Alpha-1 antitrypsin modulators

Abstract

Pyrano[4,3-b]indole derivatives are used as α-1 antitrypsin modulators for the treatment of α-1 antitrypsin deficiency (AATD).

Description

[0001] This application claims 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.

[0002] This disclosure provides compounds capable of modulating α-1 antitrypsin (AAT) activity and methods for treating α-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 bloodstream, but it is also produced by other cell types, including lung epithelial cells and certain leukocytes. AAT inhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase [NE], protease 3, and cathepsin G), thereby protecting organs such as the lungs from protease-induced damage, especially during inflammation.

[0004] The most common AATD-related mutation involves the substitution of lysine for glutamic acid in the SERPINA1 gene, which encodes the AAT protein (E342K). This mutation, known as a Z mutation or Z allele, results in the translated protein misfolding, thus preventing its secretion into the bloodstream and allowing it to aggregate within generative cells. Consequently, circulating AAT levels are significantly reduced in individuals homozygous for the Z allele (PiZZ); only about 15% of the mutant Z-AAT protein folds correctly and is secreted by cells. Another consequence of the Z mutation is that the secreted Z-AAT exhibits reduced activity compared to the wild-type protein, ranging from 40% to 80% of the normal antiprotease activity (American Thoracic Society / European Respiratory Society, Am J Respir Crit Care Med. 2003; 168(7):818-900; and Ogushi et al. J Clin Invest. 1987; 80(5):1366-74).

[0005] The accumulation of Z-AAT protein within hepatocytes leads to gain-of-function cytotoxicity, which can cause cirrhosis or hepatocellular carcinoma in 12% of patients later in life, as well as neonatal hepatopathy. This accumulation may resolve spontaneously, but is fatal in a small number of children. The lack of circulating AAT results in unregulated protease activity, which degrades lung tissue over time, leading to a form of chronic obstructive pulmonary disease (COPD), namely emphysema. This effect is severe in PiZZ individuals and typically manifests in middle age, resulting in decreased quality of life and shortened lifespan (mean 68 years) (Tanash et al., Int J Chron Obstruct Pulm Dis. 2016; 11:1663-9). The effects are more pronounced in smoking PiZZ individuals, leading to a further shortened lifespan (58 years) (Piitulainen and Tanash, COPD 2015; 12(1):36-41). PiZZ individuals constitute the majority of patients with clinically relevant AATD lung disease. Therefore, additional effective treatments for AATD are needed.

[0006] The milder form of AATD is associated with the SZ genotype, in which the Z allele binds to the S allele. The S allele is associated with reduced circulating AAT levels but does not cause cytotoxicity in hepatocytes. The result is clinically significant lung disease, rather than liver disease (Fregonese and Stolk, Orphanet J Rare Dis. 2008; 33:16). Similar to the ZZ genotype, the lack of circulating AAT in SZ genotype subjects leads to unregulated protease activity, which degrades lung tissue over time and can contribute to emphysema, particularly in smokers.

[0007] For individuals with AAT deficiency who have or show signs of developing significant lung or liver disease, the current standard of care is either intensive therapy or protein replacement therapy. Intensive therapy involves administering a human AAT protein concentrate purified from pooled donor plasma to enhance the missing AAT. Although plasma protein infusion has been shown to improve survival or slow the progression of emphysema, intensive therapy is often insufficient in challenging conditions, such as during active lung infections. Similarly, while protein replacement therapy has shown promise in slowing disease progression, intensive therapy does not restore the normal physiological regulation of AAT in patients, and its efficacy is difficult to demonstrate. Furthermore, intensive therapy requires weekly follow-up and does not address liver disease driven by acquired toxicity of the Z allele. Therefore, there is a continued need for new and more effective AAT treatments.

[0008] One aspect of this disclosure provides formulas (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-5) for the treatment of AATD (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (Va-1)-(Va-2), (Vb-1)-(Vb-5), and (VIb-1)-(VIb-5). Compounds of formula (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), 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, compounds of formula (Ia) or (Ib), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing can be described as follows:

[0009]

[0010] in:

[0011] W 1 It does not exist or is a key, -O- or -CR D R D -;

[0012] W 2 -O-, -(CR) D R D ) p -or -C=O;

[0013] The condition is W 1 and W 2 Neither of them are -O-;

[0014] R A and R B Each is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0015] Or alternatively R A and R B Each is independently a C1-C3 alkyl or C1-C3 alkoxy, and R A and R BTogether with their intercalary C atoms, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups containing at least one oxygen atom;

[0016] R C It is independently hydrogen, -OH, C1-C3 alkyl or C1-C3 haloalkyl.

[0017] R D Each time it appears, it is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0018] Or alternatively R D Each time it appears, it is independently C1-C3 alkyl or C1-C3 alkoxy, and both R... D The groups together with their intercalary C atoms form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups containing at least one oxygen atom;

[0019] U 1 and U 2 Each can be independently hydrogen, halogen, -NH2, -CH3, or -OH;

[0020] The condition is U 1 and U 2 One of them is -OH or -NH2, but U 1 and U 2 Not all of them are -OH or -NH2 and U 1 and U 2 Not all of them are hydrogen;

[0021] Ring A is C3-C 12 Carbocyclic or 3 to 12-membered heterocyclic groups;

[0022] X does not exist, so it is -(CR) E R E ) q -or -CH2OCH2-; where:

[0023] R E Each time it appears, it is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0024] Y is -COOH or

[0025] Ring B is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, phenyl, or 5 to 6-membered heteroaryl;

[0026] R 1 and R 2Each time it appears, it is independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or O-(C3-C6 cycloalkyl); and

[0027] R 3 Each time it appears, it is independently a 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 ) r COOH, phenyl, or 5- or 6-membered heteroaryl; wherein:

[0028] R f Each time it appears, it is independently hydrogen, halogen, or -CH3; and

[0029] R 3 The phenyl group or the 5- or 6-membered heteroaryl group may optionally be substituted with 1 to 3 groups selected from the following: halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -OH and -COOH;

[0030] R 4 Each time it appears, it is independently a halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -COOH, -CH2COOH or -OCH2COOH;

[0031] k and n are each an independent integer selected from 0, 1, 2 and 3;

[0032] j and m are each an independent integer selected from 0, 1 and 2;

[0033] p and r are each an independent integer selected from 1 and 2; and

[0034] q is an integer selected from 1, 2, and 3.

[0035] Equations (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-5) (e.g., equation (Ia)). Compounds (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) are modulators of ATT activity. In some implementations, formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ...2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (II Compounds of (Ib-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), as well as their tautomers, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, having an EC50 of 2.0 μM or lower when tested in an AAT functional assay. 50In some implementations, formulas (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-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ...2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb Compounds of (Ib-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), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, having an EC50 below 0.5 μM when tested in an AAT functional assay. 50 .

[0036] In some implementations, formulas (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-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb-2)). Compounds of (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), as well as their tautomers, deuterated derivatives of these compounds and their compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, having an IC50 of less than 5.0 μM when tested in the Z-AAT elastase activity assay. 50In some implementations, formulas (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-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb-5)). 2) Compounds of (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), as well as their tautomers, deuterated derivatives of these compounds and their compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, exhibiting an IC50 of less than 2.0 μM when tested in the Z-AAT elastase activity assay. 50 .

[0037] In some implementations, formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ...2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (II Compounds of (Ib-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), as well as their tautomers, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, having an EC50 of 2.0 μM or lower when tested in an AAT functional assay. 50 Furthermore, it exhibited an IC50 of 5.0 μM or lower when tested in the Z-AAT elastase activity assay. 50In some implementations, formulas (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-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ...2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb Compounds of (Ib-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), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, having an EC50 below 0.5 μM when tested in an AAT functional assay. 50 Furthermore, it exhibited an IC50 of 5.0 μM or lower when tested in the Z-AAT elastase activity assay. 50 In some implementations, formulas (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-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ...2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb Compounds of (Ib-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), as well as their tautomers, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, having an EC50 of 2.0 μM or lower when tested in an AAT functional assay. 50 Furthermore, it exhibited an IC50 value below 2.0 μM when tested in the Z-AAT elastase activity assay. 50In some implementations, formulas (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-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ...2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb-2), (IIb Compounds of (Ib-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), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, having an EC50 below 0.5 μM when tested in an AAT functional assay. 50 Furthermore, it exhibited an IC50 value below 2.0 μM when tested in the Z-AAT elastase activity assay. 50 .

[0038] In some implementations, formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb ... Compounds of (IIb-1), (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), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives are provided for the treatment of AATD.

[0039] In one aspect of this disclosure, the compounds of formula (Ia) or (Ib) for treating AATD are 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. In some embodiments of this disclosure, the compounds for treating AATD are 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.

[0040] In some embodiments, this disclosure provides pharmaceutical compositions comprising a group selected from formulas (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-5) (e.g., formulas (Ia), (Ib), ... Compounds selected from (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, the pharmaceutical composition may comprise a 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. These compositions may also comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0041] Another aspect of this disclosure provides methods for treating AATD, comprising administering to a subject in need a formula selected from (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb ... Compounds of (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, or pharmaceutical compositions comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering a compound selected from compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0042] In some implementations, the treatment method includes using a combination of formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ... Compounds selected from (Ib-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, are administered to a subject in need in the same pharmaceutical composition form or as a separate composition. In some embodiments, the method includes administering a 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, with at least one additional active agent in the same pharmaceutical composition or as 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.

[0043] In some implementations, the treatment method includes using formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb-2), (IIIa), (IIIb-1)-(Vb-5), and (VIb-1)-(VIb-5)). Compounds selected from (IVb-1)-(IVb-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, are used to administer at least one additional active agent to a subject in need, either as a pharmaceutical composition or as a separate composition, wherein the additional active agent is α-1 antitrypsin protein (AAT) derived from healthy human donor plasma. In some embodiments, the method includes administering a 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, with at least one additional active agent, either as a pharmaceutical composition or as a separate composition, wherein the additional active agent is α-1 antitrypsin protein (AAT) derived from healthy human donor plasma.

[0044] In some implementations, the treatment method includes using a combination of formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb-2), (I... Compounds selected from (IIa), (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, are administered to a subject in need in the same pharmaceutical composition form or as a separate composition, wherein the additional active agent is recombinant AAT. In some embodiments, the method includes administering a 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, with at least one additional active agent in the same pharmaceutical composition or as a separate composition, wherein the additional active agent is recombinant AAT.

[0045] Methods for modulating AAT are also provided, which include administering to subjects in need a mixture of formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb ... (IIb-1), (IIIb-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, or a pharmaceutical composition comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method of modulating AAT includes administering 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, or a pharmaceutical composition comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0046] Formulas (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), or (VIb-1)-(VIb-5) are also provided for therapies (e.g., formulas (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), or (VIb-1)-(VIb-2), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, 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 are provided for therapeutic purposes.

[0047] A pharmaceutical composition for use in a therapy is also provided, the pharmaceutical composition comprising 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), or (VIb-1)-(VIb-5) (e.g., formulas (Ia), (Ib), ... Compounds selected from (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), or (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 pharmaceutical composition for therapeutic use is provided 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.

[0048] I. Definition

[0049] As used herein, the term “AAT” refers to α-1 antitrypsin or a mutation thereof, including but not limited to mutations in the AAT gene, such as the Z mutation. As used herein, “Z-AAT” refers to an AAT mutant with a Z mutation.

[0050] As used in this article, “mutation” can refer to a mutation in the SERPINA1 gene (the gene encoding AAT) or an effect of gene sequence changes on the AAT protein. “SERPINA1 gene mutation” refers to a mutation in the SERPINA1 gene, and “AAT protein mutation” refers to a mutation that alters the amino acid sequence that produces the AAT protein. Gene defects or mutations, or changes in nucleotides within a gene, typically result in mutations in the AAT protein translated from that gene.

[0051] As used in this article, patients with a specific gene mutation who are "homozygous" have the same mutation on each allele.

[0052] As used in this article, patients with the PiZZ genotype are those who are homozygous for the Z mutation in the AAT protein.

[0053] As used in this article, the term “AATD” refers to α-1 antitrypsin deficiency, a genetic condition characterized by low circulating levels of AAT.

[0054] The term "compound," when referring to the compounds of this disclosure, means a collection of molecules having the same chemical structure, unless otherwise specified as a collection of stereoisomers (e.g., a collection of racemic mixtures, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic differences may exist between the constituent atoms of the molecules. Therefore, it will be apparent to those skilled in the art that a compound represented by a specific chemical structure containing an indicated deuterium atom will also contain a smaller amount of isotopes having hydrogen atoms at one or more designated deuterium positions in that structure. The relative amount of such isotopes in the compounds of this disclosure will depend on a number of factors, including the isotopic purity of the reagents used to prepare the compound and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as explained above, the relative amount of all such isotopes will be less than 49.9% of the compound. In other embodiments, the total relative amount of such isotopes will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0055] The compounds disclosed herein may optionally be substituted by one or more substituents. It should be understood that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Generally, the term “substituted,” whether or not preceded by the term “optionally,” refers to the substitution of a hydrogen group in a given structure by a group of a particular substituent. Unless otherwise indicated, a “optionally substituted” group may have a substituent at each substituted position of that group, and when more than one position in any given structure may be substituted by more than one substituent selected from the specified group, the substituents at each position may be the same or different. The combinations of substituents contemplated in this disclosure are combinations of substituents that result in the formation of stable or chemically viable compounds.

[0056] The term "isotope" refers to a substance whose chemical structure differs from that of a specific compound disclosed herein only in its isotopic composition. Additionally, unless otherwise stated, the structures described herein also refer to compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for replacing hydrogen with deuterium or tritium, or using... 13 C or 14 Compounds having the structure of this invention, except those with carbon substitution (C), are within the scope of this disclosure.

[0057] Unless otherwise stated, the structures illustrated herein are also intended to include all isomers of the structures, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the compounds of the present invention are within the scope of this disclosure. Unless otherwise stated, all tautomers of the compounds of this disclosure are within the scope of this disclosure.

[0058] 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 through intramolecular migration of atoms or groups.

[0059] "Stereoisomers" refers to both enantiomers and diastereomers.

[0060] As used herein, a “deuterated derivative” refers to a compound having the same chemical structure as the reference compound but with one or more hydrogen atoms replaced by deuterium atoms (“D”). It will be appreciated that there are variations in the natural isotopic abundance in the synthesized compounds, depending on the source of the chemical materials used in the synthesis. Despite such variations, the concentration of the naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Therefore, unless otherwise stated, when referring to the compounds of this disclosure as “deuterated derivatives,” at least one hydrogen atom is substituted with deuterium at a level far exceeding its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives of this disclosure have an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), or at least 6600 (99% deuterium doping) for each deuterium atom.

[0061] As used in this article, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its natural abundance.

[0062] As used herein, the term "alkyl" means a straight-chain (i.e., straight-chain or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or may contain one or more saturated units, but is not entirely aromatic. Unless otherwise stated, an alkyl group contains 1-12 alkyl carbon atoms. In some embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In other embodiments, the alkyl group contains 1-8 aliphatic carbon atoms. In other embodiments, the alkyl group contains 1-6 alkyl carbon atoms; in other embodiments, the alkyl group contains 1-4 alkyl carbon atoms; and in other embodiments, the alkyl group contains 1-3 alkyl carbon atoms and 1-2 alkyl carbon atoms.

[0063] As used herein, the term "heteroalkyl" refers to an aliphatic group in which one or both carbon atoms are independently substituted by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroalkyl groups can be substituted or unsubstituted, branched or unbranched.

[0064] As used herein, the term "alkenyl" refers to a straight-chain (i.e., straight or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more carbon-carbon double bonds.

[0065] The terms "cycloalkyl", "cyclic alkyl", "carbocyclic", and "carbocyclic" refer to fused, spirocyclic, or bridged monocyclic C-rings. 3-9 Hydrocarbons or fused, spirocyclic or bridged bicyclic or tricyclic C 8-14Hydrocarbons that are fully saturated or contain one or more unsaturated units, but are not fully aromatic, wherein any single ring in the bicyclic system has 3-9 members. Typically, cycloalkyl groups are fully saturated, while carbocyclic groups may contain one or more unsaturated units, but are not aromatic. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 12 carbon atoms. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 8 carbon atoms. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 6 carbon atoms.

