.8Hz,1H), 4.91(p,J=8.2Hz,1H), 3.78(tt,J=8.7,3.5Hz,2H ), 3.47(d,J=11.2Hz,2H), 2.84(ddd,J=13.1,6.9,3.1Hz,2H), 2.50(d,J=12 .5Hz,3H), 2.41(d,J=12.6Hz,3H), 2.29(d,J=1.9Hz,3H), 1.13-0.93(m,6H). LCMS m / z 504.43[M+H] + .

[0220] Compounds 11~19 Compounds 11-19 were prepared from S1 and the appropriate carbonyl reagent. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] a Standard procedure A was performed at 45°C. b The reaction was carried out according to standard procedure B but using formic acid in MeOH and THF at 50° C. instead of ammonium formate. c In the reduction step, the procedure was the same as for compound 13, but EtOH was replaced with MeOH. d Standard procedure A was modified by replacing DCE with dichloromethane. e Standard procedure B was modified by replacing ammonium formate with room temperature hydrogen. f Standard procedure A was modified by removing Et3SiH. g Standard procedure B was modified by using Pd(OH)2 instead of Pd / C and MeOH and EtOAc as solvents. h Standard procedure A was modified by replacing DCE with dichloromethane at 50° C. in a closed vessel.

[0221] Compound 20 and Compound 21 5"-(4-Fluoro-3-methylphenyl)-9"-hydroxy-4",4"-dimethyl-4",5"-dihydro-3"H-dispiro[cyclobutane-1,1'-cyclobutane-3',1"-pyrano[4,3-b]indole]-3-carboxylic acid (20) and enantiomer (21) [ka] 5"-(4-Fluoro-3-methylphenyl)-9"-hydroxy-4",4"-dimethyl-4",5"-dihydro-3"H-dispiro[cyclobutane-1,1'-cyclobutane-3',1"-pyrano[4,3-b]indole]-3-carboxylic acid (17) was separated by chiral SFC to give 5"-(4-fluoro-3-methylphenyl)-9"-hydroxy-4",4"-dimethyl-4",5"-dihydro-3"H-dispiro[cyclobutane-1,1'-cyclobutane-3',1"-pyrano[4,3-b]indole]-3-carboxylic acid (20). 1 H NMR(400MHz,chloroform-d)δ 7.16-6.99(m,3H), 6.81(dd,J=8.2,7.6Hz,1H), 6.34(dd,J=7.6,0.8Hz,1H), 6.28(dd,J=8.2,0.8Hz,1H), 3.3 7(s,2H), 3.17-2.96(m,2H), 2.59-2.46(m,2H), 2.46-2.33(m,3H), 2.31-2.20(m,4H), 0.98(t,J=4.3Hz,6H). LCMS m / z 450.6[M+H] + .

[0222] SFC separation also afforded 5″-(4-fluoro-3-methylphenyl)-9″-hydroxy-4″,4″-dimethyl-4″,5″-dihydro-3″H-dispiro[cyclobutane-1,1′-cyclobutane-3′,1″-pyrano[4,3-b]indole]-3-carboxylic acid ( 21 ). 1 H NMR(400MHz,chloroform-d)δ 7.16(p,J=7.3Hz,4H), 6.91(t,J=7.8Hz,1H), 6.41(dd,J=21.4,7.9Hz,2H), 5.07(s,1H), 3.46 (s,2H), 3.17(s,1H), 2.60(d,J=8.5Hz,2H), 2.49(d,J=9.4Hz,2H), 2.35(s,4H), 1.08(s,6H). LCMS m / z 450.6[M+H] + .

[0223] Compounds 22-29 Compounds 22-29 were prepared from S2 or S3 and the appropriate ketone or ketone equivalent. [Table 2-1] [Table 2-2] [Table 2-3] a Standard procedure A was modified by replacing DCE with dichloromethane at a temperature between room temperature and 50° C. in a sealed vessel. b Standard procedure B was modified by replacing ammonium formate with room temperature hydrogen and using MeOH and EtOAc as solvents. c Standard procedure A was modified by replacing DCE with dichloromethane. d Standard procedure B was modified by using BBr3 under dichloromethane conditions as described for synthesis compounds 5 and 6. e Standard procedure A was modified by removing Et3SiH. f Standard procedure B was modified by replacing ammonium formate with room temperature hydrogen and using EtOH as the solvent or EtOH and THF as co-solvents. g 1 mL of TFA was added upon completion of the reductive alkylation reaction and the mixture was stirred for 10 min.

[0224] compound 30 2-((1R,3R)-5'-(3,4-difluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)propanoic acid (30) [ka] Step 1. Synthesis of (1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl acetate (C71) and (1s,3s)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl acetate (C72) A vial was charged with 2-[4-benzyloxy-1-(3,4-difluorophenyl)indol-2-yl]-2-methyl-propan-1-ol (1.2 g, 2.95 mmol), (3-oxocyclobutyl)acetate (750 mg, 5.85 mmol), dichloromethane (5 mL), followed by the addition of triethylsilane (200 μL, 1.25 mmol) and methanesulfonic acid (300 μL, 4.62 mmol). After 4 h, the reaction was directly purified by column chromatography (120 g gold column, eluting with 0-100% ethyl acetate in heptane) to give product C71 (805 mg, 48%), LCMS m / z 518.51 [M+H]. + and product C72 (400 mg, 21%), LCMS m / z 518.47 [M+H] +obtained.

[0225] Step 2. Synthesis of (1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-ol (C73) NaOH (3 mL of 2 M, 6.000 mmol) was added to a mixture of (1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl acetate (C71) (800 mg, 1.30 mmol) in MeOH (10 mL) and THF (10 mL), and the reaction was stirred for 2 h at 60° C. It was then acidified with 0.1 N HCl and extracted with EtOAc (3×150 mL).

[0226] The combined organic fractions were washed with brine (1 × 50 mL), water (2 × 50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (120 g gold column, eluting with 0 to 100% ethyl acetate in heptane) afforded (1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-ol (C73) (700 mg, 98%). LCMS m / z 476.47 [M+H] + .

[0227] Step 3. Synthesis of ethyl 2-(((1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)propanoate (C74) Ethyl 2-diazopropanoate (75 mg, 0.585 mmol) was added dropwise over 10 min to a mixture of 9-benzyloxy-5-(3,4-difluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutan]-1'-ol C73 (100 mg, 0.210 mmol) and diacetoxyrhodium (10 mg, 0.0453 mmol) in dichloromethane (2 mL). Another batch of diacetoxyrhodium (10 mg, 0.0453 mmol) was added, followed by the dropwise addition of ethyl 2-diazopropanoate (75 mg, 0.585 mmol) over 10 min. After an additional 10 minutes, the reaction was directly purified by column chromatography (40 g gold column, eluting with 0-100% ethyl acetate in heptane) to give ethyl 2-(((1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)propanoate (C74) (90 mg, 61%). LCMS m / z 576.53 [M+H] + .

[0228] Step 4. Synthesis of 2-(((1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)propanoic acid (C75) NaOH (750 μL of 2 M, 1.5 mmol) was added to 2-(((1R,3R)-9′-(benzyloxy)-5′-(3,4-difluorophenyl)-4′,4′-dimethyl-4′,5′-dihydro-3′H-spiro[cyclobutane-1,1′-pyrano[4,3-b]indol]-3-yl)oxy)propanoate (C74) (90 mg, 0.142 mmol) in MeOH (3 mL) and THF (2 mL). After 1 h at 60° C., the reaction was cooled to room temperature, DMSO (2 mL) and TFA (200 μL, 2.60 mmol) were added, and most of the solvent was evaporated. Purification by reverse-phase chromatography (50 g column, elution with 10-100% ACN in water with 0.1% TFA) gave 2-(((1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)propanoic acid (C75) (85 mg, 105%). LCMS m / z 548.54 [M+H] + .

[0229] Step 5. Synthesis of 2-((1R,3R)-5'-(3,4-difluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)propanoic acid (30) A reaction vessel was charged with 2-(((1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)propanoic acid (C75) (80 mg, 0.14 mmol) and EtOH (5 mL), and Pd / C (50 mg, 0.04698 mmol) was added. The flask was evacuated, and then hydrogen was introduced via a balloon. After 2 h, the reaction was filtered through Celite® and concentrated. Purification by reverse-phase chromatography (50 g column, eluting with 10–100% ACN in water with 0.1% FA) gave product 30 (50.1 mg, 76%). 1H NMR(400MHz,chloroform-d)δ 7.46-7.08(m,3H), 6.94(t,J=7.9Hz,1H), 6.59(d,J=7.7Hz,1H), 6.33(d,J=8.2Hz,1H), 4.64(t,J=7.3Hz,1H),4. 20(q,J=6.9Hz,1H), 3.62-3.27(m,4H), 2.73(q,J=9.9,9.2Hz,2H), 1.57(d,J=6.9Hz,3H), 1.09(t,J=4.3Hz,6H). LCMS m / z 458.42[M+H] + .

[0230] compound 31 2-(((1S,3S)-5'-(3,4-difluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)oxy)propanoic acid (31) [ka] This was prepared in the same manner as 30 but using intermediate C72 instead of C71 in step 2.

[0231] 1 H NMR(400MHz, methanol-d4)δ 7.44(dt,J=10.5,8.8Hz,1H), 7.35(ddd,J=10.3,7.1,2.5Hz,1H), 7.18(ddt,J=8.5,4.0,2.0 Hz,1H), 6.83(t,J=7.9Hz,1H), 6.42(d,J=7.6Hz,1H), 6.19(d,J=8.2Hz,1H), 4.46(ddt,J=10. 0,6.9,2.9Hz,1H), 4.03(q,J=6.8Hz,1H), 3.43(s,2H), 3.26-3.11(m,2H), 2.43(dt,J=14.6,2 .8Hz,1H), 2.34(dt,J=12.9,2.7Hz,1H), 1.43(d,J=6.9Hz,3H), 1.06(dd,J=11.7,8.3Hz,6H). LCMS m / z 458.38[M+H] + .