[0066] As used herein, the terms "heterocycle," "heterocyclic group," or "heterocyclic" refer to a fused, spirocyclic, or bridged non-aromatic monocyclic, bicyclic, or tricyclic system in which one or more ring members are heteroatoms. In some embodiments, the "heterocycle," "heterocyclic group," or "heterocyclic" group has 3 to 14 ring members, wherein 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, the heterocyclic group contains 3 to 12 ring member atoms. In some embodiments, the heterocyclic group contains 3 to 8 ring member atoms. In some embodiments, the heterocyclic group contains 3 to 6 ring member atoms.

[0067] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituted nitrogen of a heterocycle, such as N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or NR). + (e.g., in N-substituted pyrroleyl groups).

[0068] As used herein, the term "alkoxy" refers to an alkyl group as defined above, wherein one carbon atom of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is attached between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, fused, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon containing at least one alkoxy group but not an aromatic hydrocarbon. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetane, 8-oxabicyclo[3.2.1]octyl, and oxetaneheptyl.

[0069] The terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group substituted with one or more halogen atoms, as appropriate. The term "halogen" may refer to F, Cl, Br, or I. In some embodiments, the halogen is selected from F, Cl, and Br. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CF2-, and perhaloalkyl groups, such as -CF2CF3.

[0070] As used in this article, “=O” refers to an oxo group.

[0071] As used in this article, the "cyano" or "nitrile" group refers to -C≡N.

[0072] As used in this article, "hydroxyl group" refers to -OH.

[0073] As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having delocalized π-electron orbitals consisting of [4n+2]p orbital electrons, where n is an integer from 0 to 6. Non-limiting examples of aryl groups include aryl and heteroaryl groups.

[0074] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, the aryl group contains 6 or 10 carbon atoms. A non-limiting example of an aryl group is a benzene ring.

[0075] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system having a total of 5 to 10 ring members, wherein at least one ring in the system is aromatic, the at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members. In some embodiments, the heteroaryl group contains 6 or 10 ring atoms.

[0076] Examples of useful protecting groups containing nitrogen-containing groups such as amines include, for example, tert-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylamine, and p-toluenesulfonamide. Methods for adding (commonly referred to as “protection”) and removing (commonly referred to as “deprotection”) such amine protecting groups are well known in the art and can be found, for example, in PJ Kocienski, Protecting Groups, Thieme, 1994, which is incorporated herein by reference in its entirety, and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition (John Wiley & Sons, New York, 1999).

[0077] Examples of suitable solvents that can be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene dichloro" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropanol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0078] Examples of suitable bases that may be used in this disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0079] This disclosure includes pharmaceutically acceptable salts of the disclosed compounds. Salts of the compounds are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0080] As used herein, the term "pharmaceutically acceptable" means a component that, to a reasonable extent of medical judgment, is suitable for contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt that can directly or indirectly provide the compounds of this disclosure when administered to a recipient. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SMBerge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0081] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, pharmaceutically acceptable salts of this class include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, decanoates, heptanoates, propionates, oxalates, malonates, succinates, caprylates, sebacic acid, fumarates, maleates, and butynedi-1,4-dicarboxylic acid. Salts, including hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0082] Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1-4 Alkyl)4 salts. This disclosure also contemplates quaternization of any basic nitrogen-containing group in the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0083] The terms “patient” and “subject” are used interchangeably and refer to animals including humans.

[0084] The terms “effective dose,” “effective amount,” “therapeutic effective dose,” and “therapeutic effective amount” are used interchangeably herein and refer to the amount of compound that produces the desired effect of administering the compound (e.g., improving AATD or AATD symptoms, reducing the severity of AATD or AATD symptoms, and / or reducing the incidence or morbidity of AATD or AATD symptoms). The exact amount of the effective dose will depend on the therapeutic purpose and will be determined by someone skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0085] As used herein, the term "treatment" and its cognates (e.g., "treat / treating") refer to improving a subject's AAT or its symptoms, delaying the onset of a subject's AAT or its symptoms, or reducing the severity of a subject's AAT or its symptoms. 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 deterioration (e.g., emphysema), reducing skin disease (e.g., necrotizing panniculitis), increasing growth in children, improving appetite, and reducing fatigue. Improvement in any of these symptoms or reduction in their severity can be readily assessed using methods and techniques known in or subsequently developed in the art.

[0086] When used in conjunction with the dosage, amount, or weight percentage of an ingredient in a composition or dosage form, the terms "about" and "approximately" include a specified dose, amount, or weight percentage, or a range thereof, that would be considered by a person of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage. Typically, the term "about" refers to a variation of up to 10%, up to 5%, or up to 2% of a given value.

[0087] Equations (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-5) (e.g., equations (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb-2) Compounds of (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 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 implementations, the formulas selected are (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2)). The compound is selected once daily 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 compound is selected once daily 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 implementations, the formulas selected are (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2)). At least one compound 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 shall be administered twice daily. In some embodiments, a compound 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 shall be administered twice daily. In some implementations, the formulas selected are (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2)). The compound is selected from compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing, and is administered three times daily. In some embodiments, the compound is selected from compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds, or pharmaceutically acceptable salts of any of the foregoing, and is administered three times daily.

[0088] Compounds of formulas (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 or tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered in combination with AAT intensification therapy or AAT replacement therapy 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.

[0089] As used in this article, “AAT enhancement therapy” refers to using α-1 antitrypsin protein (AAT) from healthy donor plasma to enhance (increase) the level of α-1 antitrypsin circulating in the blood. “AAT replacement therapy” refers to the administration of recombinant AAT.

[0090] 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 formulas (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), or (VIb-1)-(VIb-5) (e.g., compounds of 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) or (VIb-1)-(VIb-2)), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and at least one pharmaceutically acceptable salt of any of the foregoing, 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 2000 mg, or 400 mg to 600 mg of the compound selected from compounds 1-210 are administered once daily, twice daily, or three times daily.

[0091] Those skilled in the art will recognize that when the amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. It should be noted that the disclosed amounts of compounds, tautomers, deuterated derivatives, and pharmaceutically acceptable salts are based on the free base form of a reference compound. For example, “10 mg of at least one compound selected from formula (Ia) or formula (Ib) and its pharmaceutically acceptable salt” includes 10 mg of a compound of formula (Ia) or formula (Ib) and a pharmaceutically acceptable salt of a compound of formula (Ia) or formula (Ib) at a concentration equivalent to 10 mg of the compound of formula (Ia) or formula (Ib).

[0092] As used in this article, the term "environmental conditions" refers to room temperature, outdoor conditions, and uncontrolled humidity conditions.

[0093] It should be understood that this document refers to the use of one or more compounds (e.g., formulas (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) or (VIb-1)-(VIb-5)) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2)). Compounds of (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), or (VIb-1)-(VIb-2)), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, for treatment methods (e.g., methods for treating AATD) should also be interpreted as referring to:

[0094] - One or more compounds used in methods for treating, for example, AATD (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), or (VIb-1)-(VIb-5)) (e.g., formula (Ia), (Ib), ( Compounds of (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) or (VIb-1)-(VIb-2)), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds; and / or

[0095] - One or more compounds (e.g., of 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) or (VIb-1)-(VIb-5)) (e.g., of 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) or (VIb-1)-(VIb-2)) and tautomers of these compounds, deuterated derivatives of these compounds and tautomers and pharmaceutically acceptable salts of these compounds) for the manufacture of medicaments for the treatment of, for example, AATD.

[0096] Example implementation plan:

[0097] Without restrictions, some embodiments of this disclosure include:

[0098] 1. A compound represented by one of the following structural formulas:

[0099]

[0100] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0101] W 1 It does not exist or is a key, -O- or -CR D R D -;

[0102] W 2 -O-, -(CR) D R D ) p -or -C=O;

[0103] The condition is W 1 and W 2 Neither of them are -O-;

[0104] R A and R B Each is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0105] Or alternatively R Aand R B Each is independently a C1-C3 alkyl or C1-C3 alkoxy, and R A and R B Together with their intercalary C atoms, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups containing at least one oxygen atom;

[0106] R C It is independently hydrogen, -OH, C1-C3 alkyl, or C1-C3 haloalkyl;

[0107] R D Each time it appears, it is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0108] Or alternatively R D Each time it appears, it is independently C1-C3 alkyl or C1-C3 alkoxy, and both R... D The groups together with their intercalary C atoms form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups containing at least one oxygen atom;

[0109] U 1 and U 2 Each can be independently hydrogen, halogen, -NH2, -CH3, or -OH;

[0110] The condition is U 1 and U 2 One of them is -OH or -NH2, but U 1 and U 2 Not all of them are -OH or -NH2 and U 1 and U 2 Not all of them are hydrogen;

[0111] Ring A is C3-C 12 Carbocyclic or 3 to 12-membered heterocyclic groups;

[0112] X does not exist, so it is -(CR) E R E ) q -or -CH2OCH2-; where:

[0113] R E Each time it appears, it is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0114] Y is -COOH or

[0115] Ring B is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, phenyl, or 5 to 6-membered heteroaryl;

[0116] R 1 and R 2 Each time it appears, it is independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or O-(C3-C6 cycloalkyl); and

[0117] R 3 Each time it appears, it is independently a 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 ,

[0118] -(CR f R f ) r COOH, phenyl, or 5- or 6-membered heteroaryl; wherein:

[0119] R f Each time it appears, it is independently hydrogen, halogen, or -CH3; and

[0120] R 3 The phenyl group or the 5- or 6-membered heteroaryl group may optionally be substituted with 1 to 3 groups selected from the following: halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -OH and -COOH;

[0121] R 4 Each time it appears, it is independently a halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -COOH, -CH2COOH or -OCH2COOH;

[0122] k and n are each an independent integer selected from 0, 1, 2 and 3;

[0123] j and m are each an independent integer selected from 0, 1 and 2;

[0124] p and r are each an independent integer selected from 1 and 2; and

[0125] q is an integer selected from 1, 2, and 3.

[0126] 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1, wherein:

[0127] R A and R BEach is independently hydrogen, halogen, -OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy;

[0128] Or alternatively R A and R B Each is independently a C1-C3 alkyl group, and R A and R B Together with their intercalating carbon atoms, they form cyclopropyl or cyclobutyl groups;

[0129] R D Each time it appears, it is independently hydrogen, halogen, -OH, C1-C2 alkyl, C1-C2 haloalkyl or C1-C2 alkoxy;

[0130] Or alternatively R D Each time it appears, it is independently a C1-C3 alkyl group, and both R... D Together with their intercalating carbon atoms, they form cyclopropyl or cyclobutyl groups;

[0131] Furthermore, all other variables not specifically defined herein are defined as described in the aforementioned implementation scheme.

[0132] 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1 or Embodiment 2, represented by one of the following structural formulas:

[0133]

[0134] Where R A and R B Each is independently hydrogen or C1-C2 alkyl; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0135] 4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 3, wherein:

[0136] U 1 It can be -NH2 or -OH;

[0137] U 2 It can be hydrogen, halogen, or -CH3;

[0138] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0139] 5. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 4, wherein the compound is represented by the following structural formula:

[0140]

[0141] Among them U 2 It is hydrogen, F, or Cl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0142] 6. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 5, wherein ring A is optionally converted by R. 3 The ring A is replaced by a 4- to 9-membered carbocyclic group or a 5- or 6-membered heterocyclic group; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0143] 7. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 6, wherein ring A is optionally converted by R 3 The ring A is substituted with cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, tetrahydro-2H-pyranyl, piperidinyl, spiro[2.3]hexyl, or 1-iminohexahydro-1λ. 6 -Thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl 1,1-dioxide or 2,3-dihydro-1H-indenyl, and all other variables not specifically defined herein as defined in any of the foregoing embodiments.

[0144] 8. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 7, wherein ring A is optionally converted by R. 3 Replace and ring A is Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0145] 9. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 7, wherein R 3 Each time it appears, it is independently a halogen, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -OH, -O(CR) f R f ) r COOH, =O, -COOH

[0146] -C(=O)NR f R f 、-(CR f R f ) r COOH, phenyl, or 5-membered heteroaryl; wherein:

[0147] R fEach time it appears, it is independently either hydrogen or -CH3; and

[0148] R 3 The phenyl group or the 5-membered heteroaryl group may optionally be substituted with one to three groups selected from the following groups: halogen, C1-C2 alkyl, C1-C2 alkoxy, -OH and -COOH;

[0149] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0150] 10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 9, wherein:

[0151] R 3 Each time it appears, it is independently F, -CH3, -CF3, -CHF2, -CH2F, -OH.

[0152] -OCH3, -COOH, -CH2COOH, -CF2COOH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2,=O

[0153] -OCH2COOH, -OCHCH3COOH, phenyl, pyrazolyl, or oxazolyl; wherein:

[0154] R 3 The phenyl group is replaced by -COOH;

[0155] R 3 The pyrazol group is replaced by -COOH and -CH3; and

[0156] R 3 The oxazolyl group is replaced by -COOH;

[0157] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0158] 11. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 10, represented by one of the following structural formulas:

[0159]

[0160] Where n is an integer selected from 0, 1, and 2, and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0161] 12. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 11, represented by one of the following structural formulas:

[0162]

[0163] Where R 3 For F, -CH3, -CF3, -CHF2, - CH2F, -OH, or -OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0164] 13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1, represented by one of the following structural formulas:

[0165]

[0166] in:

[0167] R A and R B Each is independently hydrogen, halogen, -OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy;

[0168] R C It is independently hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl;

[0169] X does not exist, so it is -(CR) E R E ) q -or -CH2OCH2-; where:

[0170] R E Each time it appears, it is independently hydrogen, C1-C2 alkyl, or C1-C2 alkoxy;

[0171] Furthermore, all other variables not specifically defined herein are defined as in Implementation Scheme 1.

[0172] 14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 or 13, wherein:

[0173] R A and R B Each is independently hydrogen or C1-C2 alkyl;

[0174] U 1 It can be -NH2 or -OH;

[0175] U 2 It can be hydrogen, halogen, or -CH3;

[0176] X does not exist; it is -CH2-, -(CH2)2-, -(CH2)3-, or -CH2OCH2-.

[0177] Furthermore, all other variables not specifically defined herein are defined as in Implementation Scheme 1 or Implementation Scheme 13.

[0178] 15. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1, 13, and 14, represented by one of the following structural formulas:

[0179]

[0180] in:

[0181] U 2 It can be hydrogen, F, or Cl;

[0182] R C It is hydrogen, -CH3 or -CF3; and

[0183] X either does not exist or is -CH2-;

[0184] Furthermore, all other variables not specifically defined herein are defined as in any of the implementation schemes 1, 13, and 14.

[0185] 16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 and 13 to 15, represented by one of the following structural formulas:

[0186]

[0187] All other variables not specifically defined herein are defined as in any of Implementation Scheme 1 and 13 to 15.

[0188] 17. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 and 13 to 16, wherein ring B is optionally converted by R 4 The ring B is substituted and is a C3-C6 cycloalkyl, phenyl, or 5-membered heteroaryl; and all other variables not specifically defined herein are as defined in any of embodiments 1 and 13 to 16.

[0189] 18. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 and 13 to 17, wherein ring B is optionally converted by R 4 Replace and ring B is Furthermore, all other variables not specifically defined herein are defined as in any of Implementation Scheme 1 and 14 to 17.

[0190] 19. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 and 13 to 18, wherein ring B is optionally converted by R 4 Replace and ring B is Furthermore, all other variables not specifically defined herein are defined as in any of Implementation Scheme 1 and 14 to 18.

[0191] 20. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 and 13 to 19, wherein R 4 Each occurrence is independently F, Cl, -CH3, -OCH3, -COOH, or -OCH2COOH; and all other variables not specifically defined herein are defined as in any of embodiments 1 and 14 to 19.

[0192] 21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 20, represented by one of the following structural formulas:

[0193]

[0194] Where j is an integer selected from 0, 1, and 2; and where all other variables not specifically defined herein are defined as in any of Implementation Schemes 1 and 13 through 20.