[0232] Compounds 32~63 Compounds 32-63 were prepared from S4 and the appropriate ketone or ketone equivalent. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] a Standard procedure A was modified by replacing DCE with dichloromethane at 50° C. in a closed vessel. b Standard procedure B was modified by replacing ammonium formate with room temperature hydrogen and using MeOH and EtOAc as solvents. c Standard procedure A was modified by replacing DCE with dichloromethane. d Standard procedure B was modified by using EtOH and THF as solvents. e Standard procedure B was modified by using BBr3 under dichloromethane conditions as described for synthesis compounds 5 and 6. f Standard procedure B was modified by replacing ammonium formate with room temperature hydrogen and using EtOH as the solvent. g Standard procedure B was modified by replacing ammonium formate with hydrogen, replacing Pd / C with Pd(OH)2, and using MeOH and EtOAc as solvents. h Standard procedure A was modified by removing Et3SiH. i Prior to the debenzylation step, the ester was hydrolyzed using the same procedure as described for the synthesis of compound C55, with the following modifications: THF and MeOH as solvent, 6 M NaOH, 50° C. for 1 hour. j Prior to the debenzylation step, the ester was hydrolyzed using the same procedure as described for the synthesis of compound C55, with the following modifications: THF and MeOH as solvent, 1 M NaOH, 50° C. for 1 hour. k Standard procedure B was modified by replacing ammonium formate with hydrogen l Prior to the debenzylation step, the ester was hydrolyzed using the same procedure as described for the synthesis of compound C55, with the following modifications: dichloromethane and MeOH as solvent, LiOH as base, at room temperature for 2 hours. m Standard procedure B was modified by replacing ammonium formate with hydrogen, replacing Pd / C with Pd(OH)2, and using MeOH and THF as solvents. n 1 mL of TFA was added upon completion of the reductive alkylation reaction and the mixture was stirred for 10 min.

[0233] compound 64 2-(5'-(3,4-Difluorophenyl)-7'fluoro-9'-hydroxy-4',4'-dimethyl-2-oxo-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)acetic acid (64) [ka] Step 1: Synthesis of methyl 2(9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)acetate (C76) This reaction was carried out following standard procedure A from S5 using methyl 2-(4-oxo-1-piperidyl)acetate as the ketone building block to afford C76 (120 mg, 44%). Dichloromethane was used as the solvent instead of DCE. 1 H NMR(400MHz,chloroform-d)δ 7.67-7.58(m,2H), 7.47-7.29(m,4H), 7.22-7.10(m,2H), 6.42(dd,J=11.7,2.1Hz,1H), 6.07(dd,J=9.1,2.1Hz,1H), 5.36(s,2H), 3.7 3(s,3H), 3.50(s,2H), 3.25(s,2H), 3.02-2.82(m,2H), 2.73(pd,J=10.1,9.1,3.5Hz,4H), 1.77(dq,J=13.7,2.6Hz,2H), 1.08(s,6H).

[0234] Step 2: Synthesis of methyl 2-(9'-(benzyloxy)-5'-(3,4-difluorophenyl)-7'-fluoro-4',4'-dimethyl-2-oxo-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)acetate (C77) To a mixture of 2-(9'-(benzyloxy)-5'-(3,4-difluorophenyl)-7'-fluoro-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)methyl acetate (C76) (120 mg, 0.207 mmol) and sodium bicarbonate (2 mL of 1 M, 2 mmol) in THF (6 mL) was added molecular iodine (395 mg, 1.56 mmol). The reaction mixture was stirred for 40 min and then quenched with saturated NaHCO3, sodium thiosulfate (10 mL). Purification by column chromatography (12 g column; 10–50% EtOAc in heptane) gave C77 (75 mg, 58%). 1 H NMR(400MHz,chloroform-d)δ 7.56-7.34(m,6H), 7.28-7.11(m,2H), 6.47(dd,J=11.3,2.1Hz,1H), 6.13(ddd, J=9.1,2.1,1.0Hz,1H), 5.25-4.98(m,2H), 4.39(d,J=17.1Hz,1H), 3.72-3.83(m 4H), 3.59-3.36(m,4H), 2.97-2.67(m,3H), 1.94(ddt,J=11.2,5.0,3.1Hz,1H), 1.14-1.01(m,6H). LCMS m / z 593.27[M+H] + .

[0235] Step 3: Synthesis of 2-(9'-(benzyloxy)-5'-(3,4-difluorophenyl)-7'fluoro-4',4'-dimethyl-2-oxo-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)acetic acid (C78) To a solution of methyl 2-[9-benzyloxy-5-(3,4-difluorophenyl)-7'-fluoro-4,4-dimethyl-2'-oxo-spiro[3H-pyrano[4,3-b]indole-1,4'-piperidin]-1'-yl]acetate C77 (65.0 mg, 0.110 mmol) in MeOH (0.5 mL), THF (1 mL), and water (0.5 mL) was added LiOH (50 mg, 1.19 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction was neutralized with aqueous HCl (630 μL of a 2 M solution, 1.26 mmol), extracted with dichloromethane, and the organics were concentrated. Purification by column chromatography (12 g gold column; 0–60% EtOAc in heptane) gave C78 (63.5 mg, 51%). LCMS m / z 579.23[M+H] + .

[0236] Step 4: Synthesis of 2-(5'-(3,4-difluorophenyl)-9'-hydroxy-4',4'-dimethyl-2-oxo-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)acetic acid (64) The reaction was carried out following standard procedure B from C78 using EtOH and THF as solvents to give product 64 (3.8 mg, 14%). 1 H NMR (400 MHz, methanol-d4) δ 7.26-7.21 (m, 1H), 7.16 (dddd, J = 9.8, 7.2, 5.1, 2.5 Hz, 1H), 7.12-7.04 (m, 1H), 6.22 (dd, J = 11.0, 2.2 Hz, 1H), 5.90 (dd, J = 9.4, 2.2 Hz, 1H), 4.36 (d, J = 17.4 Hz, 1H), 3.83 (d ,J=17.3Hz,1H), 3.76-3.61(m,2H), 3.42(t,J=2.2Hz,2H), 3.28-3.22(m,1H), 3.21-3 .02(m,1H), 2.73-2.53(m,1H), 2.00(d,J=14.0Hz,1H), 0.98(dd,J=15.8,2.0Hz,6H). LCMS m / z 489.16[M+H] + .

[0237] Compound 65~82 Compounds 65-82 were prepared from S5 and the appropriate ketone or ketone equivalent. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] a Standard procedure A was modified by replacing DCE with dichloromethane. b Standard procedure A was modified by removing Et3SiH. c Standard procedure B was modified by using EtOH and THF as solvents and heating somewhere in the range of 40-60°C. d Standard procedure B was modified by replacing ammonium formate with room temperature hydrogen and using MeOH and EtOAc as solvents. e Standard procedure B was modified by replacing ammonium formate with room temperature hydrogen and using MeOH as the solvent. f Prior to the debenzylation step, the ester was hydrolyzed using the same procedure as described for the synthesis of compound C47, with the following modifications: THF as solvent, 1 M LiOH, room temperature for 1 hour. g Standard procedure B was modified by replacing ammonium formate with room temperature hydrogen and using EtOH and THF as solvents. hPrior to the debenzylation step, the ester was hydrolyzed using the same procedure as described for the synthesis of compound C47, with the following modifications: dichloromethane and MeOH as solvent, LiOH as base, at room temperature for 2 hours. i Standard procedure A was modified by replacing DCE with dichloromethane and heating the reaction in a closed vessel at 55°C. j 1 mL of TFA was added upon completion of the reductive alkylation reaction and the mixture was stirred for 10 min.

[0238] compound 83 5-(4-Fluorophenyl)-9-hydroxy-1'-imino-4,4-dimethyl-2',3',4,5,5',6'-hexahydro-1'H,3H-1'λ6-spiro[pyrano[4,3-b]indole-1,4'-thiopyran] 1'-oxide (83) [ka] Step 1: Synthesis of 9-(benzyloxy)-5-(4-fluorophenyl)-4,4-dimethyl-2',3',4,5,5',6'-hexahydro-3H-spiro[pyrano[4,3-b]indole-1,4'-thiopyran] (C79) The reaction was carried out according to standard procedure A. Dichloromethane was used as the solvent to give the product C79 (428 mg, 82%). LCMS m / z 444.24 [M+H] + .

[0239] Step 2: Synthesis of 9-(benzyloxy)-5-(4-fluorophenyl)-1'-imino-4,4-dimethyl-2',3',4,5,5',6'-hexahydro-1'H,3H-1'λ6-spiro[pyrano[4,3-b]indole-1,4'-thiopyran]1'-oxide (C80) To a solution of C79 (150 mg, 0.308 mmol) in dichloromethane (3 mL), (diacetoxyiodo)-benzene (218 mg, 0.677 mmol) and ammonium carbamate (84 mg, 1.08 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted twice with dichloromethane, and the phases were separated using a phase separator. The organics were concentrated. Purification was achieved by column chromatography (C18 50 g column; aqueous TFA / MeCN). The pure fractions were concentrated in vacuo, diluted with dichloromethane, and neutralized with aqueous NaHCO3. The organic phase was passed through a phase separator, and the resulting filtrate was concentrated in vacuo to give the product C80 (220 mg, 47%). 1 H NMR (400 MHz, DMSO-d6) δ 7.60-7.52(m,2H), 7.51-7.44(m,2H), 7.42(d,J=8.7Hz,2H), 7.39-7.32( m,2H), 7.30-7.22(m,1H), 6.88-6.81(m,1H), 6.52(d,J=7.9Hz,1H), 6.20( d,J=8.2Hz,1H), 5.42(s,2H), 3.54(d,J=4.2Hz,2H), 3.50-3.38(m,2H), 3 .32-3.22(m,2H), 3.07-2.93(m,2H), 2.13(d,J=13.7Hz,2H), 1.01(s,6H). LCMS m / z 519.37[M+H] + .