[0195] 22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 and 13 to 21, represented by one of the following structural formulas:

[0196]

[0197]

[0198] Where j is an integer selected from 0, 1, and 2; and where all other variables not specifically defined herein are defined as in any of Implementation Schemes 1 and 13 to 21.

[0199] 23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1, 13, and 14, wherein:

[0200] X is -(CH2)2-, -(CH2)3-, or -CH2OCH2-;

[0201] Y represents -COOH;

[0202] Furthermore, all other variables not specifically defined herein are defined as in implementation schemes 1, 13, or 14.

[0203] 24. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 23, wherein R 1 and R 2 Each of these variables is independently halogen, C1-C2 alkyl, or C1-C2 alkoxy, and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0204] 25. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 24, wherein R 1 Each occurrence is independently F, Cl, -CH3, or -OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0205] 26. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 25, wherein R 2 F is the variable that appears in each instance; and m is an integer selected from 0 and 1; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0206] 27. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 26, wherein k is an integer selected from 1 and 2; and wherein all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0207] 28. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 27, wherein m is 0; and wherein all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0208] 29. A compound selected from compounds 1-210, their tautomers, deuterated derivatives of said compounds or tautomers, or a pharmaceutically acceptable salt of any of the foregoing.

[0209] 30. A pharmaceutical composition comprising at least one compound according to any one of embodiments 1 to 29, a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0210] 31. A method for treating α-1 antitrypsin (AAT) deficiency, the method comprising administering to a patient in need a therapeutically effective amount of at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of embodiments 1 to 29, or a therapeutically effective amount of a pharmaceutical composition according to embodiment 30.

[0211] 32. A method for modulating α-1 antitrypsin (AAT) activity, the method comprising the step of contacting the AAT with a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 29, or a therapeutically effective amount of a pharmaceutical composition according to embodiment 30.

[0212] 33. The method according to embodiment 31 or embodiment 32, wherein the therapeutically effective amount of at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt is administered in combination with AAT intensification therapy and / or AAT replacement therapy.

[0213] II. Compounds and Compositions

[0214] In some embodiments, the compounds disclosed herein are compounds of formula (Ia) or formula (Ib):

[0215]

[0216] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0217] W 1 It does not exist or is a key, -O- or -CR D R D -;

[0218] W 2 -O-, -(CR) D R D ) p -or -C=O;

[0219] The condition is W 1 and W 2 Neither of them are -O-;

[0220] R A and R B Each is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0221] Or alternatively R A and R BEach is independently a C1-C3 alkyl or C1-C3 alkoxy, and R A and R B Together with their intercalary C atoms, they form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups containing at least one oxygen atom;

[0222] R C It is independently hydrogen, -OH, C1-C3 alkyl, or C1-C3 haloalkyl;

[0223] R D Each time it appears, it is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0224] Or alternatively R D Each time it appears, it is independently C1-C3 alkyl or C1-C3 alkoxy, and both R... D The groups together with their intercalary C atoms form C3-C6 cycloalkyl groups or 3- to 6-membered heterocyclic groups containing at least one oxygen atom;

[0225] U 1 and U 2 Each can be independently hydrogen, halogen, -NH2, -CH3, or -OH;

[0226] The condition is U 1 and U 2 One of them is -OH or -NH2, but U 1 and U 2 Not all of them are -OH or -NH2 and U 1 and U 2 Not all of them are hydrogen;

[0227] Ring A is C3-C 12 Carbocyclic or 3 to 12-membered heterocyclic groups;

[0228] X does not exist, so it is -(CR) E R E ) q -or -CH2OCH2-; where:

[0229] R E Each time it appears, it is independently hydrogen, halogen, -OH, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 alkoxy;

[0230] Y is -COOH or

[0231] Ring B is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, phenyl, or 5 to 6-membered heteroaryl;

[0232] R 1and R 2 Each time it appears, it is independently a halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or O-(C3-C6 cycloalkyl); and

[0233] R 3 Each time it appears, it is independently a 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 ) r COOH, phenyl, or 5- or 6-membered heteroaryl; wherein:

[0234] R f Each time it appears, it is independently hydrogen, halogen, or -CH3; and

[0235] R 3 The phenyl group or the 5- or 6-membered heteroaryl group may optionally be substituted with 1 to 3 groups selected from the following: halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -OH and -COOH;

[0236] R 4 Each time it appears, it is independently a halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, -COOH, -CH2COOH or -OCH2COOH;

[0237] k and n are each an independent integer selected from 0, 1, 2 and 3;

[0238] j and m are each an independent integer selected from 0, 1 and 2;

[0239] p and r are each an independent integer selected from 1 and 2; and

[0240] q is an integer selected from 1, 2, and 3.

[0241] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, wherein:

[0242] R A and R B Each is independently hydrogen, halogen, -OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy;

[0243] Or alternatively RA and R B Each is independently a C1-C3 alkyl group, and R A and R B Together with their intercalating carbon atoms, they form cyclopropyl or cyclobutyl groups;

[0244] R D Each time it appears, it is independently hydrogen, halogen, -OH, C1-C2 alkyl, C1-C2 haloalkyl or C1-C2 alkoxy;

[0245] Or alternatively R D Each time it appears, it is independently a C1-C3 alkyl group, and both R... D Together with their intercalating carbon atoms, they form cyclopropyl or cyclobutyl groups;

[0246] Furthermore, all other variables not specifically defined herein are defined as described in the aforementioned implementation scheme.

[0247] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIa-1) or formula (IIa-2):

[0248]

[0249] Where R A and R B Each is independently hydrogen or C1-C2 alkyl; and all other variables not specifically defined herein are as defined in the foregoing embodiments.

[0250] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, wherein:

[0251] U 1 It can be -NH2 or -OH;

[0252] U 2 It can be hydrogen, halogen, or -CH3;

[0253] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0254] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIIa):

[0255]

[0256] Among them U 2 It is hydrogen, F, or Cl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0257] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is a 4- to 9-membered carbocyclic group or a 5- or 6-membered heterocyclic group and optionally R 3 Replace; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0258] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, ring A is selected from cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, tetrahydro-2H-pyranyl, piperidinyl, spiro[2.3]hexyl, 1-iminohexahydro-1λ 6 -Thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl 1,1-dioxide, or 2,3-dihydro-1H-indenyl; and ring A is optionally surrounded by R 3 Replace; where all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0259] In some embodiments, ring A is selected from the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. And arbitrarily R 3 Replace; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0260] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 3 Each time it appears, it is independently a 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:

[0261] R f Each time it appears, it is independently either hydrogen or -CH3; and

[0262] R 3 The phenyl group or the 5-membered heteroaryl group may optionally be substituted with one to three groups selected from the following groups: halogen, C1-C2 alkyl, C1-C2 alkoxy, -OH and -COOH;

[0263] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0264] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 3 Each occurrence is independently 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:

[0265] R 3 The phenyl group is replaced by -COOH;

[0266] R 3 The pyrazol group is replaced by -COOH and -CH3; and

[0267] R 3 The oxazolyl group is replaced by -COOH;

[0268] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0269] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IVa-1), formula (IVa-2), or formula (IVa-3):

[0270]

[0271] Where n is an integer selected from 0, 1, and 2; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0272] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (Va-1) or formula (Va-2):

[0273]

[0274] Where R 3 The variable is F, -CH3, -CF3, -CHF2, -CH2F, -OH, or -OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0275] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIb-1) or formula (IIb-2):

[0276]

[0277] in:

[0278] R A and R B Each is independently hydrogen, halogen, -OH, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy;

[0279] R C It is independently hydrogen, C1-C2 alkyl, or C1-C2 haloalkyl;

[0280] X does not exist, so it is -(CR) E R E ) q -or -CH2OCH2-; where:

[0281] R E Each time it appears, it is independently hydrogen, C1-C2 alkyl, or C1-C2 alkoxy;

[0282] Furthermore, all other variables not specifically defined in this paper are defined for equation (Ia) or equation (Ib).

[0283] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein:

[0284] R A and R B Each is independently hydrogen or C1-C2 alkyl;

[0285] U 1 It can be -NH2 or -OH;

[0286] U 2 It can be hydrogen, halogen, or -CH3;

[0287] X does not exist; it is -CH2-, -(CH2)2-, -(CH2)3-, or -CH2OCH2-.

[0288] Furthermore, all other variables not specifically defined in this paper are defined for any of the equations (Ia), (Ib), (Va-1), and (Va-2).

[0289] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIIb-1) or formula (IIIb-2):

[0290]

[0291]

[0292] in:

[0293] U 2 It can be hydrogen, F, or Cl;

[0294] R C It is hydrogen, -CH3 or -CF3; and

[0295] X either does not exist or is -CH2-;

[0296] Furthermore, all other variables not specifically defined herein are defined for any of the equations (Ia), (Ib), (Va-1), (Va-2), (IIb-1), and (IIb-2).

[0297] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IVb-1) or formula (IVb-2):

[0298]

[0299] All other variables not specifically defined in this paper are defined for any of the equations (Ia), (Ib), (Va-1), (Va-2), (IIb-1), (IIb-2), (IIIb-1), and (IIIb-2).

[0300] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, wherein ring B is optionally replaced by R 4 The ring B is substituted and is a C3-C6 cycloalkyl, phenyl, or 5-membered heteroaryl; and all other variables not specifically defined herein are defined as those for any of the formulas (Ia), (Ib), (Va-1), (Va-2), (IIb-1), (IIb-2), (IIIb-1), (IIIb-2), (IVb-1), and (IVb-2).

[0301] In some embodiments, cyclic B is selected from the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. And arbitrarily R 4Replace; and all other variables not specifically defined in this document are defined for any of the equations (Ia), (Ib), (Va-1), (Va-2), (IIb-1), (IIb-2), (IIIb-1), (IIIb-2), (IVb-1), and (IVb-2).

[0302] In some embodiments, cyclic B is selected from the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. And arbitrarily R 4 Replace; and all other variables not specifically defined in this document are defined for any of the equations (Ia), (Ib), (Va-1), (Va-2), (IIb-1), (IIb-2), (IIIb-1), (IIIb-2), (IVb-1), and (IVb-2).

[0303] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 4 Each occurrence is independently F, Cl, -CH3, -OCH3, -COOH, or -OCH2COOH; and all other variables are as defined in any of the foregoing embodiments.

[0304] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (Vb-1), (Vb-2), (Vb-3), (Vb-4), or (Vb-5):

[0305]

[0306] Where j is an integer selected from 0, 1, and 2; and where all other variables not specifically defined herein are defined for any of equations (Ia), (Ib), or the foregoing implementations.

[0307] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (VIb-1), (VIb-2), (VIb-3), (VIb-4), or (VIb-5):

[0308]

[0309] Where j is an integer selected from 0, 1, and 2; and where all other variables not specifically defined herein are defined for equation (I) or any of the foregoing implementation schemes.

[0310] In some embodiments, in compounds of formula (IIb-1) or (IIb-2), tautomers, deuterated derivatives, or pharmaceutically acceptable salts:

[0311] R A and R B Each is independently hydrogen or C1-C2 alkyl;

[0312] U 1 It can be -NH2 or -OH;

[0313] U 2 It can be hydrogen, halogen, or -CH3;

[0314] X does not exist; it is -CH2-, -(CH2)2-, -(CH2)3-, or -CH2OCH2-.

[0315] Furthermore, all other variables not specifically defined in this paper are defined for any of the equations (Ia), (Ib), (IIb-1), and (IIb-2).

[0316] In some embodiments, in compounds of formula (IIb-1) or (IIb-2), tautomers, deuterated derivatives, or pharmaceutically acceptable salts:

[0317] X is -(CH2)2-, -(CH2)3-, or -CH2OCH2-;

[0318] Y represents -COOH;

[0319] Furthermore, all other variables not specifically defined in this paper are defined for any of the equations (Ia), (Ib), (IIb-1), and (IIb-2).

[0320] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 and R 2 Each of these variables is independently halogen, C1-C2 alkyl, or C1-C2 alkoxy, and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0321] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 Each occurrence is independently F, Cl, -CH3, or -OCH3; and all other variables are defined as in any of the aforementioned implementation schemes.

[0322] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2F is the variable that appears each time; and m is an integer selected from 0 and 1; and all other variables are defined as in any of the aforementioned implementation schemes.

[0323] In some embodiments, among the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, k is an integer selected from 1 and 2; and all other variables are as defined in any of the foregoing embodiments.

[0324] In some embodiments, m is 0 in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein; and all other variables are as defined in any of the foregoing embodiments.

[0325] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are selected from compounds 1-210 (Table A), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0326] Table A. Compounds 1-210

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345] Some embodiments of this disclosure include compounds 1-210 or formulas (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-5). (For example, derivatives of compounds of 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)) or their tautomers. In some embodiments, the derivative is a silicon derivative selected from compounds 1-210 or formulas (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-5). (For example, in one of the compounds of 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)), at least one carbon atom in the compound has been replaced by silicon.In some embodiments, the derivative is a boron derivative, wherein the derivative is selected from compounds 1-210 or formulas (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-5) (e.g. At least one carbon atom in a compound of 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)) or a tautomer thereof has been replaced by boron. In other embodiments, the derivative is a phosphate derivative, wherein it is selected from compounds 1-210 or formulas (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-5) (e.g. In a compound of formulas (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), at least one carbon atom in the compound or its tautomer has been replaced by phosphorus. Since the general properties of silicon, boron, and phosphorus are similar to those of carbon, replacing carbon with silicon, boron, or phosphorus can produce compounds with similar biological activities to the original carbon-containing compound.

[0346] In some embodiments, the derivative is a silicon derivative, wherein the derivative is selected from compounds 1-210 or formulas (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-5) (e.g. In a compound of formulas (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), and their tautomers, at least one carbon atom has been substituted with silicon. In other embodiments, two carbon atoms have been substituted with silicon. The silicon-substituted carbon may be a non-aromatic carbon. In some embodiments, the quaternary carbon atom of the tert-butyl moiety may be substituted with silicon. In some embodiments, the silicon derivatives of this disclosure may contain one or more deuterium-substituted hydrogen atoms. For example, one or more hydrogen atoms of the tert-butyl moiety (where the carbon has been substituted with silicon) may be substituted with deuterium. In other embodiments, the compounds are selected from compounds 1-210 or formulas (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-5) (e.g., formula (Ia)). Silicon derivatives of compounds and their tautomers may have silicon incorporated into the heterocycle.

[0347] Another aspect of this disclosure provides pharmaceutical compositions comprising a group selected from formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)). A compound of any one of (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), compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a pharmaceutical composition comprising a drug composition selected from formulas (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-5) is administered to a patient in need. At least one compound comprising (Ia-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)) and compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0348] 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 pharmaceutically acceptable mediators and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0349] It should also be understood that the pharmaceutical compositions disclosed herein can be used in combination therapies; that is, the pharmaceutical compositions described herein may further comprise at least one other active agent. Alternatively, they may comprise formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(IIb-2)). A pharmaceutical composition comprising 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 may be administered as a standalone composition concurrently with, before, or after a composition comprising at least one additional active agent. In some embodiments, a pharmaceutical composition comprising 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 may be administered as a standalone composition concurrently with, before, or after a composition comprising at least one additional active agent.

[0350] In some implementations, formulas (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) or (VIb-1)-(VIb-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Vb-5)). Compounds of (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), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active agent for the treatment of AATD simultaneously, alone or sequentially. In some implementations, when used simultaneously, formulas selected from (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), or (VIb-1)-(VIb-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2)). The compounds of (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, and the at least one additional active agent are contained in a separate pharmaceutical composition.In some implementations, when used simultaneously, formulas (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), or (VIb-1)-(VIb-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2)) The pharmaceutical composition comprises compounds of (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), or (VIb-1)-(VIb-2), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and the at least one additional active agent. In some embodiments, the compound is 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.