[0240] Step 3: Synthesis of 5-(4-fluorophenyl)-9-hydroxy-1'-imino-4,4-dimethyl-2',3',4,5,5',6'-hexahydro-1'H,3H-1'λ6-spiro[pyrano[4,3-b]indole-1,4'-thiopyran]1'-oxide (83) The reaction was carried out from C80 according to standard procedure B with the following modifications: Pd(OH)2 was used as a catalyst, which gave product 83 (46 mg, 25%). 1H NMR(400MHz,DMSO-d6)δ 10.05(s,1H), 7.52-7.35(m,4H), 6.80(dd,J=8.6,7.3Hz,1H), 6.42(dd,J=7.7,0.9Hz,1H), 6.09(dt,J=8.3,1.3 Hz,1H), 3.52(d,J=4.2Hz,2H), 3.43-3.22(m,4H), 2.89(d,J=12.7Hz,2H), 2.05(d,J=13.1Hz,2H), 1.01(s,6H). LCMS m / z 429.3[M+H] + .

[0241] compound 84 2-(((1S,4S)-5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indol]-4-yl)oxy)acetic acid (84) [ka] Step 1. (1S,4S)-9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indol]-4-ol (C81) and (1r,4r)-9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indol]-4-ol (C82) The reaction was carried out according to standard procedure A. Dichloromethane was used as the solvent to give the cis product C81 (860 mg, 41%), LCMS m / z 485.43 [M+H] + and trans product C82 (920 mg, 47%), LCMS m / z 485.48 [M+H] + obtained.

[0242] Step 2. Synthesis of 2-(((1S,4S)-9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indol]-4-yl)oxy)ethyl acetate (C83) To a mixture of C81 (200 mg, 0.370 mmol) and diacetoxyrhodium (25 mg, 0.113 mmol) in dichloromethane (5 mL), ethyl 2-diazoacetate (13 w / v%, 350 μL, 0.399 mmol) was added dropwise over 10 min, and the reaction was stirred for 2 h. Purification by column chromatography (40 g gold column; elution with 0-100% ethyl acetate in heptane) gave product C83 (140 mg, 59%). LCMS m / z 572.38 [M+H] + .

[0243] Step 3. Synthesis of 2-(((1S,4S)-9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indol]-4-yl)oxy)acetic acid (C84) NaOH (2 M, 1 mL, 2 mmol) was added to a solution of C83 (140 mg, 0.217 mmol) in MeOH (3 mL) and THF (2 mL). The reaction was stirred at room temperature for 1 h. DMSO (2 mL) and TFA (250 μL, 3.25 mmol) were added, and the mixture was partially concentrated. Purification by reverse-phase chromatography (50 g, C18 column, eluting with 10-100% ACN in water with 0.1% TFA) gave product C84 (105 mg, 81%). LCMS m / z 543.36 [M+H] + .

[0244] Step 4. Synthesis of 2-(((1S,4S)-5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indol]-4-yl)oxy)acetic acid (84) This reaction was carried out from C84 according to standard procedure B with the following modifications: EtOH and THF were used as solvents and hydrogen was used instead of ammonium formate to give product 84 (39 mg, 48%). 1 H NMR(400MHz, methanol-d4)δ 7.39-7.30(m,2H), 7.26(t,J=8.6Hz,2H), 6.79(t,J=7.9Hz,1H), 6.39(d,J=7.6Hz,1H), 6.14(d,J=8.1Hz,1H), 4.16(s,2H), 3.62(tt,J=11. 4,4.0Hz,1H), 3.48(s,2H), 2.80(td,J=14.2,13.7,4.3Hz,2H), 1.96-1.84(m,4H), 1.79(dd,J=11.8,3.8Hz,1H), 1.74(s,1H), 1.04(s,6H). LCMS m / z 454.22[M+H] + .

[0245] compound 85 4-(5'-(4-Fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane 1,1'pyrano[4,3-b]indol]-3-yl)benzoic acid (85) [ka] Step 1: Synthesis of 9-benzyloxy-3'-bromo-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,1'-cyclobutane]C85 To a mixture of 2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-propan-1-ol S6 (100.0 mg, 0.257 mmol) and 3-bromocyclobutanone (80.0 mg, 0.537 mmol) in dichloromethane (1.5 mL), methanesulfonic acid (35 μL, 0.54 mmol) was added, followed by triethylsilane (89 μL, 0.557 mmol), and the resulting dark solution was stirred at room temperature for 16 hours. This was quenched with saturated aqueous NaHCO3, extracted with dichloromethane, filtered through a phase separator, and concentrated to give the product C85 as a mixture of isomers (60.0 mg, 41%). LCMS m / z 519.94 [M+H] + .

[0246] Step 2: Synthesis of ethyl 4-(9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indol]-3-yl)benzoate (C86) A vial was charged with the photocatalytic acid Ir[dF(CF)ppy](dtbbpy)PF (4.0 mg, 0.00357 mmol), 9-benzyloxy-3'-bromo-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,1'-cyclobutane] (175 mg, 0.336 mmol), ethyl 4-bromobenzoate (80 mg, 0.349 mmol), bis(trimethylsilyl)silyl-trimethyl-silane (112 μL, 0.363 mmol), and toluene (960 μL) and 1,4-dioxane (4 mL). To the above mixture, 2,6-lutidine (195 mg, 1.82 mmol) and 100 μl of NiCl2.dtbppy (prepared using nickel dichloride; 1,2-dimethoxyethane (0.4 mg, 1.820 μmol), and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.5 mg, 1.86 mmol) were added. The mixture was sparged with nitrogen for 10 minutes and irradiated in a photoreactor for 16 hours. The reaction was quenched with water and extracted with dichloromethane (3 × 20 mL). The organic layer was dried, concentrated, and purified using column chromatography to give the product C86 (63.7 mg, 31%). 1 H NMR(400MHz,chloroform-d)δ 7.77-7.69(m,2H), 7.43-7.33(m,2H), 7.31-7.20(m,3H), 7.20-7.14(m,2H), 7.11(d,J= 8.3Hz,2H), 7.07-6.97(m,2H), 6.83(t,J=8.0Hz,1H), 6.53(dd,J=7.9,0.8Hz,1H), 6.23 (dd,J=8.3,0.7Hz,1H), 5.11(s,2H), 4.17(q,J=7.1Hz,2H), 3.28(s,2H), 3.24-3.10(m, 2H), 2.64(tt,J=9.7,4.5Hz,1H), 2.31-2.01(m,2H), 1.20(t,J=7.1Hz,3H), 0.88(s,6H).

[0247] Step 3: Synthesis of 4-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutan]-1'-yl]benzoic acid (C87) To a solution of C86 (70 mg, 0.118 mmol) in MeOH (0.7 mL), THF (0.3 mL), and water (200 μL) was added LiOH monohydrate (50 mg, 1.19 mmol), and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo, neutralized with HCl (0.6 mL of 2 M, 1.19 mmol), and back-extracted with dichloromethane (3 × 10 mL). The organic layer was dried (NaSO) and concentrated to give 4-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutan]-1'-yl]benzoic acid C87 (50.0 mg, 72%). LCMS m / z 561.82 [M+H] + .

[0248] Step 4: Synthesis of 4-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutan]-1'-yl]benzoic acid (85) To a solution of 4-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutan]-1'-yl]benzoic acid C87 in EtOH (1 mL) and THF (0.3 mL) was added 10% Pd / C (20 mg, Degussa wet) and NHClOH (50.0 mg, 0.79 mmol). The mixture was heated at 50 °C for 1 h. The reaction mixture was filtered and concentrated to give 15.5 g of HP Purification using a C18 column (formic acid modifier) ​​gave ethyl 4-(9′-(benzyloxy)-5′-(4-fluorophenyl)-4′,4′-dimethyl-4′,5′-dihydro-3′H-spiro[cyclobutane-1,1′-pyrano[4,3-b]indol]-3-yl)benzoate 85 (30 mg, 70%). 1H NMR(400MHz, methanol-d4)δ 8.01(d,J=8.0Hz,2H), 7.64(d,J=8.1Hz,2H), 7.37(dd,J=8.7,5.0Hz,2H), 7.22(t,J=8.4Hz,2H), 6.92(t,J=7.9Hz,1H), 6.5 6(d,J=7.6Hz,1H), 6.29(d,J=8.2Hz,1H), 3.92(dt,J=10.1,5.2Hz,1H), 3.64-3.50(m,4H), 2.72-2.46(m,2H), 1.08(s,6H). LCMS m / z 472.07[M+H] +

[0249] compound 86 2-(5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)oxazole-4-carboxylic acid (86) [ka] Step 1: Synthesis of 9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indole] (C88) To a mixture of 2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-propan-1-ol S6 (600.0 mg, 1.541 mmol) and piperidin-4-one hydrochloride (272 mg, 2.02 mmol) in dichloromethane (9 mL), methanesulfonic acid (210 μL, 3.24 mmol) was added, and the resulting dark solution was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous NaHCO3, extracted with dichloromethane (3 × 30 mL), filtered through a phase separator, and concentrated to give product C88 (740 mg, 91%). LCMS m / z 471.21 [M+H]+.

[0250] Step 2: Synthesis of 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,4'-piperidin]-1'-yl]oxazole-4-carboxylate (C89) To a solution of 9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,4'-piperidine C88 (240 mg, 0.510 mmol) in DMSO (4 mL) was added methyl 2-chlorooxazole-4-carboxylate (105 mg, 0.650 mmol) and N-ethyl-N-isopropyl-propan-2-amine (140 μL, 0.804 mmol). The mixture was microwaved at 120° C. for 30 minutes and then diluted with dichloromethane (20 mL). It was washed with brine, the layers were separated through a phase separator, and the organics were concentrated to give crude product C89 (300 mg, 83%) as a dark solid. LCMS m / z 596.11 [M+H] + .

[0251] Step 3: Synthesis of 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,4'-piperidin]-1'-yl]oxazole-4-carboxylic acid (C90) To a solution of methyl 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,4'-piperidin]-1'-yl]oxazole-4-carboxylate C89 (270.0 mg, 0.382 mmol) in MeOH (2 mL), THF (3 mL), and water (600 μL) was added lithium hydroxide hydrate (163 mg, 3.84 mmol), and the mixture was heated in a microwave at 100° C. for 3 hours. The mixture was evaporated, neutralized with HCl (1.9 mL of 2 M, 3.8 mmol), and back-extracted with dichloromethane (3×20 ml). The dichloromethane layer was dried and concentrated to give 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,4'-piperidin]-1'-yl]oxazole-4-carboxylic acid C90 (30 mg, 13%). LCMS m / z 582.07 [M+H]

[0252] Step 4: Synthesis of 2-(5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)oxazole-4-carboxylic acid (86) To a solution of 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indole-1,4'-piperidin]-1'-yl]oxazole-4-carboxylic acid C90 (30 mg, 0.0516 mmol) in dichloromethane (6 mL) at 0 °C, 1,2,3,4,5-pentamethylbenzene (152 mg, 1.03 mmol) and trichloroborane (1.5 mL of 1 M, 1.5 mmol) were added, and the mixture was stirred at 0 °C for 10 min. The reaction was quenched with saturated NaHCO3, diluted with dichloromethane, and the layers were separated through a phase separator. The organic layer was concentrated and purified by reverse-phase chromatography (acetonitrile, formic acid modifier) ​​to give product 86 (6.1 mg, 23%). 1H NMR(400MHz, methanol-d4)δ 7.82(s,1H), 7.42-7.29(m,2H), 7.29-7.14(m,2H), 6.86(t,J=7.9Hz,1H), 6.53-6.31(m,1H), 6.26(dd,J=8.2,0.8Hz,1 H), 4.00(dd,J=13.1,4.7Hz,2H), 3.61-3.42(m,4H), 3.06(td,J=13.5,4.9Hz,2H), 1.87(d,J=13.7Hz,2H), 1.08(s,6H). LCMS m / z 492.09[M+H]+

[0253] compound 87 2-(5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidine-4,1'-pyrano[4,3-b]indol]-1-yl)oxazole-5-carboxylic acid (87) [ka] Compound 87 was synthesized in the same manner as 86 using ethyl 2-bromooxazole-5-carboxylate in step 2. 1 H NMR(400MHz,DMSO-d6)δ 9.69(s,1H), 7.56(s,1H), 7.55-7.36(m,4H), 6.88-6.68(m,1H), 6.40(d,J=7.6Hz,1H), 6.11(d,J=8.2Hz,1H ), 4.10-3.78(m,2H), 2.88(dt,J=13.9,7.0Hz,2H), 2.56-2.47(m,4H), 1.81(d,J=13.6Hz,2H), 1.01(s,6H). LCMS m / z 492.13[M+H] +

[0254] Compounds 88~177 Compounds 88-177 were prepared from S6 and the appropriate ketone or ketone equivalent. [Table 5-1] [Table 5-2]

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

Table 5-14

Table 5-15

Table 5-16

Table 5-17

Table 5-18

Table 5-19

[0255] compound 178 (1S,3S)-5'-(4-Fluorophenyl)-9'-hydroxy-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxamide (178) [ka] A flask was charged with (1S,3S)-5'-(4-fluorophenyl)-9'-hydroxy-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid 111 (96 mg, 0.235 mmol) and CDI (130 mg, 0.802 mmol), followed by THF (2 mL), and the mixture was stirred at room temperature. After 4 h, ammonium hydroxide (500 μL of 28 w / v%, 4.0 mmol) was added at room temperature. After 40 min, brine and EtOAc were added, and the layers were separated. The combined organics were dried (NaSO), filtered, and concentrated. Ether was added, the mixture was sonicated, and the white solid was filtered. Further purification was performed by column chromatography (C18 AQ 40 g column; aqueous TFA / MeCN). The pure fractions were partially concentrated, water was added, and the mixture was extracted with EtOAc. The layers were separated. The aqueous layer was re-extracted with EtOAc, and the combined organics were concentrated. EtOAc was added, and the product 178 was filtered (27.9 mg, 28%). 1 H NMR(400MHz,DMSO-d6)δ 9.87(s,1H), 7.50-7.36(m,4H), 7.13(s,1H), 6.84-6.77(m,1H), 6.64(s,1H), 6.47(dd,J=7.7,0.9Hz,1H), 6.08(dd,J=8.2,0.8Hz,1H), 3.29(s,2H), 2.93-2.83(m,2H), 2.69-2.60(m,2H), 1.46(s,3H), 0.96(s,6H). LCMS m / z 409.13[M+H] + .

[0256] Compound 179 (1S,3S)-8'-chloro-5'-(4-fluorophenyl)-9'-hydroxy-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (179) [ka] To (1S,3S)-5'-(4-fluorophenyl)-9'-hydroxy-3,4',4'-trimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid 116 (48 mg, 0.117 mmol) in a 2-dram vial was added NaOH (1.5 mL of 1 M, 1.5 mmol), which dissolved the solid. Within 1 min, sodium hypochlorite (300 μL of 5 w / v%, 0.202 mmol) was added, and the reaction immediately turned tan. After 10 min, water (3 mL) was added, followed by HCl (3 mL of a 1 M solution, 3 mmol), and the mixture was extracted three times with dichloromethane. The layers were separated using a phase separator, and the combined organics were concentrated. Purification was achieved by column chromatography (C18 50 g column; aq. TFA / MeCN). The pure fractions were partially concentrated, and the mixture was extracted with dichloromethane. The layers were separated using a phase separator cartridge. The aqueous layer was re-extracted with dichloromethane, and the combined organics were concentrated. Trituration with EtOAc gave a white solid, which was dried on a frit. 8-Chloro-5-(4-fluorophenyl)-9-hydroxy-1',4,4-trimethyl-spiro[3H-pyrano[4,3-b]indole-1,3'-cyclobutane]-1'-carboxylic acid (179) (2.2 mg, 4%). 1 H NMR(400MHz,DMSO-d6)δ 11.90(s,1H), 9.62(s,1H), 7.53-7.46(m,2H), 7.45-7.37(m,2H), 6.98(d,J=8.7Hz,1H), 6.16(d, J=8.7Hz,1H), 3.32(s,2H), 2.92(d,J=11.4Hz,2H), 2.69-2.60(m,2H), 1.51(s,3H), 0.96(s,6H). LCMS m / z 444.24[M+H] + X-ray crystallography confirmed ortho-chlorination.

[0257] Compound 180~185 Compounds 180-185 were prepared from S7 and the appropriate ketone. [Table 6-1] [Table 6-2] a Standard procedure A was modified by replacing DCE with dichloromethane. b Standard procedure A was modified by removing Et3SiH. c Standard procedure B was modified by using EtOH and THF as solvents and heating at temperatures ranging from 50 to 55°C.

[0258] Compounds 186~189 Compounds 186-189 were prepared from S8 and the appropriate ketone. [Table 7] a Standard procedure A was modified by removing Et3SiH and heating at 45°C. i Standard procedure B was modified by using BBr3 under dichloromethane conditions as described for synthesis compounds 7 and 8.

[0259] Compound 190 and Compound 191 Compounds 190-191 were prepared from S9 and the appropriate ketone. [Table 8] a Standard procedure A was carried out at 50°C. b The product from standard procedure A was hydrolyzed using the same procedure as described for the synthesis of compound C47, with the following modifications: dioxane as solvent, 1M aqueous LiOH as base, 160° C. in a microwave.

[0260] compound 192 4-(9-(4-Fluorophenyl)-5-hydroxy-1,1,4-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-4-yl)benzoic acid 192 [ka] Standard synthetic sequence A Step 1: Synthesis of methyl 4-(5-(benzyloxy)-9-(4-fluorophenyl)-1,1,4-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-4-yl)benzoate (C91) To a solution of 4-benzyloxy-1-(4-fluorophenyl)indole S10 (700 mg, 2.21 mmol) and bismuth(III) trifluoromethanesulfonate (81 mg, 0.131 mmol) in dichloromethane (14 mL) at −10° C. was added a solution of methyl 4-(2-methyloxiran-2-yl)benzoate (661 mg, 3.44 mmol) dropwise. The reaction was allowed to stir at −10° C. for 30 min. LC / MS indicated the presence of the desired epoxide-released product. Quenching with saturated aqueous NaHCO, extracting with dichloromethane, concentrating, and flashing through an ISCO (40 g gold column) gave crude methyl 4-[1-[4-benzyloxy-1-(4-fluorophenyl)indol-3-yl]-2-hydroxy-1-methyl-ethyl]benzoate (305 mg, 17%). LCMS m / z 510.08(M+H) + To a solution of methyl 4-[1-[4-benzyloxy-1-(4-fluorophenyl)indol-3-yl]-2-hydroxy-1-methyl-ethyl]benzoate (300 mg, 0.3648 mmol) in dichloromethane (3 mL) was added 2,2-dimethoxypropane (300.0 μL, 2.440 mmol) and methanesulfonic acid (30.0 μL, 0.4623 mmol). The mixture was stirred at 25° C. for 16 hours. The mixture was quenched with saturated aqueous NaHCO3, extracted with dichloromethane, concentrated, and purified using an ISCO (24 g gold column; 0–60% ethyl acetate in heptane) to give methyl 4-[5-benzyloxy-9-(4-fluorophenyl)-1,1,4-trimethyl-3H-pyrano[3,4-b]indol-4-yl]benzoate (C91) (174 mg, 73%). 1H NMR(400MHz,chloroform-d)δ 7.79-7.54(m,2H), 7.36-7.25(m,2H), 7.20-7.02(m,8H), 6.87(t,J=8.0Hz,1H), 6.84-6.69(m,2H), 6.48-6.13(m,2H), 4.72(d,J=11.8Hz,1H), 4.46(d,J=11.7Hz,1H), 3.82(s,3H), 3.75-3.60(m,1H), 1.79(s,3H), 1.33(s,3H), 1.26(s,3H). LCMS m / z 550.03(M+H) +