[0351] In some implementations, formulas (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) or (VIb-1)-(VIb-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ...2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), Compounds of (Ib-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), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided in a method for treating AATD, wherein the method comprises 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0352] In some implementations, formulas (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) or (VIb-1)-(VIb-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Va-2), (Vb-1)-(Vb-5)). Compounds of (IIb-1), (IIIb-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), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with an additional active agent, are provided in a method for 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0353] In some embodiments, in a method of providing an additional active agent for treating AATD, the method includes co-administering the additional active agent and formulas (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), or (VIb-1)-(VIb-5) (e.g., Compounds of formulas (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), or (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, 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0354] In some implementations, formulas (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) or (VIb-1)-(VIb-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Ia-2), (IIb-1)-(Ia-2), (IIb-1)-(IIb-2), (Ia-3), (IIb-1)-(IIb-2 ...2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), (IIb-2), (IIb-1)-(IIb-2), (IIb-2), Compounds of (Ib-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), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided in a method for 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 co-administration. In some embodiments, the compound is 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.

[0355] In some implementations, formulas (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) or (VIb-1)-(VIb-5) are used (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2), (IIb-1)-(Va-2), (Vb-1)-(Vb-5)). Compounds of (IIb-1), (IIIb-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), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, combined with an additional active agent, are provided in a method for 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 co-administration. In some embodiments, the compound is 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.

[0356] In some embodiments, in the method of providing an additional active agent for treating AATD, the additional active agent is prepared for use with 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), or (VIb-1)-(VIb-5) (e.g., formula (Ia) This includes compounds of the following types: (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), or (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, the compound and additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and additional active agent are prepared for simultaneous administration. In some embodiments, the compound and additional active agent are prepared for sequential co-administration. In some embodiments, the compound is 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.

[0357] In some embodiments, the additional active agent is selected from the group consisting of α-1 antitrypsin protein (AAT) derived from plasma of a healthy human donor and recombinant AAT. In some embodiments, the additional active agent is α-1 antitrypsin protein (AAT) derived from plasma of a healthy human donor.

[0358] 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 mediators. As used herein, at least one pharmaceutically acceptable carrier includes any and all solvents, diluents, other liquid mediators, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for the desired particular dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York discloses various carriers for formulating pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effects or otherwise interacting in a harmful manner with any other component of the pharmaceutical composition, its use is contemplated within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of saturated vegetable fatty acid metaglycerides, water salts and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl...). Cellulose and cellulose acetate), powdered tragacanth gum, 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, ethanol, phosphate buffer, non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavorings, aromas, preservatives, and antioxidants.

[0359] In another aspect of this disclosure, the compounds and pharmaceutical compositions described herein are used to treat AATTD. In some embodiments, the subject requiring treatment with the compounds and compositions of this disclosure carries a ZZ mutation. In some embodiments, the subject requiring treatment with the compounds and compositions of this disclosure carries an SZ mutation.

[0360] In some embodiments, the method of this disclosure includes administering to a patient in need a formula selected from (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-5) (e.g., formulas (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-5)). A 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 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 has a Z mutation in the α-1 antitrypsin gene. In some embodiments, the patient in need is homozygous for the Z mutation in the α-1 antitrypsin gene.

[0361] Another aspect of this disclosure provides methods for modulating α-1-antitrypsin activity, methods comprising reacting the α-1-antitrypsin with formulas (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-5) (e.g., formula (Ia)). The method of modulating α-1 antitrypsin activity includes contacting the α-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. In some embodiments, the method of modulating α-1 antitrypsin activity includes contacting the α-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.

[0362] In some embodiments, the method for modulating α-1-antitrypsin activity is performed in vivo. In some embodiments, the method for modulating α-1-antitrypsin activity is performed ex vivo, and the α-1-antitrypsin is derived from a biological sample obtained from a human subject. In some embodiments, the method for modulating AAT is performed in vitro, and the α-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 taken from a liver biopsy.

[0363] III. Preparation of Compounds

[0364] All genera, subgenera and specific compound formulas disclosed herein are considered part of this disclosure.

[0365] A. Compound of Formula I

[0366] The compounds disclosed herein can be prepared according to standard chemical practices or as described herein. Throughout the following synthetic schemes and for the preparation of formulas (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-5) (e.g., formulas (Ia), (Ib), (IIa-1)-(IIa-2) In the description of compounds of (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), compounds 1-210, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used:

[0367] abbreviation

[0368] BrettPhos Pd G4 = dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tris(prop-2-yl)phenyl]phenyl]phosphine; methanesulfonic acid; N-methyl-2-phenylaniline; palladium

[0369] DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-2-amino

[0370] DMA = dimethylacetamide

[0371] DMAP = dimethylaminopyridine

[0372] DME = dimethoxyethane

[0373] DMF = dimethylformamide

[0374] DMSO = dimethyl sulfoxide

[0375] EtOH = ethanol

[0376] EtOAc = Ethyl acetate

[0377] HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphine hexafluoride ion)

[0378] MeOH = methanol

[0379] MP-TMT cleaner resin = macroporous polystyrene-bonded trithiotriazine, resin-bonded 2,4,6-trithiotriazine (TMT) equivalent.

[0380] MTBE = Methyl tert-butyl ether

[0381] NMM = N-methylmorpholine

[0382] NMP = N-methylpyrrolidine

[0383] Pd(dppf)₂Cl₂=[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0384] PdCl2 = Palladium(II) dichloride

[0385] PdCl2(PPh3)2=bis(triphenylphosphine)palladium(II) dichloride

[0386] SFC = Supercritical Fluid Chromatography

[0387] SPhos Pd G3=(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

[0388] TBAF = Tetrabutylammonium fluoride

[0389] tBuXPhos Pd G1 = Chloro[2-(di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) or t-BuXPhospalladium(II) chlorinated phenethylamine

[0390] tBuXPhos Pd G3=[(2-di-tert-butylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

[0391] tBuXPhos Pd G4=di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine; dichloromethane; methanesulfonic acid; N-methyl-2-phenyl-aniline palladium(II)

[0392] TFA = Trifluoroacetic acid

[0393] THF = Tetrahydrofuran

[0394] XPhos Pd G1 = (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride or (XPhos)palladium(II) chloride phenethylamine

[0395] In some embodiments, the method for preparing a compound of formula (Ia) or (Ib), its tautomers, deuterated derivatives of these compounds and tautomers, or a pharmaceutically acceptable salt of any of the foregoing comprises reacting a compound of formula (Ia) or (Ib), its tautomers, deuterated derivatives, or a pharmaceutically acceptable salt with a deprotecting agent, as shown in Schemes 1 to 8 below (wherein all variables are as defined above for formula (Ia) or (Ib).

[0396] Option 1

[0397]

[0398] Scheme 1 refers to a method for preparing intermediates of general formulas 1-7, which can be used as intermediates in the preparation of compounds of formulas Ia and 1b. PG 1 It is any suitable alcohol protecting group. For example, PG 1 It can be benzyl, methyl, or MOM. PG 2 It is any suitable alcohol protecting group that can react with PG. 1 Orthogonal removal. For example, PG. 2 It can be based on silicon-based protecting groups, such as TBS or TBDPS. Q 1 and Q 2The compounds are halogens, such as Cl, Br, or I. Compounds of Formulas 1-3 can be prepared from 1-1 and 1-2 using any suitable conditions for the Sonagashira coupling reaction. For example, the reaction can be carried out in the presence of catalysts 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 and under heating (e.g., 50°C). Compounds of Formulas 1-4 can be prepared from compounds of 1-3 using suitable reagents for adding an alcohol protecting group. In some embodiments, TBS chloride in a dichloromethane solvent in the presence of imidazole can be used. Compounds of Formulas 1-5 can be prepared by amidation of compounds of Formulas 1-4 using any suitable conditions for Buchwald amidation. For example, in some embodiments, a 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 ambient temperature. In some embodiments, compounds of Formulas 1-7 are spontaneously formed during the reaction conditions used for amidation. In some embodiments, compounds of formulas 1-7 are formed from 1-6 using any suitable conditions for cyclizing an amine into an alkyne. For example, in some embodiments, treatment with a palladium catalyst such as PdCl2 or PdCl2(MeCN)2 can be used. The reaction can be carried out under heating. The reaction can be carried out in methanol and ethyl acetate solvents. In some embodiments, a base such as KOtBu can be used. Compounds of formulas 1-8 can be prepared from compounds of formulas 1-7 using any suitable conditions for removing the silicon protecting group. For example, a reagent such as TBAF can be used. The reaction can be carried out in a solvent such as 2-methyl-THF at 70°C.

[0399] Option 2

[0400]

[0401] Scheme 2 illustrates a method for preparing compounds of formulas 2-8, which can be used as intermediates in the preparation of compounds of formulas Ia and Ib. Compounds of formulas 2-8 can be prepared from compounds of formula 2-1 using the methods described for the preparation of compounds of formulas 1-8.

[0402] Option 3

[0403]

[0404] Scheme 3 illustrates a method for preparing compounds of formulas 3-3 from compounds of formulas 1-8. Compounds of formula 3-2 can be prepared from 1-8 by reductive alkylation followed by intramolecular cyclization to a ketone of formula 3-1. In some embodiments, the reaction can 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 can be used. The reaction can be carried out at room temperature in a solvent such as dichloroethane. Compounds of formula 3-3 can be used to remove PG... 1 The alcohol protecting group is prepared by any suitable method from 3-2. In some embodiments, in PG 1 In the case of a benzyl group, transfer hydrogenation conditions can be used. For example, the compound of formula 3-2 can be treated with palladium on carbon and ammonium formate in solvents such as ethanol and ethyl acetate to give the compound of formula 3-3. In some embodiments, a Pd(OH)₂ catalyst can be used. In some instances, a dealkylating agent such as BBr₃ in a solvent such as dichloromethane can be used to remove the benzyl protecting group.

[0405] Option 4

[0406]

[0407] Scheme 4 illustrates a method for preparing compounds of formula 4-3. Compounds of formula 4-3 can be prepared from compounds 2-8 using a similar method for preparing compounds of formula 3-3.

[0408] Option 5

[0409]

[0410] Scheme 5 illustrates a method for preparing compounds of formula 5-3. A reductive alkylation and cyclization reaction between compounds of formulas 1-8 and a ketone of formula 5-1 yields a compound of formula 5-2. This reaction can be carried out in the presence of triethylsilane and methanesulfonic acid. The reaction can be carried out in solvents such as dichloroethane or dichloromethane. The reaction can also be carried out under heating, for example, up to 50°C. Standard alcohol deprotection methods can be used to prepare compounds of formula 5-3 from compounds of formula 5-2.

[0411] Option 6

[0412]

[0413] Scheme 6 illustrates a method for preparing compounds of formula 6-3 from compounds of formulas 2-8. Compounds of formula 6-3 can be prepared from compounds of formulas 2-8 using methods similar to those used for preparing compounds of formula 5-3.

[0414] Option 7

[0415]

[0416] Scheme 7 shows a method for preparing compounds of formula 7-3 from compounds of formula 7-1. 21 It is any suitable alkyl group that forms an ester protecting group. For example, R 21 It can be Me, Et, iPr, or tBu. The compound of formula 7-2 can be prepared from 7-1 using any suitable method for ester deprotection. 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, in R... 21 When the group is tert-butyl, the compound of formula 7-1 can be treated with trifluoroacetic acid to obtain the compound of formula 7-2.

[0417] Option 8

[0418]

[0419] Scheme 8 shows a method for preparing compound of formula 8-2 from compound of formula 8-1. Conditions similar to those used for preparing compound of formula 7-3 can be used. Example

[0420] To provide a fuller understanding of the disclosure described herein, the following embodiments are illustrated. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting this disclosure in any way.

[0421] Example 1. Synthesis of the compound

[0422] All specific and general compounds, methods for preparing those compounds, and intermediates disclosed for preparing those compounds are considered part of this disclosure.

[0423] A. Synthetic starting materials

[0424] The preparation of S1-S22 describes the synthetic route for the intermediates used to synthesize compounds 1-210.

[0425] Preparation of S1

[0426] 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S1)

[0427]

[0428] Step 1. Synthesis of 1-benzyloxy-3-bromo-2-iodobenzene (C2)

[0429] A solution of 3-bromo-2-iodophenol C1 (129 g, 431.6 mmol) in acetone (1.5 L) was stirred for 5 minutes. 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 hours. The mixture was then cooled to room temperature, filtered, and washed with acetone (2 × 100 mL). The combined filtrates were concentrated under vacuum. 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, filtered, and concentrated under vacuum. Purification by silica gel chromatography (0–50% ethyl acetate / heptane) gave product C2 (162 g, 96%) as a white solid. 1 ¹H NMR (300MHz, 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).

[0430] Step 2. Synthesis of 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol (C3)

[0431] In a 3L three-necked round-bottom flask equipped with a top stirrer, temperature probe, reflux condenser, and nitrogen inlet, a solution of 1,4-dioxane (1.1L) containing 1-benzyloxy-3-bromo-2-iodobenzene C2 (160g, 411.3mmol) and 2,2-dimethylbut-3-yn-1-ol (51g, 519.6mmol) was added and stirred for 5 minutes. Then, N-isopropylprop-2-amine (370mL, 2.64mol) was added. The reaction mixture was purged with nitrogen for approximately 15 minutes, followed by the addition of cuprous iodide (3.7g, 19.4mmol) and PdCl2 (12.5g, 17.8mmol). The resulting reaction mixture was heated to 50°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and poured into water (300mL). A saturated aqueous solution of NH4Cl (approximately 400mL) was added, followed by ethyl acetate (approximately 2L), and the mixture was stirred for 15 minutes. The organic layer was separated, washed with 1N HCl solution (2 x 200 mL) and brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Purified by silica gel chromatography (gradient: 0-50% ethyl acetate / heptane) to give the product as a yellow solid: 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol (130 g, 88%).1 HNMR(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] + .

[0432] Step 3. Synthesis of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-acetyoxy]-tert-butyl-dimethyl-silane (C4)

[0433] A solution of 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol C3 (130 g, 361.9 mmol) in DMF (850 mL) was placed in a 3 L, 3-necked, round-bottom flask equipped with a top-mounted stirrer, temperature probe, reflux condenser, and nitrogen inlet. The mixture was stirred at ambient temperature for 5 min, 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 (~1 L) and extracted with MTBE (2 x 1 L). The organic phase was washed with 1 N HCl (2 x 200 mL) and brine (200 mL), 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 / heptane) to product C4 as a clear, pale yellow oil. [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethyl-silane (164g, 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).

[0434] 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)

[0435] A solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethyl-silane C4 (2 g, 4.224 mmol) and 4-fluoro-2-methyl-aniline (600 mg, 4.794 mmol) in dioxane (8 mL) was bubbled under nitrogen for 5 min. Sodium tert-butoxide (5 mL, 2 M, 10.00 mmol) was added to the mixture, followed by tBuXphosPalladacycle (150 mg, 0.2184 mmol). The reaction was monitored by LC-MS. The reaction was completed within 30 min. 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, and the layers were again separated by a phase separator, and the combined organic matter was concentrated. The product C5 (2.1 g, 96%) was purified by column chromatography (40 g column; 0-20% heptane solution of EtOAc) to obtain a straw-colored oily product. 1 HNMR (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), 6.39-6.3 1(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).

[0436] Step 5. Synthesis of [2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-propoxy]-tert-butyl-dimethyl-silane (C6)

[0437] PdCl2 (150 mg, 0.846 mmol) was added to a mixture of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethylbut-1-ynyl]-N-(4-fluoro-3-methyl-phenyl)aniline C5 (2.1 g, 96%) in CH3CN (20 mL) and stirred for 20 min. The reaction mixture was concentrated and then purified by elution with 0–30% EtOAc / heptane through a 40 g silica gel cartridge to give the product (1.3 g, 59%). 1H 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,1 H), 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).