[0261] Step 2: Synthesis of 4-[5-benzyloxy-9-(4-fluorophenyl)-1,1,4-trimethyl-3H-pyrano[3,4-b]indol-4-yl]benzoic acid (C92) To a solution of methyl 4-[5-benzyloxy-9-(4-fluorophenyl)-1,1,4-trimethyl-3H-pyrano[3,4-b]indol-4-yl]benzoate C91 (170 mg, 0.309 mmol) in MeOH (1.5 mL), THF (2 mL), and water (750 μL) was added lithium hydroxide hydrate (132 mg, 3.15 mmol), and the mixture was heated at 80° C. for 2 h. The reaction mixture was evaporated, neutralized with HCl (2 M, 1.6 mL, 3.2 mmol), and back-extracted with dichloromethane (3×40 ml). The dichloromethane layer was dried (NaSO) and concentrated to give product C92 (165 mg, 81%). LCMS m / z 536.43 [M+H] + .

[0262] Step 3: Synthesis of 4-[9-(4-fluorophenyl)-5-hydroxy-1,1,4-trimethyl-3H-pyrano[3,4-b]indol-4-yl]benzoic acid (192) To a solution of 4-[5-benzyloxy-9-(4-fluorophenyl)-1,1,4-trimethyl-3H-pyrano[3,4-b]indol-4-yl]benzoic acid C92 (165 mg, 0.308 mmol) in EtOH (3 mL) and THF (1 mL) was added 10% Pd / C (70 mg, Degussa type, wet) and NHClOH (180 mg, 2.86 mmol). The mixture was heated at 50 °C for 1 h. The reaction mixture was filtered, concentrated, and purified using 15.5 g reverse-phase chromatography (15.5 g C18 column, formic acid modifier) ​​to give 4-[9-(4-fluorophenyl)-5-hydroxy-1,1,4-trimethyl-3H-pyrano[3,4-b]indol-4-yl]benzoic acid 192 (75 mg, 51%). 1 H NMR(400MHz, methanol-d4)δ 7.95-7.77(m,2H), 7.48-7.34(m,4H), 7.20(dddd,J=9.2,7.8,3.7,2.1Hz,2H), 6.83(t,J=7.9Hz,1 H), 6.25(ddd,J=20.4,7.9,0.8Hz,2H), 3.89-3.65(m,2H), 1.93(s,3H), 1.38(s,3H), 1.31(s,3H). LCMS m / z 446.24[M+H] +

[0263] Compounds 193~199 Compounds 193-199 were prepared from S10 or S11 and the appropriate epoxide and ketone / ketone equivalents. [Table 9-1] [Table 9-2] [Table 9-3]

[0264] compound 200 Compound 200 was prepared from S12 and the appropriate ketone. [Table 10] a Standard procedure A was carried out in dichloromethane in a closed vial at 60°C. b Standard procedure B was modified by replacing ammonium formate with hydrogen and using EtOH as the solvent.

[0265] Compound 201 9-(4-Fluorophenyl)-5-hydroxy-1,1-dimethyl-2-oxo-1,2,3,9-tetrahydrospiro[carbazole-4,1'-cyclobutane]-3'-carboxylic acid (201) [ka] Step 1: Synthesis of 2-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-2-methylpropanal (C93) To a mixture of S6 (7.24 g, 18.6 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (10 g, 23.6 mmol) with ice bath cooling. After several minutes, the reaction mixture was removed from the cooling bath. After 3 hours, the reaction was concentrated and then purified through a silica plug (200 g) with dichloromethane to give the product C93 (6.3 g, 87%). 1 H NMR(400MHz,chloroform-d)δ 9.55(s,1H), 7.59-7.53(m,2H), 7.49-7.43(m,2H), 7.41-7.36(m,1H), 7.27-7.17(m,4H), 7.05(t,J=8.0Hz,1 H), 6.83(d,J=0.8Hz,1H), 6.65(dd,J=7.8,0.6Hz,1H), 6.43(dt,J=8.3,0.7Hz,1H), 5.28(s,2H), 1.39(s,6H).

[0266] Step 2: Synthesis of dimethyl (3-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-3-methyl-2-oxobutyl)phosphonate (C94) A solution of [methoxy(methyl)phosphoryl]oxymethane (2.5 mL, 23.1 mmol) in THF (25 mL) was cooled to −78° C., and nBuLi (2.5 M, 7.7 mL, 19.3 mmol) was added over 17 min. After 45 min, C93 (3 g, 7.74 mmol) in THF (11 mL) was added over 15 min at −78° C. After stirring for an additional 5 min at −78° C., the reaction mixture was placed in an ice bath. After 45 min, the reaction was quenched with saturated aqueous NH4Cl. Ethyl acetate was added, and the reaction mixture was allowed to stand overnight. The next day, water and EtOAc were added, and the white insoluble material was filtered. The filtrate phases were separated, and the aqueous phase was extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and concentrated.

[0267] To a solution of this residue in dichloromethane (80 mL) with ice bath cooling, NaHCO3 (780 mg, 9.29 mmol) was added, followed by Dess-Martin periodinane (4.3 g, 10.1 mmol). After 75 min, saturated aqueous sodium bicarbonate (100 mL) and 1 M sodium thiosulfate (50 mL) were added, and the mixture was stirred vigorously for 15 min. The layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane, the layers were again separated through a phase separator, and the combined organics were concentrated. Purification by column chromatography (120 g gold column; 20–75% EtOAc in heptane) gave the product C94 (2.14 g, 54%). 1 H NMR(400MHz,chloroform-d)δ 7.58-7.53(m,2H), 7.47-7.42(m,2H), 7.41-7.35(m,1H), 7.26-7.14(m,4H), 7.04(t,J=8.0Hz,1H), 6.85(d,J=0.8Hz,1 H), 6.64(d,J=7.7Hz,1H), 6.42-6.37(m,1H), 5.26(s,2H), 3.74(d,J=11.2Hz,6H), 3.11(d,J=20.5Hz,2H), 1.42(s,6H). LCMS m / z 510.57[M+H] + .

[0268] Step 3: Synthesis of benzyl 3-(3-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-3-methyl-2-oxobutylidene)cyclobutane-1-carboxylate (C95) To a suspension of NaH (60 w / w%, 97 mg, 2.43 mmol) in THF (5 mL) was added C94 (1.13 g, 2.21 mmol) in THF (6 mL) over 5 min. A solution of benzyl 3-oxocyclobutanecarboxylate (454 mg, 2.22 mmol) in THF (2 mL) was added, and the mixture was heated at 50 °C overnight. Saturated aqueous NH4Cl was added, and the mixture was extracted twice with EtOAc. The combined organics were concentrated and then purified by column chromatography (C18 AQ 100 g column; aqueous TFA / MeCN) to give the product C95 as a pale yellowish sticky solid (524 mg, 40%). 1 H NMR(400MHz,chloroform-d)δ 7.58-7.53(m,2H), 7.47-7.40(m,2H), 7.39-7.31(m,5H), 7.19-7.13(m,2H), 7.13-7.04(m,2H), 7.01(t,J=8.0Hz,1H), 6.82(d,J=0.8Hz,1H), 6.63(dd,J=7 .9,0.6Hz,1H), 6.41-6.38(m,1H), 6.19(q,J=2.2Hz,1H), 5.26(s,2H), 5.19- 5.11(m,2H), 3.41-3.26(m,3H), 3.10-2.94(m,2H), 1.42(s,3H), 1.33(s,3H). LCMS m / z 588.41[M+H] + .

[0269] Step 4: Synthesis of benzyl 5-(benzyloxy)-9-(4-fluorophenyl)-1,1-dimethyl-2-oxo-1,2,3,9-tetrahydrospiro[carbazole-4,1'-cyclobutane]-3'-carboxylate (C96) To a solution of C95 (479 mg, 0.815 mmol) in deuterated MeCN (10 mL) was added bismuth triflate (130 mg, 0.210 mmol) at room temperature. After 2 h, the reaction was concentrated. The residue was purified by column chromatography (C18 150 g column; aqueous TFA / MeCN) and the relevant fractions were concentrated. MeOH was added and the product C96 was filtered as a pale yellow solid (397 mg, 83%). LCMS m / z 588.41 [M+H] + .

[0270] Step 5: Synthesis of 9-(4-fluorophenyl)-5-hydroxy-1,1-dimethyl-2-oxo-1,2,3,9-tetrahydrospiro[carbazole-4,1'-cyclobutane]-3'-carboxylic acid (201) Standard procedure B was followed from C96, but ammonium formate was replaced with hydrogen gas, and MeOH, EtOAc, and THF were used as solvents. 201 was obtained as a mixture of isomers. One isomer is annotated: 1 H NMR(400MHz,DMSO-d6)δ 7.51(dd,J=8.8,5.1Hz,2H), 7.42(t,J=8.7Hz,2H), 6.83(t,J=7.9Hz,1H), 6.53(d,J=7.7 Hz,1H), 6.02(d,J=8.1Hz,1H), 3.40-3.20(m,3H), 3.06(s,2H), 2.11(m,2H), 1.16(s,6H). LCMS m / z 408.27[M+H] + .

[0271] Compound 202 9-(4-Fluorophenyl)-2,5-dihydroxy-1,1-dimethyl-1,2,3,9-tetrahydrospiro[carbazole-4,1'-cyclobutane]-3'-carboxylic acid (202) [ka] Step 1: Synthesis of benzyl 5-(benzyloxy)-9-(4-fluorophenyl)-2-hydroxy-1,1-dimethyl-1,2,3,9-tetrahydrospiro[carbazole-4,1'-cyclobutane]-3'-carboxylate (C97) To a solution of C96 (307 mg, 0.522 mmol) in 2-MeTHF (9 mL) was added sodium borohydride (80 mg, 2.12 mmol) at room temperature. After 5 h, 250 mg more of reducing agent was added and stirring was continued overnight. Water and EtOAc were added and the layers were separated. The aqueous layer was re-extracted with EtOAc and the combined organics were dried (Na2SO4), filtered and concentrated to give the product C97 as a straw-colored oil (308 mg, 100%). LCMS m / z 590.93 [M+H] + .

[0272] Step 2: Synthesis of 9-(4-fluorophenyl)-2,5-dihydroxy-1,1-dimethyl-1,2,3,9-tetrahydrospiro[carbazole-4,1'-cyclobutane]-3'-carboxylic acid (202) Performed from C97 according to standard procedure B, but replacing ammonium formate with hydrogen gas and using THF as the solvent, 202 was obtained as two isomers that were biologically active (31 mg, 14%). 1 H NMR(400MHz, methanol-d4)δ 7.42-7.24(m,4H), 6.80(dd,J=8.2,7.7Hz,1H), 6.45(dd,J=7.6,0.9Hz,1H), 6.07(dd,J=8.2,0.9Hz,1H), 3.57-3.44(m,2H), 3.42- 3.33(m,1H), 2.96(t,J=11.0Hz,1H), 2.44-2.35(m,2H), 2.26(d,J=11.5Hz,1H), 2.08(t,J=12.4Hz,1H), 1.15(s,3H), 0.97(s,3H). LCMS m / z 410.3[M+H] + .

[0273] compound 203 (1S,3S)-5'-(4-Fluoro-3-methylphenyl)-9'-hydroxy-3',3'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (203) [ka] Step 1: Synthesis of 5-(2-(benzyloxy)-6-bromophenyl)-2-methylpent-4-yn-2-ol (C98) A 20 mL drum vial with a red pressure-release cap was sequentially charged with 1-benzyloxy-3-bromo-2-iodo-benzene C2 (3.51 g, 9.02 mmol), 2-methylpent-4-yn-2-ol (930 mg, 9.48 mmol), and then DMF (14 mL). Nitrogen gas was bubbled through the mixture for 15–20 min. To this solution, Pd(PPh3)2Cl2 (410 mg, 0.584 mmol) was added. CuI (172 mg, 0.903 mmol) was added, followed by diethylamine (1.4 mL, 13.5 mmol), and the mixture was heated to 40 °C for 60 h. The reaction mixture was then loaded directly onto a reverse-phase column (C18 275 g column; 5–95% MeCN in aqueous TFA) for purification. Pure fractions were combined and partially concentrated under reduced pressure. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure to give the product C98 (2.01 g, 62%). 1 H NMR(400MHz,chloroform-d)δ 7.40-7.20(m,5H), 7.11(dd,J=8.1,1.0Hz,1H), 6.98(t,J=8.2Hz,1H), 6.77 (dd,J=8.4,1.0Hz,1H), 5.06(s,2H), 2.61(s,2H), 2.20(s,1H), 1.27(s,6H).

[0274] Step 2: Synthesis of 5-(2-(benzyloxy)-6-((4-fluoro-3-methylphenyl)amino)phenyl)-2-methylpent-4-yn-2-ol (C99) Nitrogen was bubbled through a solution of 5-(2-benzyloxy-6-bromo-phenyl)-2-methyl-pent-4-yn-2-ol C98 (2.01 g, 5.60 mmol) and 4-fluoro-2-methyl-aniline (840 mg, 6.71 mmol) in dioxane (4.5 mL) and t-BuOH (7.5 mL) for 10 min. Sodium t-butoxide (915 mg, 9.52 mmol) and tBuXphos palladacycle (195 mg, 0.284 mmol) were added, and bubbling continued for an additional 5 min. The vial was then placed on a heating block set at 45 °C overnight. Water and ethyl acetate were added. The aqueous layer was re-extracted with ethyl acetate, and the organic layer was separated and dried over sodium sulfate. The combined organic layers were concentrated under reduced pressure. Purification by column chromatography (80 g column; 0-25% EtOAc in heptane) gave the product C99 (2.26 g, 100%). 1 H NMR (400 MHz, chloroform-d) δ 7.58-7.54(m,1H), 7.51-7.33(m,4H), 7.19-6.93(m,4H), 6.84-6.63(m, 2H), 6.55-6.38(m,1H), 5.28(s,1H), 5.14(d,J=11.6Hz,1H), 2.86(d,J=1 .2Hz,1H), 2.71(s,1H), 2.37(d,J=2.1Hz,1H), 2.29-2.25(m,1H), 2.22( d,J=2.0Hz,1H), 1.31(d,J=18.2Hz,5H), 1.17-1.12(m,3H), 1.08(s,1H).

[0275] Step 3: Synthesis of 1-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylpropan-2-ol (C100) To a solution of C99 (2.26 g, 5.60 mmol) in 2-MeTHF (20 mL) was added potassium t-butoxide (5.6 mL of 1 M, 5.60 mmol) at room temperature, and the reaction mixture was stirred overnight. Ethyl acetate and water, brine, and saturated ammonium chloride were added, the layers were separated, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (80 g gold silica column, 0–100% ethyl acetate in heptane). Fractions 10–13 were combined to give 980 mg of the indole product C100 (980 mg, 43%). 1 H NMR(400MHz,chloroform-d)δ 7.56-7.51(m,2H), 7.44-7.31(m,3H), 7.13(td,J=5.6,3.0Hz,2H), 7.02(t,J=8.0Hz,1H), 6.75-6.71(m,1H), 6.67(d,J=8.3Hz,1H) , 6.63(d,J=7.8Hz,1H), 5.25(s,2H), 2.84(s,2H), 2.34(d,J=2.0Hz,3H), 2.19(d,J=2.0Hz,1H), 1.71(s,1H), 1.12(d,J=1.6Hz,6H). LCMS m / z 404.27[M+H] + .

[0276] Step 4: Synthesis of (1S,3S)-9'-(benzyloxy)-5'-(4-fluoro-3-methylphenyl)-3',3'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (C101) Using 3-oxocyclobutanecarboxylic acid as the ketone, the reaction was carried out from C100 according to standard procedure A to give product C101 (58 mg, 49%). LCMS m / z 500.58 [M+H] + .

[0277] Step 5: Synthesis of (1S,3S)-5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-3',3'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-carboxylic acid (203) To a solution of C101 (58 mg, 0.116 mmol) in dichloromethane (3.5 mL) at 0-5 °C, BBr3 (290 μL of 1 M, 0.290 mmol) was added dropwise over 3 min. After 15 min, the reaction was quenched with water. Dichloromethane was added and the layers were separated on a phase separator. The organics were concentrated. Purification by column chromatography (4 g GOLD column; 0-10% MeOH in dichloromethane) gave product 203 (10.7 mg, 21%). 1 H NMR(400MHz, methanol-d4)δ 7.23-7.17(m,2H), 7.16-7.11(m,1H), 6.88(dd,J=8.2,7.6Hz,1H), 6.60(dd,J=8.2,0.9Hz,1H), 6.49(dd,J=7.7,0. 8Hz,1H), 3.42-3.36(m,1H), 3.27-3.20(m,2H), 2.79-2.72(m,2H), 2.44(s,2H), 2.33(d,J=2.0Hz,3H), 1.29(s,6H). LCMS m / z 410.16[M+H] + .

[0278] compound 204 Compound 204 was prepared from C2 and the appropriate alkyne using the same procedure as compound 203. [Table 11] a For step 5, standard procedure B was used rather than the BBr3-based method.

[0279] Compound 205 and Compound 206 Compounds 205-206 were prepared from S14 and the appropriate ketone. [Table 12] a Standard procedure A was carried out in dichloromethane rather than DCE. b Standard procedure B was modified by replacing ammonium formate with hydrogen and using MeOH as the solvent.

[0280] Compound 207 and Compound 208 Compounds 207-208 were prepared from S16 and the appropriate ketone. [Table 13] a Standard procedure A was carried out in dichloromethane rather than DCE. b Standard procedure B was modified by replacing ammonium formate with hydrogen and using EtOH as the solvent. b This was a by-product observed from over-reduction during the synthesis of compound 208.

[0281] Compound 209 and Compound 210 Compounds 209-210 were prepared from S15 and the appropriate ketone. [Table 14-1] [Table 14-2] a Standard procedure A was carried out in dichloromethane rather than DCE. b Standard procedure B was modified by replacing ammonium formate with hydrogen and using EtOH as the solvent. b This was a by-product observed from over-reduction during the synthesis of compound 209.