[0438] Step 6. Synthesis of 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-prop-1-ol (S1)

[0439] At room temperature, tetrabutylammonium fluoride (1M THF solution, 4 mmol) was added to a solution of C6 (1.6 g, 3.09 mmol) in THF (5 mL). TLC at 8:47 AM showed approximately 50% conversion to the product (confirmed by LCMS). After 90 minutes, 2 mL of TBAF was added at room temperature. After 2 hours, the reaction was concentrated and purified by column chromatography (80 g column; 0-100% EtOAc in heptane solution) to give product S1 as a grayish-white solid. 1 H NMR (400MHz, chloroform-d) δ7.45-7.41(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] +

[0440] Preparation of S2

[0441] 2-(4-(benzyloxy)-1-(3-chloro-4-fluorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S2)

[0442]

[0443] 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)

[0444] [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethylsilane C7 (1.94 g, 4.10 mmol) and 3-chloro-4-fluoroaniline (650 mg, 4.47 mmol) in xylene (50 mL) were added under nitrogen atmosphere with NaOtBu (1.18 g, 12.3 mmol), followed by the addition of tBuXPhos Pd G3 (145 mg, 0.183 mmol). The reaction mixture was stirred at room temperature for 4 hours, then diluted with water and saturated NH4Cl aqueous solution and extracted twice with EtOAc. The combined organic compounds were concentrated to dryness and purified by silica gel chromatography (eluting with a heptane solution of 0-50% EtOAc). The purified fractions were combined and concentrated to give a light brown oil (2.21 g, 100%).

[0445] Step 2. Synthesis of 4-(benzyloxy)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropyl-2-yl)-1-(3-chloro-4-fluorophenyl)-1H-indole (C8)

[0446] Potassium 2-methylpropionic acid (1 M, 5 mL, 5 mmol) was added 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) at room temperature. After 5 hours, the reaction was quenched with saturated NH4Cl aqueous solution and extracted twice with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated to give the product (2.21 g, 100%), which was then used for the next reaction without further purification. LCMS m / z 538.36 [M+1] +

[0447] Step 3. Synthesis of 2-(4-(benzyloxy)-1-(3-chloro-4-fluorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S2)

[0448] TBAF (1M THF solution, 8 mL, 8 mmol) was added to a solution of 4-(benzyloxy)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropyl-2-yl)-1-(3-chloro-4-fluorophenyl)-1H-indole C8 (2.21 g, 4.10 mmol) in 2-MeTHF (5 mL). After 4 days, another 10 mL of TBAF solution was added, and the mixture was heated overnight at 70 °C. The reaction mixture was concentrated. Purification by column chromatography (120 g column; 0-75% EtOAc in heptane solution) yielded a straw-colored oily product (625 mg, 36%). 1 H NMR (400MHz, chloroform-d) δ7.57-7.30(m,8H),7.02(t,J=8.0Hz,1H),6.74(d,J=0.8Hz,1H),6.63(d,J=7.8H z, 1H), 6.33 (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] +

[0449] Preparation of S3

[0450] 2-(4-(benzyloxy)-1-(3-fluoro-4-methylphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S3)

[0451]

[0452] Step 1. Synthesize 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(3-fluoro-4-methylphenyl)aniline (C9).

[0453] [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethyl-silane C4 (4 g, 8.45 mmol), 3-fluoro-4-methyl-aniline (1.5 g, 12.0 mmol), and sodium 2-methylprop-2-ol (2 g, 20.8 mmol) were placed in a flask, followed by 25 mL of THF. The mixture was stirred for 5 min and then degassed with nitrogen for ~10 min. tBuXPhos Pd G1 (0.2 g, 0.3071 mmol) was added, and the reaction mixture was degassed again for a few minutes. The resulting reaction mixture was warmed to 60 °C and stirred at this temperature for 3 h. The solvent was evaporated. The product (3.58 g, 75%) was purified by column chromatography (20 g column, eluted with heptane solution of 0-100% ethyl acetate). LCMS m / z 518.51 [M+1] +

[0454] Step 2. Synthesis of 2-(4-(benzyloxy)-1-(3-fluoro-4-methylphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S3)

[0455] 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 loaded into 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 hours, and then the solvent was evaporated. Purification by column chromatography (80 g column, eluted with heptane solution of 0-100% ethyl acetate) yielded 2-[4-benzyloxy-1-(3-fluoro-4-methyl-phenyl)indol-2-yl]-2-methyl-prop-1-ol (2.3 g, 84%). 1 H NMR (400MHz, methanol-d4) δ7.53-7.46(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] +

[0456] Preparation of S4

[0457] 2-(4-(benzyloxy)-1-(3,4-difluorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S4)

[0458]

[0459] 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)

[0460] To a solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethyl-silane C4 (11 g, 23.2 mmol) and 3,4-difluoroaniline (3.27 g, 25.33 mmol) in xylene (60 mL), NaOtBu (6 g, 62.4 mmol) was added under nitrogen, followed by the addition of 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 NH4Cl and extracted with EtOAc (x2). The combined organic compounds were concentrated to dryness and purified by silica gel chromatography (column: 220 g silica, gradient: 0-50% heptane solution of EtOAc) to give a product (11.6 g, 96%) as a yellow oil. 1 H 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), 6.86-6.8 0(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] + .

[0461] Step 2. Synthesis of 2-[4-benzyloxy-1-(3,4-difluorophenyl)indol-2-yl]-2-methyl-prop-1-ol (C24)

[0462] 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 hour. 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: 0-75% 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=8.0Hz ,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] + .

[0463] Preparation of S5

[0464] 2-(4-(benzyloxy)-1-(3,4-difluorophenyl)-6-fluoro-1H-indol-2-yl)-2-methylprop-1-ol (S5)

[0465]

[0466] Step 1. Synthesis of 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol (C12)

[0467] A solution of 1-benzyloxy-3-bromo-5-fluoro-2-iodobenzene C11 (5 g, 12.3 mmol) and 2,2-dimethylbut-3-yn-1-ol (1.8 g, 18.3 mmol) in 1,4-dioxane (40 mL) and Et3N (40 mL) was purged with nitrogen for 10 min, followed by the addition of CuI (157 mg, 0.82 mmol) and PdCl2(PPh3)2 (500 mg, 0.71 mmol). The resulting reaction mixture was heated to 50 °C and stirred overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and partitioned between saturated NH4Cl aqueous solution (~50 mL) and ethyl acetate (~150 mL). After stirring for 10 min, the organic layer was separated, washed with 1N HCl solution (2 x 50 mL), water (30 mL), and brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 0-70% ethyl acetate in heptane solution) to give a clear, yellow, viscous oily product. 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol C12 (4.23 g, 90%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.49 (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] + .

[0468] Step 2. Synthesis of ((4-(2-(benzyloxy)-6-bromo-4-fluorophenyl)-2,2-dimethylbut-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane (C13)

[0469] Imidazole (561 mg, 8.24 mmol) was added in a single addition 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) at room temperature. After 40 minutes, water and dichloromethane were added. The layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane and the layers were again separated by a phase separator, and the combined organic matter was concentrated. The product C13 was purified by column chromatography (80 g column; 0-40% EtOAc in heptane solution). 1¹H NMR (400MHz, 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).

[0470] 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)

[0471] To a solution of [4-(2-benzyloxy-6-bromo-4-fluorophenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethylsilane C13 (2.35 g, 4.78 mmol) and 3,4-difluoroaniline (540 μL, 5.45 mmol) in xylene (20 mL), NaOtBu (1.2 g, 12.5 mmol) was added under nitrogen. Nitrogen was bubbled through the mixture for 10 min. tBuXPhos PdG3 (48 mg, 60.4 μmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with 2x EtOAc. The combined organic matter was dried (Na2SO4), filtered, and concentrated. Purification was achieved by silica gel column chromatography (80 g) elution with a heptane solution of 0–50% EtOAc to give product C14 (2.56 g, 99%). 1 H NMR (300MHz, chloroform-d) δ7.50-7.44(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=8.3,4.1H z,1H),6.52(s,1H),6.34(dd,J=11.0,2.3Hz,1H),6.14(dd,J=10.5,2.3H z,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] + .

[0472] Step 4. Synthesis of 2-(4-(benzyloxy)-1-(3,4-difluorophenyl)-6-fluoro-1H-indol-2-yl)-2-methylprop-1-ol (S5)

[0473] A flask was filled with 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethylbut-1-ynyl]-N-(3,4-difluorophenyl)-5-fluoroaniline C14 (2.56 g, 4.74 mmol), methanol (30 mL), and ethyl acetate (15 mL), and degassed with nitrogen for 30 min. PdCl2(CH3CN)2 (100 mg, 0.386 mmol) was added, and the mixture was heated to 60 °C overnight. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (80 g column; 0-30% EtOAc in heptane) to give product S5 (1.75 g, 87%) as an orange solid. 1 H NMR (400MHz, chloroform-d) δ7.56-7.51(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] + .

[0474] Preparation of S6

[0475] 2-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S6)

[0476]

[0477] Step 1. 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(4-fluorophenyl)aniline (C15)

[0478] A solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethylsilane 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 min. Then, NaOtBu (24.5 g, 255 mmol) and tBuXPhos Pd G3 (2.03 g, 2.56 mmol) were added in a single batch, and the reaction mixture was stirred at 35 °C for 4 hours. Filtration. The filtered solid was washed with xylene and the filtrate was concentrated. The filtered solid was washed with 1:1 EtOAc and water, and the organic layers of the filtrates were combined and concentrated with xylene filtrate to give a dark brown oil. Purification was performed by silica gel chromatography (gradient: 0-20% EtOAc in heptane solution) to give product C15 (40.3 g, 94%) as a light yellow oil. 1 H NMR (400MHz, chloroform-d) δ7.53 (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] + .

[0479] Step 2. Synthesis of [2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-propoxy]-tert-butyl-dimethyl-silane (C16)

[0480] PdCl2 (567 mg, 3.2 mmol) was added 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). The reaction mixture was stirred overnight at 60 °C and then filtered. The filtrate was concentrated to dryness, ground with MeCN, and filtered again. The method was repeated 3–4 times, and all solids were combined and dried under vacuum to give product C16 (38.1 g, 95%) as a brown solid. 1 H NMR (400MHz, chloroform-d) δ7.60-7.55(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] + .

[0481] Step 3. Synthesis of 2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-prop-1-ol (S6)

[0482] TBAF (40 mL, 1 M, 40.0 mmol) was added 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). The mixture was stirred at 55 °C for 4 hours, then concentrated and purified by silica gel chromatography (gradient: 0-50% EtOAc in heptane solution) to give the product 2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-prop-1-ol S6 (3.15 g, 85%) as a grayish-white solid. 1 H NMR (400MHz, chloroform-d) δ7.51-7.17(m,7H),7.08(q,J=8.3,7.9Hz,2H),6.88(t,J=7.9Hz,1H),6.6 2(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] + .

[0483] Preparation of S7

[0484] 2-(4-(benzyloxy)-6-fluoro-1-(4-fluorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S7)

[0485]

[0486] 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)

[0487] To a solution of [4-(2-benzyloxy-6-bromo-4-fluorophenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethylsilane C13 (2.76 g, 5.62 mmol) and 4-fluoroaniline (600 μL, 6.33 mmol) in xylene (50 mL), NaOtBu (1.35 g, 14.1 mmol) was added under nitrogen, and nitrogen was bubbled through the mixture for 10 min. Then, tBuXPhos Pd G3 (130 mg, 0.164 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and brine and extracted twice with EtOAc. The combined organic matter was dried (Na2SO4), filtered and concentrated, and purified by silica gel chromatography (120 g) with a heptane solution of 0-20% EtOAc to give product C17 as a pale yellow oil. The product solidified upon standing to give a grayish-white solid (2.76 g, 94%). 1 H NMR (400MHz, chloroform-d) δ7.50-7.46(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),6.25(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] + .

[0488] Step 2. Synthesis of 2-(4-(benzyloxy)-6-fluoro-1-(4-fluorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S7)

[0489] A flask was filled with 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethylbut-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 min. PdCl2(CH3CN)2 (220 mg, 0.8480 mmol) was added, and the mixture was heated at 60 °C. A precipitate formed, so another portion of EtOAc (20 mL) was added. After two months, the reaction was concentrated under reduced pressure and then purified by column chromatography (80 g column; 50–100% heptane solution of EtOAc) to give product S7 (2 g, 93%) as a brown solid. LCMS m / z 408.14 [M+H] + .

[0490] Preparation of S8

[0491] 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S8)

[0492]

[0493] Step 1. Synthesis of 4-(benzyloxy)-1-bromo-2-iodobenzene (C19)

[0494] 1-Benzyloxy-3-iodobenzene (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 through a feeding funnel. During the addition, the temperature was raised to 15 °C. After stirring overnight, the reaction mixture was poured into 1 L of water to form an emulsion suspension, which was extracted with dichloromethane (3 x 100 mL). The extract was washed with a saturated aqueous solution of NaHCO3 and the organic layer was dried (Na2SO4), filtered, and concentrated. The crude oil was purified by rapid chromatography (Combiflash ISCO, 330 g gold column) eluting with 0–20% EtOAc / hexane to give product C19 (18 g, 47%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.54–7.31 (m, 7H), 6.83–6.81 (s, 1H), 5.00 (s, 2H).

[0495] Step 2. Synthesis of 4-(5-benzyloxy)-2-bromophenyl)-2,2-dimethylbut-3-yn-1-ol (C20)

[0496] 4-Benzyloxy-1-bromo-2-iodobenzene 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 min. Bisphenylphosphine 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 off using EtOAc and then concentrated. Purification by column chromatography (330 g column; 0–100% EtOAc in heptane) gave product C20 (10 g, 81%) as a pale yellow oil. 4-(5-Benzyloxy-2-bromo-phenyl)-2,2-dimethylbut-3-yn-1-ol (10g, 81%) 1H NMR (400MHz, chloroform-d) δ7.45(d,J=8.9Hz,1H),7.44-7.34(m,5H),7.09(d,J=3.0Hz,1H),6.82(d d,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 / z359.17[M+H] + .

[0497] Step 3. Synthesis of ((4-(5-(benzyloxy)-2-bromophenyl)-2,2-dimethylbut-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane (C21)

[0498] 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), tert-butylchloro-diphenyl-silane (3 mL, 11.5 mmol) was added, followed by imidazole (1.93 g, 28.4 mmol), and the mixture was stirred overnight at room temperature. Another portion of tert-butylchloro-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 (Na2SO4), filtered, and concentrated. Purification by column chromatography (120 g gold column; 0-10% EtOAc in heptane solution) gave product C21 (2 g, 31%). 1 H NMR (400MHz, chloroform-d) δ7.78-7.72(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).

[0499] 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)

[0500] ((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-methylaniline (500 mg, 4.00 mmol) were dissolved in dioxane (6 mL) and t-BuOH (6 mL). Sodium tert-butoxide (767 mg, 7.98 mmol) and tBuXphosPalladacycle (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 then passed through an EtOAc tube. The product was filtered and then concentrated. It was purified by column chromatography (80g gold column, heptane) to obtain product C22 (1.22g, 54%), which was a straw-colored oil. 1 ¹H 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).

[0501] Step 5. Synthesis of 5-(benzyloxy)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropyl-2-yl)-1-(4-fluoro-3-methylphenyl)-1H-indole (C23)

[0502] Potassium 2-methylprop-2-olate (1 M THF solution, 5.1 mL, 5.1 mmol) was added 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) at room temperature. After 4 hours, the reaction mixture was diluted with water and saturated ammonium chloride and extracted twice with EtOAc. The combined organic matter was dried (Na2SO4), filtered, and concentrated to give product C23 (2.19 g, 100%), which was then used for the next reaction without further characterization.

[0503] Step 6. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S8)

[0504] TBAF (1M THF solution, 5.5 mL, 5.5 mmol) was added to a solution of 5-(benzyloxy)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropyl-2-yl)-1-(4-fluoro-3-methylphenyl)-1H-indole C23 (2.19 g, 4.23 mmol) in THF (10 mL) at room temperature. After 1 hour, another 2.5 mL of TBAF solution was added at room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with water and saturated ammonium chloride and extracted twice with EtOAc. The combined organic matter was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (80 g silica gel column; 0-100% ethyl acetate in heptane solution) to give product S8 (970 mg, 57%) as a pale yellow-white solid. 1 H NMR (400MHz, chloroform-d) δ7.51-7.31(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=0.8 Hz, 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] + .

[0505] Preparation of S9

[0506] 2-(5-fluoro-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S9)

[0507]

[0508] Step 1. Synthesis of 4-(2-bromo-5-fluorophenyl)-2,2-dimethylbut-3-yn-1-ol (C25)

[0509] 1-Bromo-4-fluoro-2-iodobenzene 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 min. Bisphenylphosphine 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 off using EtOAc and then concentrated. Purification by column chromatography (80 g column; 0–100% heptane solution of EtOAc) gave product C25 (2.73 g, 78%). 1 H NMR (400MHz, chloroform-d) δ7.54 (dd, J=8.9, 5.3Hz, 1H), 7.18 (dd, J=8.9, 3.0Hz, 1H), 6.91 (d dd,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] + .

[0510] Step 2. Synthesis of ((4-(2-bromo-5-fluorophenyl)-2,2-dimethylbut-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane (C26)

[0511] 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) was mixed with tert-butylchloro-diphenyl-silane (2.66 mL, 10.2 mmol), followed by the addition of imidazole (1.5 g, 22.0 mmol), and the mixture was stirred for 4 hours. The compound C26 (4.25 g, 83%) was purified by column chromatography (C18 AQ 275 g column; TFA / MeCN aqueous solution) to obtain a pure compound C26 as a colorless oil. 1 ¹H NMR (400MHz, chloroform-d) δ 7.70–7.64 (m, 4H), 7.46 (dd, J = 8.8, 5.3 Hz, 1H), 7.42–7.31 (m, 6H), 7.06 (dd, J = 9.0, 3.0 Hz, 1H), 6.82 (ddd, J = 8.9, 7.9, 3.1 Hz, 1H), 3.58 (s, 2H), 1.33 (s, 6H), 1.06 (s, 9H).

[0512] Step 3. Synthesize 2-(4-((tert-butyldiphenylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-4-fluoro-N-(4-fluoro-3-methylphenyl)aniline (C27).

[0513] C26 (2.06 g, 4.04 mmol), 4-fluoro-3-methylaniline (610 mg, 4.874 mmol), and sodium tert-butoxide (880 mg, 9.16 mmol) were suspended / dissolved in dioxane (8 mL) and t-BuOH (8 mL), and the reaction mixture was purged with nitrogen for several minutes. During purging, tBuXphosPalladacycle (139 mg, 0.202 mmol) was added, and the reaction mixture was stirred at 45 °C for 4 hours. The reaction mixture was diluted with water and dichloromethane. The layers were separated using a phase separator, and the combined organic compounds were concentrated. Purification by column chromatography (80 g gold column, heptane) yielded product C27 (2.24 g, 100%) as a straw-colored oil. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.75–7.67 (m, 4H), 7.50–7.34 (m, 6H), 7.04 (dd, J = 9.0, 2.9 Hz, 1H), 6.98–6.82 (m, 5H), 6.06 (s, 1H), 3.62 (s, 2H), 2.23 (d, J = 2.0 Hz, 3H), 1.36 (s, 6H), 1.08 (s, 9H).

[0514] Step 4. Synthesis of 2-(1-((tert-butyldiphenylsilyl)oxy)-2-methylpropyl-2-yl)-5-fluoro-1-(4-fluoro-3-methylphenyl)-1H-indole (C28)

[0515] At room temperature, potassium 2-methylpropionic acid (4.1 mL of 1M solution, 4.100 mmol) was added to a solution of C27 (2.24 g, 4.05 mmol) in 2-MeTHF (5 mL). After 2 hours, the reaction was added to brine and EtOAc. The layers were separated, and the organic matter was dried (Na2SO4), filtered, and concentrated. Purification by column chromatography (80 g gold column, heptane) yielded product C28 (1.394 g, 62%) as a straw-colored oil. 1H NMR (400MHz, chloroform-d) δ7.72-7.68(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).

[0516] Step 5. Synthesis of 2-(5-fluoro-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S9)

[0517] 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), TBAF (1 M THF solution, 3 mL, 3 mmol) was added, and the mixture was heated overnight at 70 °C. Water and dichloromethane were added, the layers were separated, and the organic matter was dried (Na2SO4), filtered, and concentrated. Purification by column chromatography (40 g column; 0-75% EtOAc in heptane solution) yielded product S9 (350 mg, 82%) as a straw-colored oil. LCMS m / z 316.13 [M+H] + .

[0518] Preparation of S10

[0519] 4-(benzyloxy)-1-(4-fluorophenyl)-1H-indole (S10)

[0520]

[0521] Step 1. Synthesis of 4-(benzyloxy)-1-(4-fluorophenyl)-1H-indole (S10)

[0522] Nitrogen gas was bubbled through a mixture of 4-benzyloxy-1H-indole C29 (20 g, 89.6 mmol), 1-fluoro-4-iodobenzene (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 hours. The reaction mixture was diluted with water (1 L) and EtOAc (500 mL). The organic layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to give a brown solid. The solid was ground with ether and filtered to give product S10 (19 g, 64%) as a gray solid. 1 H NMR(400MHz,DMSO-d6)δ7.66-7.58(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] + .

[0523] Preparation of S11

[0524] 4-Benzyloxy-6-fluoro-1-(4-fluorophenyl)indole (S11)

[0525]

[0526] Step 1. Synthesis of 4-bromo-6-fluoro-1-(4-fluorophenyl)indole (C31)

[0527] Triethylamine (6.5 mL, 46.6 mmol) was added 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), and the mixture was vigorously stirred in air. Further addition of dichloromethane (100 mL), 4-fluorophenylboronic acid (5.7 g), Cu(OAc)2, and NEt3 (6 mL) was added, and the mixture was vigorously stirred. The reaction mixture was passed through EtOAc. The product was filtered and then concentrated. It was purified by column chromatography (gradient: 0-50% EtOAc in heptane solution) to give product C31 (2.84 g, 39%) as a white solid. 1H 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] + .

[0528] Step 2. Synthesis of 4-benzyloxy-6-fluoro-1-(4-fluorophenyl)indole (S11)

[0529] Add 2.14 g (6.95 mmol) of 4-bromo-6-fluoro-1-(4-fluorophenyl)indole C31, 38 mg (0.21 mmol) of allyl palladium chloride, 293 mg (0.63 mmol) of di-tert-butyl-[6-methoxy-3-methyl-2-(2,4,6-triisopropylphenyl)phenyl]phosphine, and 4.2 g (12.9 mmol) of Cs₂CO₃ to a vial, followed by 14 mL of toluene and 1.4 mL of benzyl alcohol. Stir the mixture under nitrogen at 90–100 °C. Pass the mixture through… Filter and concentrate the filtrate. Add EtOAc, sonicate the mixture and filter to give product S11 (1.8 g, 77%) as a white solid. 1 H 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).

[0530] Preparation of S12

[0531] 3-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-3-methylbut-1-ol (S12)

[0532]

[0533] Step 1. Synthesis of 5-(2-benzyloxy-6-bromo-phenyl)-3,3-dimethyl-pentan-4-yn-1-ol (C32)

[0534] A solution of 1-benzyloxy-3-bromo-2-iodobenzene C2 (60 g, 154.2 mmol), 3,3-dimethylpentan-4-yn-1-ol (23 g, 205.0 mmol), and N-isopropylprop-2-amine (140 mL, 998.9 mmol) in 1,4-dioxane (400 mL) was purged with nitrogen for 10 min, 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 h, then cooled to room temperature and filtered to remove the pale brown solid. The filtrate was concentrated to dryness and then partitioned between water and EtOAc. The mixture was subjected to... Filtration was used to aid in the separation of the layers. The organic layer was concentrated to dryness and purified by silica gel chromatography (gradient: 0-50% EtOAc in heptane solution) to give product C32 (47 g, 82%) as an orange oil. 1 H NMR (400MHz, chloroform-d) δ7.52-7.48(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,1 H), 6.85 (dd, 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] + .

[0535] Step 2. Synthesis of [5-(2-benzyloxy-6-bromo-phenyl)-3,3-dimethyl-pentan-4-alkynoxy]-tert-butyl-dimethyl-silane (C33)

[0536] TBS-Cl (19.9 g, 132.0 mmol) and imidazole (9.0 g, 132.2 mmol) were added to a solution of 5-(2-benzyloxy-6-bromo-phenyl)-3,3-dimethyl-pentan-4-yn-1-ol C32 (47 g, 125.9 mmol) in dichloromethane (500 mL). The reaction mixture was stirred at room temperature over a period of time. The brown precipitate was removed by filtration, and the filtrate was washed with water (2x). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give product C33 (59.3 g, 97%) as a pale yellow oil. 1H NMR (400MHz, chloroform-d) δ7.50(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] + .

[0537] Step 3. Synthesis of 3-benzyloxy-2-[5-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-pent-1-ynyl]-N-(4-fluorophenyl)aniline (C34)

[0538] 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, followed by the addition of NaOtBu (35.1 g, 365.2 mmol) and tBuXPhos Pd G3 (2.9 g, 3.65 mmol) in a single step. The reaction mixture was stirred at 35 °C for 1 hour, and then... Filtration. The filter pad was washed with a 1:1 EtOAc / water mixture, and the organic layer of the filtrate was combined with xylene and concentrated to dryness. The resulting brown oil was purified by silica gel chromatography (gradient: 0-25% EtOAc in heptane) to give the desired product C34 (56.1 g, 89%) as an amber oil. 1 H NMR (400MHz, chloroform-d) δ7.52(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,1H),6.40(dd,J=8.3,0.8Hz,1H),6.38(s,1H),5.15(s,2H),3.9 4-3.86(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] + .

[0539] Step 4. Synthesis of [3-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-3-methyl-butoxy]-tert-butyl-dimethyl-silane (C35)

[0540] PdCl2 (965 mg, 5.44 mmol) was added to a solution of C34 (56.1 g, 108.4 mmol) in MeCN (500 mL). The reaction mixture was incubated overnight at 65 °C, then cooled to room temperature and filtered. The filtrate was concentrated to dryness, ground with MeCN, and filtered again. The solids were combined and washed with cold MeCN, then dried under vacuum to give product C35 (48.7 g, 87%) as a white solid. 1 H NMR (400MHz, chloroform-d) δ7.54(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] + .

[0541] Step 5. Synthesis of 3-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-3-methylbut-1-ol (S12)

[0542] A solution of TBAF (1 M THF, 24 mL, 24 mmol) was added 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). The mixture was stirred at 60 °C for 2 hours and then concentrated. Purification by silica gel chromatography (gradient: 0-50% EtOAc in heptane) yielded S12 (540 mg, 71%). LCMS m / z 404.32 [M+H] + .

[0543] Preparation of S13

[0544] 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indole (S13)

[0545]

[0546] Step 1. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indole (S13)

[0547] Nitrogen gas was bubbled through a mixture of 5-benzyloxy-1H-indole C36 (2 g, 8.96 mmol), 1-fluoro-4-iodo-2-methylbenzene (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 overnight at 120 °C. The reaction mixture was diluted with water and EtOAc. The organic layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. Purification was achieved by silica gel chromatography (gradient: 0–15% EtOAc in heptane solution) to give S13 (2.4 g, 81%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.58–7.46 (m, 3H), 7.15 (t, J = 8.8 Hz, 1H), 6.98 (dd, J = 9.0, 2.5 Hz, 1H), 6.59 (dd, J = 3.3, 0.9 Hz, 1H), 5.16 (s, 2H), 2.38 (d, J = 2.1 Hz, 3H).

[0548] Preparation of S14

[0549] 2-(4-(benzyloxy)-1-(4-fluoro-3-methoxyphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S14)

[0550]

[0551] 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)

[0552] C4 (3.39 g, 7.16 mmol) and 4-fluoro-3-methoxy-aniline (1.10 g, 7.794 mmol) were added to a solution of xylene (30 mL) under nitrogen atmosphere with NaOtBu (1.75 g, 18.2 mmol), followed by the addition of 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 NH4Cl aqueous solution and extracted twice with EtOAc. The combined organic compounds were concentrated to dryness and purified by elution with a heptane solution of 0–50% EtOAc using silica gel chromatography (80 g column). The purified fractions were combined and concentrated to give product C37 (3.65 g, 96%) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ7.52-7.47(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, 3.8,2.6Hz,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] + .

[0553] Step 2. Synthesis of 2-(4-(benzyloxy)-1-(4-fluoro-3-methoxyphenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S14)

[0554] Nitrogen gas was bubbled through a mixture of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethylbut-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 minutes. PdCl2(CH3CN)2 (75 mg, 0.289 mmol) was then added and the mixture was stirred overnight, followed by concentration. The product S14 (1 g, 35%) was purified by column chromatography (80 g column; 0-75% EtOAc in heptane solution). 1H NMR (400MHz, chloroform-d) δ7.57-7.50(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=0.8H z,1H),6.61(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] + .

[0555] Preparation of S15

[0556] 2-(4-(benzyloxy)-1-(4-chloro-3-fluorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S15)

[0557]

[0558] 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)

[0559] [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethylsilane C4 (4 g, 8.45 mmol), 4-chloro-3-fluoroaniline (2 g, 13.7 mmol), and sodium 2-methylprop-2-ol (2 g, 20.8 mmol) were added to a reaction vessel in THF (25 mL). Nitrogen gas was bubbled through the mixture for 10 minutes. tBuXPhos Pd G1 (0.2 g, 0.307 mmol) was added, and nitrogen gas was bubbled through the mixture again for 5 minutes. The reaction mixture was heated at 60 °C for 3 hours. LCMS showed partial conversion, so a further amount of tBuXPhos Pd G1 (0.2 g, 0.307 mmol) was added, and heating was continued overnight at 100 °C. The solvent was evaporated. The product C38 (840 mg, 43% purity, 8%) was purified by column chromatography (80 g column; 0-100% EtOAc in heptane solution). LCMS m / z 538.45 [M+H] + .

[0560] Step 2. Synthesize 2-(4-(benzyloxy)-1-(4-chloro-3-fluorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S15).

[0561] Nitrogen gas was bubbled through a mixture of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethylbut-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 minutes. PdCl2(CH3CN)2 (50 mg, 0.193 mmol) was then added, and the mixture was stirred overnight at 60 °C and concentrated. Purification by column chromatography (80 g column; 0-100% EtOAc in heptane solution) yielded product S15 (210 mg, 92% purity, 29%). LCMS m / z 424.3 [M+H] + .

[0562] Preparation of S16

[0563] 2-(4-(benzyloxy)-1-(4-chlorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S16)

[0564]

[0565] Step 1. Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)-3,3-dimethylbut-1-yn-1-yl)-N-(4-chlorophenyl)aniline (C39)

[0566] [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethyl-silane C4 (4 g, 8.45 mmol), 4-chloroaniline (1.5 g, 11.8 mmol), and sodium 2-methylprop-2-ol (2 g, 20.8 mmol) were added to a reaction vessel in THF (25 mL). Nitrogen gas was bubbled through the mixture for 10 minutes. tBuXPhos Pd G1 (0.2 g, 0.307 mmol) was added, and nitrogen gas was bubbled through the mixture again for 5 minutes. The reaction mixture was heated at 60 °C for 3 hours. LCMS showed partial conversion, so a further amount of tBuXPhos Pd G1 (0.2 g, 0.307 mmol) was added, and heating was continued overnight at 100 °C. The solvent was evaporated. The product C39 (3.47 g, 72% purity, 57%) was purified by column chromatography (80 g column; 0-100% EtOAc in heptane solution). LCMS m / z 520.49 [M+H] + .

[0567] Step 2. Synthesis of 2-(4-(benzyloxy)-1-(4-chlorophenyl)-1H-indol-2-yl)-2-methylprop-1-ol (S16)

[0568] Nitrogen gas was bubbled through a mixture of C39 (1.75 g, 3.36 mmol) in methanol (15 mL) and ethyl acetate (15 mL) for 10 minutes. Then, PdCl2(CH3CN)2 (100 mg, 0.386 mmol) was added, and the mixture was stirred overnight at 60 °C, followed by concentration. The product S16 (370 mg, 92% purity, 25%) was purified by column chromatography (80 g column; 0-100% EtOAc in heptane). LCMS m / z 406.34 [M+H] + .