[0282] Assays for detecting and measuring the AAT modulator properties of compounds A. AAT functional assay (MSD assay NL20-SI cell line) Alpha-1 antitrypsin (AAT) is a SERPIN (serine protease inhibitor) that inactivates enzymes by covalently binding to them. This assay measured the amount of functionally active AAT in a sample in the presence of the disclosed compounds 1-210 by determining AAT's ability to form an irreversible complex with human neutrophil elastase (hNE). In practice, samples (cell supernatants, blood samples, or other) were incubated with excess hNE to allow AAT-elastase complexes to form with all functional AAT in the sample. This complex was then captured on a microplate coated with an anti-AAT antibody. The plate-captured complex was detected with a labeled anti-elastase antibody and quantified using a set of AAT standards spanning the concentration range present in the sample. A Meso Scale Discovery (MSD) plate reader, sulfo-tagged labeling, and microplates were used to provide high sensitivity and a wide dynamic range. [Table 15] [Table 16]

[0283] Assay Protocol Day 1 Cell culture 1. Harvest NL20 human bronchial epithelial cells expressing human Z-AAT in OptiMEM™ with Pen / Strep (P / S) 2. Seed 16,000 cells / well in 30 μL (384-well plate) 3. Briefly centrifuge the plate at maximum speed (1200 rpm) and place the plate in a 37°C incubator overnight. Day 2: Compound addition and coating of plates with capture antibody Compound addition: 1. Using a multidrop Combi in the hood, dispense 40 μL of OptiMEM™ (P / S) containing doxycycline (1:1000 stock = final 0.1 μM) into each well of the compound plate. 2. Remove cell plate from incubator, invert / blot, and immediately place in Bravo and transfer compound. 3. Return the plate to the incubator overnight Coating MSD plates 1. Dilute capture antibody (polyclonal goat anti-AAT) to 5 μg / mL (1:200) in PBS (no BSA). 2. Using a Multidrop equipped with a standard cassette, dispense 25 μL of diluted capture antibody into all wells of an MSD 384-well high-binding plate. 3. Incubate overnight at 4°C. Prepare Blocker A (BSA) solution 1. Prepare a solution of 5% MSD Blocker A (BSA) according to the manufacturer's instructions. 2. If necessary, further dilute the 5% MSD Blocker A to 1% (Blocker A) in PBS. Day 3: Performing the MSD assay Blocking the plate 1. Wash one plate with 50 μL of wash buffer (PBS + 0.5% Tween® 20) and add 35 μL of 5% Block A buffer to block non-specific binding on the washer dispenser 2. Rotate the plate on a shaker at 600 rpm for 1 hour Prepare m-AAT standards 1. Dilute M-AAT stock to 1.6 μg / mL in 1% BSA Blocker A (store at -70°C), then prepare 12 x 1:2 serial dilutions in 1% Blocker A. 2. The highest starting final concentration on the MSD plate is 320 ng / mL. These dilutions correspond to final concentrations of 320, 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.312, and 0.156 ng / mL. Dilution Plate 1. Using the Multidrop Combi, add 80 μL of 1% assay buffer to all wells except column 1 / 24 (standard). 2. Add diluted standards to columns 1 and 24. 3. Centrifuge the dilution plate briefly at 1200 rpm Cell plates 1.16 Using a pin aspirator, aspirate the column that will have the standards from the cell plate in the hood Prepare human neutrophil elastase (hNE) Prepare 1 μg / mL human neutrophil elastase by dilution in 1.1% Blocker A. a. Small 100µg vial - add 1mL of PBS (100µg / mL) i. This can then be diluted 1:100 in 1% assay buffer for a final concentration of 1 μg / mL. Add MSD-hNE (20 μL / well) 1. After the MSD plates have been blocked for at least 1 hour, wash one plate with 50 μL of wash buffer (PBS+0.5% Tween® 20) and then add 20 μL of hNE to each well. Bravo-Cell Plate-Dilution Plate-MSD Plate Using the Bravo, aspirate 10 μL from the cell plate and transfer to the dilution plate (9x dilution). Mix 1.3 x 25 μL, then aspirate 5 μL and transfer to MSD plate (5x dilution) Mix 10 μL of 2.3x. The total dilution is 45x. 3. Shake the plate at 600 rpm for 1.5 hours. Add functional detection hNE antibody 1. Wash one plate with wash buffer 2. Add 25 μL of sulfo-tagged anti-elastase (monoclonal mouse anti-elastase) diluted to 0.45 μg / mL (1:2000) in 1% Blocker A to all wells of the functionally active MSD plate using a washer / dispenser. NOTE: The dilution required for sufficient signal must be determined for each new lot of labeled antibody. Incubate at room temperature with shaking at 3.600 rpm for 1 hour. Final washing and MSD image reading 1. Wash one plate and add 25 μL of wash buffer to the plate. 2. Make two reading buffers 3. Remove the wash buffer from the MSD plate 4. Using the Bravo, transfer 35 μL of the two read buffers to the MSD plate, take to the MSD and read immediately Data analysis and EC in MSD Discovery Workbench 4.0 software 50 Values ​​were determined using Genedata.

[0284] B. Biochemical Assay (Z-AAT Elastase Activity Assay) This assay used purified Z-AAT protein and purified human neutrophil elastase (hNE) to measure the modulation of Z-AAT serpin activity by compounds 1-210. Normally, when active monomeric Z-AAT encounters a protease, such as trypsin or elastase, it forms a 1:1 covalent "suicide" complex, irreversibly inactivating both the AAT and the protease. However, compounds that bind to Z-AAT can result in a decrease in serpin activity. In such cases, when a protease encounters compound-bound Z-AAT, the protease cleaves and inactivates Z-AAT without itself being inactivated. material reagent PBS buffer (media preparation) + 0.01% BRIJ® 35 detergent (Calbiochem catalog number 203728) Opti-MEM medium (Fisher 11058-021) Human neutrophil elastase (hNE, Athens Research No. 16-14-051200) A 3.4 μM stock (0.1 mg / mL) was prepared in 50 mM Na acetate, pH 5.5, 150 mM NaCl and stored at -80°C. Elastase Substrate V (ES V, fluorogenic peptide substrate MeOSuc-Ala-Ala-Pro-Val-AMC, Calbiochem catalog number 324740) 20 mM stock in DMSO stored at -20°C Purified Z-AAT protein from human plasma; Z-AAT Vertex Cambridge sample 4942, 12.9 μM (0.67 mg / mL) from patient 061-SSN, was stored at -80°C. plate Corning 4511 (384-well black low volume) device PerkinElmer® EnVision™ Assay Protocol Pre-incubation of Z-AAT with compounds 1. 7.5 μL of Z-AAT (20 nM) was incubated with compounds 1–210 in a GCA plate at room temperature for 1 hour. Addition of hNE 1. 7.5 ul of HNE solution (3 nM in PBS + 0.01% BRIJ® 35) was added into the GCA plate. 2. Incubate the plate for 30 minutes to allow for the formation of the Z-AAT / HNE suicide complex. Add substrate and read plate on PE Envision 1. 7.5 μL of substrate (300 μM solution of elastase substrate (ES V) in PBS + 0.01% BRIJ® 35) was dispensed per well into the GCA plate. 2. Read immediately with Envision. C. EC50 and Z-AAT esterase activity data for compounds 1–210

[0285] The compounds of formula (I) are useful as modulators of AAT activity. Table 15 below shows the EC values ​​of compounds 1-210 determined using the procedure described in Section A above. 50 Table 15 below also provides Z-AAT elastase activity using the procedure described in Section B above. In Table 15 below, the following means: EC 50 and IC 50 "+++" means <1.2 μM, "++" means 1.2 μM-3.0 μM, and "+" means >3.0 μM. "N / A" means activity not assessed. IC 50 For the compounds, "ND" means no detectable activity up to 30 μM. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5]

[0286] Other embodiments The present description provides merely exemplary embodiments of the disclosed subject matter. Those skilled in the art will readily appreciate from this disclosure and the accompanying claims that various changes, modifications, and variations can be made thereto without departing from the spirit and scope of the present disclosure, as defined in the following claims. The present invention provides, for example, the following items. (Item 1) A compound represented by one of the following structural formulas:

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Claims

1. A compound represented by one of the following structural formulas: 【Chemistry 86】 a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: W １ is absent, -O-, or -CR Ｄ R Ｄ - and W ２ is -O-, -(CR Ｄ R Ｄ ) ｐ - or -C(=O)-, However, W １ and W ２ are not both -O-; R Ａ and R Ｂ are each independently hydrogen, halogen, —OH, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, or C １ -C ３ Is it an alkoxy? Or alternatively, R Ａ and R Ｂ are each independently C １ -C ３ Alkyl or C １ -C ３ Alkoxy or R Ａ and R Ｂ together with their intervening C atoms, ３ -C ６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl containing at least one oxygen atom, R Ｃ are independently hydrogen, —OH, C １ -C ３ Alkyl, or C １ -C ３ is haloalkyl, R Ｄ is independently for each occurrence hydrogen, halogen, —OH, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, or C １ -C ３ Is it an alkoxy? Or alternatively, R Ｄ is independently for each occurrence, C １ -C ３ Alkyl or C １ -C ３ Alkoxy or two R Ｄ The groups, together with their intervening C atoms, are C ３ -C ６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl containing at least one oxygen atom, U １ and U ２ are each independently hydrogen, halogen, or —NH ２ , -CH ３ or —OH, However, U １ and U ２ one of which is —OH or —NH ２ However, U １ and U ２ are both -OH or -NH ２ Not U １ and U ２ are not both hydrogen, Ring A is C ３ -C １２ carbocyclyl or 3- to 12-membered heterocyclyl; X is absent, -(CR Ｅ R Ｅ ) ｑ - or -CH ２ OCH ２ -, wherein R Ｅ is independently for each occurrence hydrogen, halogen, —OH, C １ -C ３ Alkyl, C １ -C ３ haloalkyl, or C １ -C ３ is an alkoxy, Y is —COOH or 【Hua 87】 and Ring B is C ３ -C １２ cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl; R １ and R ２ is independently for each occurrence a halogen, cyano, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, C １ -C ３ Haloalkoxy, or O—(C ３ -C ６ cycloalkyl), R ３ is independently for each occurrence a halogen, cyano, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, —OH, —O(CR ｆ R ｆ ) ｒ COOH, =O, -COOH, -C(=O)NR ｆ R ｆ , -(CR ｆ R ｆ ) ｒ COOH, phenyl, or 5- or 6-membered heteroaryl, wherein R ｆ is independently for each occurrence hydrogen, halogen, or —CH ３ and R ３ The phenyl or the 5- or 6-membered heteroaryl may be selected from halogen, cyano, C １ -C ２ Alkyl, C １ -C ２ Haloalkyl, C １ -C ２ optionally substituted with 1 to 3 groups independently selected from alkoxy, —OH, and —COOH; R ４ is independently for each occurrence a halogen, cyano, C １ -C ２ Alkyl, C １ -C ２ Haloalkyl, C １ -C ２ Alkoxy, —COOH, —CH ２ COOH or -OCH ２ COOH, k and n are each independently an integer selected from 0, 1, 2, and 3; j and m are each independently an integer selected from 0, 1, and 2; p and r are each independently an integer selected from 1 and 2; q is an integer selected from 1, 2, and 3; a compound, a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

2. R Ａ and R Ｂ are each independently hydrogen, halogen, —OH, C １ -C ２ Alkyl, C １ -C ２ Haloalkyl, or C １ -C ２ Is it an alkoxy? Or alternatively, R Ａ and R Ｂ are each independently C １ -C ３ alkyl or R Ａ and R Ｂ together with the intervening C atom form cyclopropyl or cyclobutyl, R Ｄ is independently for each occurrence hydrogen, halogen, —OH, C １ -C ２ Alkyl, C １ -C ２ Haloalkyl, or C １ -C ２ Is it an alkoxy? Or alternatively, R Ｄ independently for each occurrence, C １ -C ３ alkyl or two R Ｄ groups, together with the intervening C atoms, form cyclopropyl or cyclobutyl, 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein all other variables not specifically defined in this claim are as defined in claim 1.

3. represented by one of the following structural formulas: 【Hua 88】 In the formula, R Ａ and R Ｂ are each independently hydrogen or C １ -C ２ 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 or 2, wherein R is alkyl and all other variables not specifically defined in this claim are as defined in claim 1 or 2.

4. U １ But -NH ２ or —OH, U ２ is hydrogen, halogen, or -CH ３ and 4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 3, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 3.

5. The compound is represented by the following structural formula: 【Chemistry 89】 In the formula, U ２ is hydrogen, F, or Cl, and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 4.

6. Ring A is R ３ and ring A is a 4- to 9-membered carbocyclyl or a 5- or 6-membered heterocyclyl, and all other variables not specifically defined in this claim are as defined in any one of claims 1-5.

7. Ring A is R ３ and Ring A is optionally substituted with cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, tetrahydro-2H-pyranyl, piperidinyl, spiro[2.3]hexanyl, 1-iminohexahydro-1λ ６ 7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 6, wherein 2H-thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl 1,1-dioxide, or 2,3-dihydro-1H-indenyl, and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 6.

8. Ring A is R ３ and Ring A is optionally substituted with 【Chemistry 90】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 7.

9. R ３ independently for each occurrence, a halogen, C １ -C ２ Alkyl, C １ -C ２ Haloalkyl, C １ -C ２ Alkoxy, —OH, —O(CR ｆ R ｆ ) ｒ COOH, =O, -COOH, -C(=O)NR ｆ R ｆ , -(CR ｆ R ｆ ) ｒ COOH, phenyl, or a 5-membered heteroaryl, wherein R ｆ is independently for each occurrence hydrogen or —CH ３ and R ３ wherein the phenyl or the 5-membered heteroaryl is selected from the group consisting of halogen, C １ -C ２ Alkyl, C １ -C ２ optionally substituted with 1 to 3 groups independently selected from alkoxy, —OH, and —COOH; 8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 7, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 8.

10. R ３ independently for each occurrence: F, -CH ３ , -CF ３ , -CHF ２ , － CH ２ F 、 —OH, —OCH ３ , -COOH, -CH ２ COOH, -CF ２ COOH, -C(=O)NH ２ , -C(=O)NHCH ３ , -C(=O)N(CH ３ ) ２ , =O, -OCH ２ COOH, -OCHCH ３ COOH, phenyl, pyrazolyl, or oxazolyl, wherein R ３ wherein said phenyl is substituted with —COOH; R ３ The pyrazolyl is selected from the group consisting of —COOH and —CH ３ is replaced by R ３ wherein said oxazolyl is substituted with —COOH; 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 9, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 to 9.

11. represented by one of the following structural formulas: 【Chemistry 91】 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 10, wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 10.

12. represented by one of the following structural formulas: 【Chemistry 92】 In the formula, R ３ is F, -CH ３ , -CF ３ , -CHF ２ , － CH ２ F 、 —OH or —OCH ３ and all other variables not specifically defined herein are as defined in any one of claims 1 to 11.

13. represented by one of the following structural formulas: 【Chemistry 93】 During the ceremony, R Ａ and R Ｂ are each independently hydrogen, halogen, —OH, C １ -C ２ Alkyl, C １ -C ２ haloalkyl, or C １ -C ２ is an alkoxy, R Ｃ are independently hydrogen, C １ -C ２ Alkyl, or C １ -C ２ is haloalkyl, X is absent, -(CR Ｅ R Ｅ ) ｑ - or -CH ２ OCH ２ -, wherein R Ｅ is independently for each occurrence hydrogen, C １ -C ２ Alkyl, or C １ -C ２ is an alkoxy, 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1, wherein all other variables not specifically defined in this claim are as defined in claim 1.

14. R Ａ and R Ｂ are each independently hydrogen or C １ -C ２ is alkyl, U １ But -NH ２ or —OH, U ２ is hydrogen, halogen, or -CH ３ and X is absent, -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ - or -CH ２ OCH ２ - and 14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of claim 1 or 13, wherein all other variables not specifically defined in this claim are as defined in claim 1 or 13.

15. represented by one of the following structural formulas: 【Chemistry 94】 During the ceremony, U ２ is hydrogen, F, or Cl; R Ｃ is hydrogen, -CH ３ , or -CF ３ and X is absent or -CH ２ - and 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1, 13, and 14, wherein all other variables not specifically defined in this claim are as set forth in any one of claims 1, 13, and 14.

16. represented by one of the following structural formulas: 【Chemistry 95】 16. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 and 13-15, wherein all other variables not specifically defined in this claim are as defined in any one of claims 1 and 13-15.

17. Ring B is R ４ and ring B is optionally substituted with C ３ -C ６ 17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 and 13-16, wherein R is cycloalkyl, phenyl, or 5-membered heteroaryl, and all other variables not specifically defined in this claim are as defined in any one of claims 1 and 13-16.

18. Ring B is R ４ and Ring B is optionally substituted with 【Chemistry 96】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 and 14-17.

19. Ring B is R ４ and Ring B is optionally substituted with 【Chemistry 97】 and all other variables not specifically defined in this claim are as defined in any one of claims 1 and 14-18.

20. R ４ is independently for each occurrence F, Cl, —CH ３ , -OCH ３ , —COOH, or —OCH ２ 20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 and 13-19, wherein R is COOH and all other variables not specifically defined herein are as defined in any one of claims 1 and 14-19.

21. represented by one of the following structural formulas: 【Chemistry 98】 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 and 13-20, wherein j is an integer selected from 0, 1, and 2, and all other variables not specifically defined herein are as defined in any one of claims 1 and 13-20.

22. represented by one of the following structural formulas: 【Hua99】 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 and 13-21, wherein j is an integer selected from 0, 1, and 2, and all other variables not specifically defined herein are as defined in any one of claims 1 and 13-21.

23. X is -(CH ２ ) ２ -, -(CH ２ ) ３ - or -CH ２ OCH ２ - and Y is —COOH; 15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1, 13, and 14, wherein all other variables not specifically defined in this claim are as defined in claim 1, 13, or 14.

24. R １ and R ２ each occurrence independently represents a halogen, C １ -C ２ Alkyl, or C １ -C ２ 24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 23, wherein R is alkoxy and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 23.

25. R １ is independently for each occurrence F, Cl, —CH ３ , or -OCH ３ and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 24.

26. R ２ is F for each occurrence; m is an integer selected from 0 and 1; and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 25.

27. 27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 26, wherein k is an integer selected from 1 and 2, and all other variables not specifically defined in this claim are as defined in any one of claims 1 to 26.

28. 28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 27, wherein m is 0, and all other variables not specifically defined herein are as defined in any one of claims 1 to 27.

29. A compound comprising: 【Chemistry 100-1】 【Chemistry 100-2】 【Chemistry 100-3】 【Chemistry 100-4】 【Chemistry 100-5】 【Chemistry 100-6】 【Chemistry 100-7】 【Chemistry 100-8】 【Chemistry 100-9】 【100-10】 【Chemistry 100-11】 【100-12】 【Chemistry 100-13】 【100-14】 【100-15】 【100-16】 【100-17】 【100-18】 A compound selected from a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

30. 30. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 29, for use in treating alpha-1 antitrypsin (AAT) deficiency in a patient in need thereof.

31. 30. A pharmaceutical composition for use in modulating alpha-1 antitrypsin (AAT) activity, said pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of claims 1 to 29.

32. 32. The pharmaceutical composition of claim 30 or 31, wherein the pharmaceutical composition is used in combination with AAT augmentation therapy and / or AAT replacement therapy.

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