[0569] Preparation of S17

[0570] 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethanol-1-ol (S17)

[0571]

[0572] Step 1: Synthesis of 4-(2-benzyloxy)-6-bromophenyl)-but-3-yn-1-ol (C40)

[0573] 1-Benzyloxy-3-bromo-2-iodobenzene C2 (10.2 g, 26.2 mmol), but-3-yn-1-ol (2.02 g, 28.8 mmol), and then DMF (35 mL) were sequentially added to a 20 mL aspirate vial with a red vacuum cap. Nitrogen gas was bubbled through the mixture for 15–20 min. Pd(PPh3)2Cl2 (1.2 g, 1.71 mmol) was added to the solution. CuI (500 mg, 2.63 mmol) was added, followed by diethylamine (4.1 mL, 39.6 mmol), and the mixture was stirred at room temperature for 15 min, then heated to 40 °C for 65 h. The reaction was purified by reversed-phase column chromatography (C18 275 g column; 5–95% MeCN in TFA aqueous solution). The combined fractions were concentrated under reduced pressure. The mixture was extracted with two ~100 mL portions of ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give 4-(2-benzyloxy-6-bromo-phenyl)but-3-yn-1-ol C40 (6.09 g, 70%). 1 H NMR (400MHz, chloroform-d) δ7.49-7.29(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).

[0574] Step 2: Synthesis of ((4-(2-(benzyloxy)-6-bromophenyl)-but-3-yn-1-yl)oxy)(tert-butyl)dimethylsilane (C41)

[0575] Imidazole (1.9 g, 27.91 mmol) was added in a single reaction 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) at room temperature. The reaction mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted again with dichloromethane. The layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane and the layers were separated again using a phase separator, and the combined organic compounds were concentrated. Purification by column chromatography (120 g column; 0-100% EtOAc in heptane solution) gave 4-(2-benzyloxy-6-bromo-phenyl)but-3-yn-oxy-tert-butyl-dimethyl-silane C41 (7.65 g, 93%). 1 H NMR (400MHz, chloroform-d) δ7.40-7.19(m,5H),7.10(dd,J=8.1,1.0Hz,1H),6.95(t,J=8.2Hz,1H),6.74(dd,J= 8.3, 1.0Hz, 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).

[0576] Step 3: Synthesis of 3-(benzyloxy)-2-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-N-(4-fluoro-3-methylphenyl)aniline (C42)

[0577] Nitrogen gas was passed through a solution of 4-(2-benzyloxy-6-bromo-phenyl)but-3-alkynoxy-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. t-BuOH (8 mL) was added to the solution, followed by sodium tert-butoxide (2.5 g, 26.01 mmol), and then tBuXphosPalladacycle G1 (590 mg, 0.859 mmol). Bubbling continued for another 3 minutes, and the vial was then placed in a heating block set to 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 dichloromethane. C42 (5.85 g, 70%) was purified by column chromatography (80 g column; 0-20% heptane solution of EtOAc). 1 H NMR (400MHz, chloroform-d) δ7.50-7.21(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 = 7.2Hz, 1H), 2.71 (t, J = 7.1Hz, 1H), 2.20 (d, J = 2.0Hz, 2H), 0.80 (d, J = 13.9Hz, 6H), -0.09 (s, 1H).

[0578] Step 4: Synthesis of 4-(benzyloxy)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-fluoro-3-methylphenyl)-1H-indole (C43)

[0579] Potassium 2-methylprop-2-olate (1 M, 12 mL, 12 mmol) was added 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) 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%).

[0580] Step 5: Synthesis of 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethanol-1-ol (S17)

[0581] To a solution of 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]ethoxy-tert-butyl-dimethylsilane C43 (5.85 g, 11.95 mmol) in THF (70 mL), TBAF (1 M THF solution, 12 mL, 12 mmol) was added and the reaction was stirred 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 (0-100% 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) δ7.57-7.53(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] + .

[0582] Preparation of S18

[0583] 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethanol-1-ol (S18)

[0584]

[0585] Step 1: Synthesis of isopropyl 1-(hydroxymethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C45)

[0586] At -78 °C, a solution of lithium tritert-butoxyaluminum hydride (28 mL, 1 M, 28 mmol) was added to a solution of 3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diisopropyl ester C44 (3.5 g, 12.1 mmol) in THF (10 mL). The mixture was stirred overnight at room temperature, then heated to 50 °C and held 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 solution) yielded 2-(4-benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethanol-1-ol (C45) (1.6 g, 57%). 1HNMR (400MHz, chloroform-d) δ5.08(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).

[0587] Step 2: Synthesis of isopropyl 1-(fluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C46)

[0588] A solution of 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylic acid isopropyl ester (C45) (2.6 g, 11.19 mmol) in dichloromethane (20 mL) was cooled to -78 °C. 2,6-Dimethylpyridine (2.2 mL, 19 mmol) and Tf₂O (2.6 mL, 15.45 mmol) were added to the solution. The mixture was slowly heated overnight to room temperature and then quenched with water. The mixture was extracted with dichloromethane, washed with saturated aqueous NaHCO₃ solution, saturated aqueous NH₄Cl solution, and then washed with brine. The solution was dried over Na₂SO₄, filtered, and concentrated to give a trifluoromethanesulfonate intermediate. This was dissolved in THF (20 mL) and cooled to -78 °C. Tetrabutylammonium fluoride solution (1 M, 22 mL, 22 mmol) was added to the solution, stirred, and slowly heated to room temperature for 1 hour. The reaction was quenched with water at room temperature, extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered, and concentrated. The product was purified by column chromatography (40 g column; 0-30% EtOAc in heptane solution) to obtain isopropyl 1-(fluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylic acid (C46) (2.4 g, 92%). 1 ¹H NMR (400MHz, chloroform-d) δ 5.08 (p, J = 6.3Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H), 3.18 (d, J = 0.6Hz, 7H), 2.67–2.51 (m, 3H), 2.28–2.17 (m, 2H), 1.28 (d, J = 6.2Hz, 6H).

[0589] Step 3: Synthesis of 2-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)ethanol-1-ol (S18)

[0590] To a solution of 1-(fluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylic acid isopropyl ester (C46) in MeOH (10 mL), NaOH (3 M, 4 mL, 12 mmol) was added, and the mixture was stirred overnight at 55 °C. The reaction was concentrated and neutralized to pH 3 with HCl. The mixture was extracted with dichloromethane, dried over Na₂SO₄, filtered, and concentrated to give product S18 (550 mg, 45%). 1 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).

[0591] Preparation of S19

[0592] 1-(difluoromethyl)-4-oxocyclohexane-1-carboxylic acid ethyl ester (S19)

[0593]

[0594] Step 1. Synthesis of ethyl 8-(difluoromethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (C48)

[0595] DAST (1.1 mL, 8.33 mmol) was added to a solution of ethyl 8-(difluoromethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate C47 (0.9 g, 3.72 mmol) in dichloromethane (15 mL) and stirred overnight. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered, and concentrated. Purified by column chromatography (12 g column; 0-30% EtOAc in heptane solution) to give ethyl 8-(difluoromethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate C48 (800 mg, 81%). 1 ¹H NMR (400MHz, chloroform-d) δ 5.79 (t, J = 56.3Hz, 1H), 4.26 (q, J = 7.1Hz, 2H), 3.96 (d, J = 2.2Hz, 4H), 2.26–2.14 (m, 2H), 1.91–1.64 (m, 7H), 1.31 (t, J = 7.1Hz, 3H).

[0596] Step 2. Synthesis of ethyl 1-(difluoromethyl)-4-oxocyclohexane-1-carboxylate (S19)

[0597] To a solution of product 8-(difluoromethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate C48 (800 mg, 3.03 mmol) in acetone (15 mL), HCl (18 mL of 2 M solution, 36 mmol) was added and the mixture was stirred overnight at room temperature. After concentration, the residue was extracted with dichloromethane, dried over Na2SO4, filtered, and concentrated to give 1-(difluoromethyl)-4-oxocyclohexane-1-carboxylate (S19) (640 mg, 78%). 1 ¹H NMR (400MHz, chloroform-d) δ 5.98 (t, J = 56.1Hz, 1H), 4.33 (q, J = 7.1Hz, 2H), 2.61–2.31 (m, 6H), 2.09–1.91 (m, 2H), 1.35 (t, J = 7.1Hz, 3H).

[0598] Preparation of S20

[0599] 1-(difluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylic acid (S20)

[0600]

[0601] Step 1: Synthesis of isopropyl 1-formyl-3,3-dimethoxycyclobutane-1-carboxylate (C49)

[0602] A solution of 3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diisopropyl ester C44 (7.5 g, 26.0 mmol) in THF (50 mL) was cooled to -78 °C. DIBAL (50 mL of 1 M solution, 50 mmol) was added to the solution and the mixture was stirred at -78 °C for 2 hours. The reaction was quenched with NH4Cl. 200 mL of saturated Rochelle salt was added and the mixture was stirred for 2 hours. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated. Purification was performed by column chromatography (40 g column; 0-30% EtOAc in heptane solution) to give C49 (3.2 g, 53%). 1 ¹H NMR (400MHz, chloroform-d) δ 9.69 (d, J = 2.1Hz, 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).

[0603] Step 2: Synthesis of isopropyl 1-(difluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C50)

[0604] 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 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. The mixture was then heated to 25 °C and stirred at that temperature for 16 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with dichloromethane. The organic layer was dried (Na2SO4) and concentrated to give product C50 (2.18 g, 100%). 1 ¹H NMR (400MHz, chloroform-d) δ 6.05 (t, J = 56.6 Hz, 1H), 5.29–4.92 (m, 1H), 3.18 (d, J = 3.9 Hz, 6H), 2.73–2.56 (m, 2H), 2.57–2.29 (m, 2H), 1.28 (dd, J = 13.0, 6.3 Hz, 6H).

[0605] Step 3: Synthesis of 1-(difluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylic acid (S20)

[0606] LiOH·H₂O (1.46 g, 34.9 mmol) was added to a solution of 1-(difluoromethyl)-3,3-dimethoxy-cyclobutanecarboxylic acid isopropyl ester C50 (2.20 g, 8.72 mmol) in MeOH (10 mL), THF (10 mL), and water (5 mL), and the mixture was microwaved for 4 hours. The reaction mixture was concentrated, neutralized with HCl (17 mL, 2 M, 34 mmol), and back-extracted with dichloromethane (3 x 40 mL). The organic layer was dried (Na₂SO₄) and concentrated to give product S20 (400 mg, 22%). This product was used for subsequent steps without further purification. 1 ¹H NMR (400MHz, chloroform-d) δ 6.13 (t, J = 56.3Hz, 1H), 3.20 (d, J = 7.8Hz, 6H), 2.78–2.36 (m, 4H).

[0607] Preparation of S21

[0608] 1-(difluoromethyl)-4-oxocyclohexane-1-carboxylic acid (S21)

[0609] To a solution of S19 (500 mg, 2.27 mmol) in THF (2 mL) and EtOH (2 mL), NaOH (3 M, 1.5 mL, 4.5 mmol) was added 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. Purified by column chromatography (40 g column; 0-40% heptane solution of EtOAc) to give S21 (380 mg, 87%). 1 ¹H NMR (400MHz, 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).

[0610] Preparation of S22

[0611] Methyl-3-fluoro-4-(2-methylethylene oxide-2-yl)benzoate (S22)

[0612]

[0613] Trimethylsulfonyl iodide (850 mg, 4.17 mmol) and sodium hydride (170 mg, 4.25 mmol) were added to a flame-dried flask. The flask was kept under nitrogen atmosphere before introducing DMSO (3 mL) and THF (3 mL). The mixture was stirred at 25 °C for 30 min. The reaction was cooled to 0 °C and a solution of methyl 4-acetyl-3-fluorobenzoate C51 (400 mg, 2.04 mmol) in THF (2 mL) was added. The reaction was then gradually heated to 25 °C and stirred at this temperature for 16 h. The reaction was quenched with a saturated aqueous solution of NH4Cl and ethyl acetate. The layers were separated, and the organic matter was concentrated and purified by column chromatography (12 g gold column) to give product S22 (240 mg, 56%). LCMS m / z 211.13 [M+H] + .

[0614] Compound 1

[0615] (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)

[0616]

[0617] Standard Procedure A

[0618] Step 1: Synthesize (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).

[0619] Methanesulfonic acid (61 μL, 0.94 mmol) was added 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), followed by the addition of triethylsilane (89 μL, 0.557 mmol), and the resulting dark solution was stirred at room temperature. After 15 minutes, the reaction was purified directly by column chromatography (24 g gold column; 5-40% EtOAc in heptane solution).

[0620] The first eluting agent 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%). 1 H NMR (400MHz, chloroform-d) δ7.45-7.41(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=8.2,0.7H z,1H),6.41(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 that the stereoisomer is trans. Diagnoses related to this characterized stereoisomer... 1 1H NMR chemical shifts were used for structure partitioning of other compounds in this series.

[0621] The second eluting 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 ¹H NMR (400MHz, chloroform-d) δ 7.41–7.36 (m, 2H), 7.31 (ddd, J = 7.6, 6.8, 1.4 Hz, 2H), 7.27–7.22 (m, 1H), 7.10–7.00 (m, 3H), 6.88 (t, J = 8.1 Hz, 1H), 6.67 (dd, J = 8.2, 0.7 Hz, 1H), 6.50–6.47 (m, 1H), 5.39 (s, 2H), 3.92 (t, J = 5.4 Hz, 2H), 3.16–3.09 (m, 2H), 2.78–2.69 (m, 2H), 2.57 (t, J = 5.4 Hz, 2H), 2.26 (d, J = 2.0 Hz, 3H), 1.31 (s, 3H). LCMS m / z 486.29 [M+H] + .

[0622] Standard Procedure B

[0623] 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)

[0624] 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 humidified), NH4CO2H (150 mg) in EtOH (5 mL) and EtOAc (2 mL) was stirred at room temperature. The reaction mixture was then passed through EtOH. Filter and then concentrate. Add water and dichloromethane, and separate the layers again through a phase separator and concentrate the organic matter. Purify by column chromatography (12 g column; 0-10% MeOH in dichloromethane solution) to give (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%). 1H NMR (400MHz, methanol-d4) δ7.26-7.12(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] + .

[0625] Compound 2

[0626] (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)

[0627]

[0628] (1S,3S)-5'-(4-fluoro-3-methylphenyl)-9'-hydro-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) δ7.24-7.12(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] + .

[0629] Compound 3 and Compound 4

[0630] 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]indole]-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]indole]-3-yl)acetic acid (4)

[0631]

[0632] 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]indole]-3-yl)acetate (C54)

[0633] To a reaction vial, add 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-prop-1-ol S1 (90 mg, 0.223 mmol), methyl 2-(3-oxocyclobutyl)acetate (45 mg, 0.317 mmol), and dichloromethane (900 μL). Add methanesulfonic acid (36 mg, 0.375 mmol) and Et3SiH (6 μL, 0.0376 mmol) to the mixture. Stir the mixture at room temperature for 30 minutes. Direct purification was performed using 0-50% EtOAc / heptane, eluting through a 12g silica gel cartridge, to give 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]indole]-3-yl)acetate (C54) (90 mg, 76%) as a mixture of cis and trans isomers. LCMS m / z 528.6 [M+H] + .

[0634] 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]indole]-3-yl)acetic acid (C55)

[0635] To a solution 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]indole]-3-yl)acetate (C54) (90 mg, 0.171 mmol) in MeOH (5 mL), NaOH (2 M, 1 mL, 2 mmol) was added and the mixture was stirred at 50 °C for 3 hours, then neutralized to pH 3 with HCl. The mixture was concentrated, extracted with EtOAc, dried over (Na₂SO₄), filtered, and concentrated. Purified by column chromatography (0-30% EtOAc / heptane), 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]indole]-3-yl)acetic acid (C55) (45 mg, 39%) was obtained. LCMS m / z 514.6 [M+H] + .

[0636] Step 3: Synthesize 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]indole]-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]indole]-3-yl)acetic acid (4)

[0637] 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]indole]-3-yl)acetic acid (C55) (45 mg, 0.0876 mmol) and Pd(OH)₂ (20 mg, 0.142 mmol) in EtOAc (10 mL) and MeOH (1 mL) was stirred under a hydrogen balloon for 1 hour. The reaction was then carried out via... Layer filtration and concentration were performed. The solution was purified by reversed-phase chromatography to give 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]indole]-3-yl)acetic acid (3) (16.1 mg, 41%). 1H NMR (400MHz, chloroform-d) δ7.25-7.12(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=8.1Hz,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] + .

[0638] Chromatographic analysis also yielded 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]indole]-3-yl)acetic acid (4) (7.8 mg, 20%). 1 H NMR (400MHz, chloroform-d) δ7.26-7.07(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] +

[0639] Compound 5 and Compound 6

[0640] (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)

[0641]

[0642] 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)

[0643] To a mixture of 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-prop-1-ol S1 (110 mg, 0.272 mmol) and 1-methyl-3-oxo-cyclobutanecarboxylic acid (87 mg, 0.679 mmol) in DCE (500 μL), methanesulfonic acid (30 μL, 0.462 mmol) was added, followed by the addition of triethylsilane (109 μL, 0.682 mmol), and the resulting deep red solution was stirred at 45 °C. Two hours later, the reaction was purified directly by column chromatography (24 g gold column, 0-20% MeOH in dichloromethane solution) 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] + .

[0644] Step 2. Synthesize (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)

[0645] BBr3 (1M heptane solution, 730 μL, 0.73 mmol) was added 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) over 10 minutes at 0–5 °C. After 20 minutes, a saturated aqueous solution of NH4Cl was added at the same temperature and the cold bath was removed. The layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane and the layers were again separated by a phase separator, and the combined organic matter was concentrated. Purification by column chromatography (24g gold column; 0-10% MeOH in dichloromethane solution) yielded (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%). 1H NMR (400MHz, DMSO-d6) δ11.89(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=8.1,0.8Hz,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] + .

[0646] Chromatography also yielded (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%). 1 H NMR(400MHz,DMSO-d6)δ11.69(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] + .

[0647] Compound 7 and Compound 8

[0648] 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]indole]-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]indole]-3-yl)oxy)acetic acid (8)

[0649]

[0650] Step 1. Synthesis of 2-(3-benzyloxycyclobutoxy)tert-butyl acetate (C58)

[0651] Potassium hydroxide (180 mL, 35% w / v, 1.123 mol) was added to a solution of 3-benzyloxycyclobutanol (C57) (22 g, 123 mmol) in toluene (200 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, 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 stirred at room temperature for 16 h. The layers were separated, and the aqueous layer was extracted with ether. The combined organic layers were dried and concentrated to give tert-butyl 2-(3-benzyloxycyclobutoxy)acetate (C58) (32.2 g, 89%).

[0652] Step 2. Synthesis of tert-butyl 2-(3-hydroxycyclobutoxy)acetate (C59)

[0653] Pd / C (5 g) was added to a solution of 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 then carried out via... The solution was filtered and the filtrate was evaporated to dryness to give tert-butyl 2-(3-hydroxycyclobutoxy)acetate (C59) (22.2 g, 100%). 1 ¹H NMR (400MHz, 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).

[0654] Step 3. Synthesis of 2-(3-oxocyclobutoxy)tert-butyl acetate (C60)

[0655] To a solution of tert-butyl 2-(3-hydroxycyclobutoxy)acetate (C59) (5 g, 24.7 mmol) in dichloromethane (100 mL), five fractions of Des Martin periodane (15 g, 35.4 mmol) were added. Water (500 μL, 27.7 mmol) was slowly added over 10 minutes. The reaction was stirred at room temperature for 2 hours, then diluted with ether, washed with 10% Na₂S₂O₃ and saturated NaHCO₃ solution (1:1), and then washed with brine. The organic layer was dried (Na₂SO₄), filtered, and evaporated to dryness. Purification by column chromatography (220 g, eluted with 0–100% ethyl acetate in heptane) yielded tert-butyl 2-(3-oxocyclobutoxy)acetate (C60) (3.70 g, 75%). 1¹H NMR (400MHz, 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).

[0656] Step 4. Synthesize 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]indole]-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]indole]-3-yl)oxy)acetic acid (C62)

[0657] A solution of 2-[4-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]-2-methyl-prop-1-ol (S1) (600 mg, 1.49 mmol) and 2-(3-oxocyclobutoxy)acetic acid tert-butyl ester (C60) (500 mg, 2.50 mmol) in dichloromethane (4 mL) was added to a flask. 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 mixture, and the mixture was stirred for 10 minutes. The solvent was then evaporated. Purification by column chromatography (80g gold column, eluted with heptane solution of 0-100% ethyl acetate) yielded 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]indole]-3-yl)oxy)acetic acid (C61) (138 mg, 14%). LCMS m / z 530.44 [M+H] + .

[0658] Chromatographic analysis also yielded 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]indole]-3-yl)oxy)acetic acid (C62) (185 mg, 20%). LCMS m / z 530.44 [M+H] + .

[0659] 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]indole]-3-yl)oxy)acetic acid (7)

[0660] 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]indole]-3-yl)oxy)acetic acid (C61) at room temperature by replacing ammonium formate with hydrogen gas and using EtOH and THF as solvents. (64.5 mg, 73%) 1 HNMR (400MHz, methanol-d4) δ7.25-7.12(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. 1,4.2,3.4Hz,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 / z440.37[M+H] + .

[0661] 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]indole]-3-yl)oxy)acetic acid (8)

[0662] 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]indole]-3-yl)oxy)acetic acid (C62) at room temperature by replacing ammonium formate with hydrogen gas and using EtOH and THF as solvents. (74.6 mg, 59%) 1HNMR (400MHz, methanol-d4) δ7.21-7.05(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] + .

[0663] Compound 9

[0664] (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)

[0665]

[0666] Step 1. Synthesis of ethyl 4,4-diethoxy-1-fluorocyclohexane-1-carboxylate (S64)

[0667] At -10 °C, 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). The resulting brown solution was stirred at -10 °C for 30 min. The reaction was cooled to -78 °C and a solution of N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (6.4 g, 20.3 mmol) in THF (20 mL) was added. The resulting solution was gradually warmed to room temperature over 2 hours, 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. The oily ethyl 4,4-diethoxy-1-fluorocyclohexanecarboxylate (S64) (1.75 g, 51%) was purified by column chromatography (Combiflash ISCOLumen with ELSD, 80 g gold column, eluted with heptane solution of 0-100% ethyl acetate). 1¹H 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).

[0668] 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)

[0669] The reaction was 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 in a DCE, yielding C65 (227 mg, 61%). LCMS m / z 574.2 [M+H] + .

[0670] 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)

[0671] Lithium hydroxide (110 mg, 2.62 mmol) was added 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), and the mixture was stirred at 25 °C for 2 hours. 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 organic matter was concentrated. Purification by column chromatography (80g gold column, heptane solution of 0-60% ethyl acetate) yielded (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%). 1¹H NMR (400MHz, 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 .2,0.7Hz,1H),5.39(s,2H),3.51(s,2H),3.08(t,J=14.0Hz,2H),2.45(dt,J=41.6 ,12.2Hz,2H),2.33(d,J=1.9Hz,3H),1.94(t,J=12.4Hz,4H),1.07(d,J=2.3Hz,6H).

[0672] 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)

[0673] The product 9 (68.5 mg, 65%) was prepared starting from C66 according to standard procedure B. The reaction was carried out at 50 °C in EtOH and THF. 1 H NMR (400MHz, DMSO-d6) δ13.07(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] + .

[0674] Compound 10

[0675] 1-(5'-(4-fluoro-3-methylphenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-yl)-3,5-dimethyl-1H-pyrazol-4-carboxylic acid (21)

[0676]

[0677] Step 1. Synthesis of ethyl 3,5-dimethyl-1-(3-oxocyclobutyl)-1H-pyrazole-4-carboxylate (C68)

[0678] Triethylamine (310 μL, 2.22 mmol) was added to a solution of 3-bromocyclobutanone (300 mg, 2.014 mmol) in 10 mL of trichloro(deuterated)methane, and the mixture was stirred for 30 min. NMR indicated conversion to cyclobutanone. Ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate C67 (340 mg, 2.02 mmol) was added, and the mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl and extracted with dichloromethane, then concentrated to give product C68 (416 mg, 87%). 1 ¹H 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).

[0679] 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]indole]-3-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (C69)

[0680] Starting from C68, standard procedure A was used, but dichloromethane was used instead of DCE. This yielded product (C69). LCMS m / z 622.48 [M+H] + .

[0681] 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]indole]-3-yl)-3,5-dimethyl-1H-pyrazol-4-carboxylic acid (C70)

[0682] Lithium hydroxide hydrate (75 mg, 1.79 mmol) was added 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]indole]-3-yl)-3,5-dimethyl-1H-pyrazol-4-carboxylate (C69) (109 mg, 0.175 mmol) in MeOH (800 μL), THF (1 mL), and water (500 μL), 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 and concentrated, and purified by reversed-phase chromatography (TFA modifier, 15.5 g column) to give a mixture of isomers 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]indole]-3-yl)-3,5-dimethyl-1H-pyrazol-4-carboxylic acid (C70) (35 mg, 33%). The mixture was then proceeded to the next step without further purification. LCMS m / z 594.49 [M+H] + .

[0683] 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]indole]-3-yl)-3,5-dimethyl-1H-pyrazol-4-carboxylic acid (10)

[0684] Starting with C70, standard procedure B was used. The product was modified using MeOH and THF as solvents and heated at 50°C. This yielded product (10). 1 H NMR (400MHz, chloroform-d) δ7.19-7.03 (m, 3H), 6.84 (dt, J = 16.0, 7.9Hz, 1H), 6.45 (dd, J =29.1,7.6Hz,1H),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] + .

[0685] Compounds 11-19

[0686] Compounds 11-19 were prepared from S1 and a suitable carbonyl reagent.

[0687] Table 1. Preparation of compounds 11-19

[0688]

[0689]

[0690]

[0691] a Perform standard procedure A at 45°C.

[0692] b Instead of ammonium formate, the reaction was carried out according to standard procedure B, but formic acid was used in MeOH and THF at 50°C.

[0693] c The procedure is the same as for compound 13, but EtOH is replaced with MeOH in the reduction step.

[0694] d Standard procedure A was modified by replacing DCE with dichloromethane.

[0695] e Standard procedure B was modified by replacing ammonium formate with hydrogen at room temperature.

[0696] f The standard program C has been modified by removing Et3SiH.

[0697] g Standard procedure B was modified by using Pd(OH)2 instead of Pd / C and by using MeOH and EtOAc as solvents.

[0698] h Standard procedure A was modified by replacing DCE with dichloromethane in a closed container at 50°C.

[0699] Compounds 20 and 21

[0700] 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 its enantiomer (21)

[0701]

[0702] 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 obtain 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) δ7.16-6.99(m,3H),6.81(dd,J=8.2,7.6Hz,1H),6.34(dd,J=7.6,0.8Hz,1H),6.28(dd,J=8.2,0.8H z,1H),3.37(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] + .

[0703] SFC separation also yielded 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) δ7.16(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] + .

[0704] Compounds 22-29

[0705] Preparation of compounds 22-29 from S2 or S3 and suitable ketones or ketone equivalents

[0706] Table 2. Preparation of compounds 22-29

[0707]

[0708]

[0709]

[0710] a Standard Procedure A was modified by replacing DCE with dichloromethane in a closed container at a temperature between room temperature and 50°C.

[0711] b Standard procedure B was modified by replacing ammonium formate with hydrogen at room temperature and using MeOH and EtOAc as solvents.

[0712] c Standard procedure A was modified by replacing DCE with dichloromethane.

[0713] d Standard procedure B was modified by using the conditions for BBr3 in dichloromethane as described for the synthesis of compounds 5 and 6.

[0714] e Standard procedure A has been modified by removing Et3SiH.

[0715] f Standard procedure B was modified by replacing ammonium formate with hydrogen at room temperature and using EtOH as a solvent or using EtOH and THF as a co-solvent.

[0716] g Add 1 mL of TFA when the reductive alkylation reaction is complete and stir the mixture for 10 minutes.

[0717] Compound 30

[0718] 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]indole]-3-yl)oxy)propionic acid (30)

[0719]

[0720] Step 1. Synthesize (1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-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]indole]-3-yl acetate (C72).

[0721] 2-[4-benzyloxy-1-(3,4-difluorophenyl)indol-2-yl]-2-methyl-prop-1-ol (1.2 g, 2.95 mmol), (3-oxocyclobutyl)acetate (750 mg, 5.85 mmol), and dichloromethane (5 mL) were added to a vial, followed by the addition of triethylsilane (200 μL, 1.25 mmol) and methanesulfonic acid (300 μL, 4.62 mmol). After 4 hours, the reaction was purified directly by column chromatography (120 g gold column, eluted with heptane solution of 0-100% ethyl acetate) to give product C71 (805 mg, 48%), LCMS m / z 518.51 [M+H]. + Product C72 (400 mg, 21%), LCMS m / z 518.47 [M+H] + .

[0722] 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]indole]-3-ol (C73)

[0723] NaOH (3 mL, 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]indole]-3-yl acetate (C71) (800 mg, 1.30 mmol) in MeOH (10 mL) and THF (10 mL), and the reaction was stirred at 60 °C for 2 h. The mixture was then acidified with 0.1 N HCl and extracted with EtOAc (3 x 150 mL).

[0724] The combined organic fractions were washed with brine (1 x 50 mL) and water (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (120 g gold column, heptane solution of 0-100% ethyl acetate) yielded (1R,3R)-9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-ol (C73) (700 mg, 98%). LCMS m / z 476.47 [M+H] + .

[0725] 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]indole]-3-yl)oxy)propionate (C74)

[0726] Ethyl 2-diazopropionate (75 mg, 0.585 mmol) was added dropwise over 10 minutes to a mixture of 9-benzyloxy-5-(3,4-difluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutane]-1'-ol C73 (100 mg, 0.210 mmol) and rhodium diacetoxy (10 mg, 0.0453 mmol) in dichloromethane (2 mL). Another batch of rhodium diacetoxy (10 mg, 0.0453 mmol) was added dropwise, followed by ethyl 2-diazopropionate (75 mg, 0.585 mmol) over 10 minutes. Ten minutes later, the reaction was purified directly by column chromatography (40 g gold column, eluted with heptane solution of 0-100% ethyl acetate) 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]indole]-3-yl)oxy)propionate (C74) (90 mg, 61%). LCMS m / z 576.53 [M+H] + .

[0727] 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]indole]-3-yl)oxy)propionic acid (C75)

[0728] NaOH (750 μL, 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]indole]-3-yl)oxy)propionate (C74) (90 mg, 0.142 mmol) in MeOH (3 mL) and THF (2 mL). After 1 hour 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 reversed-phase chromatography (50 g column, eluted with 10-100% ACN aqueous solution containing 0.1% TFA) yielded 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]indole]-3-yl)oxypropionic acid (C75) (85 mg, 105%). LCMS m / z 548.54 [M+H] + .

[0729] 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]indole]-3-yl)oxy)propionic acid (30)

[0730] 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]indole]-3-yl)oxy)propionic acid (C75) (80 mg, 0.14 mmol) and EtOH (5 mL) were added to the reaction vessel, along with Pd / C (50 mg, 0.04698 mmol). The flask was evacuated, and hydrogen gas was introduced through a balloon. After 2 hours, the reaction was passed through... The product was filtered and concentrated. It was purified by reversed-phase chromatography (50 g column, eluted with 10-100% ACN aqueous solution containing 0.1% FA) to give product 30 (50.1 mg, 76%). 1H NMR (400MHz, chloroform-d) δ7.46-7.08(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=7.3 Hz, 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] + .

[0731] Compound 31

[0732] 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]indole]-3-yl)oxy)propionic acid (31)

[0733]

[0734] This is prepared in the same way as 30, but intermediate C72 is used instead of C71 in step 2.

[0735] 1 H NMR (400MHz, Methanol-d4) δ7.44 (dt, J=10.5, 8.8Hz, 1H), 7.35 (ddd, J=10.3, 7.1, 2.5Hz, 1H), 7.18 (ddt,J=8.5,4.0,2.0Hz,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] + .

[0736] Compounds 32-63

[0737] Compounds 32-63 were prepared from S4 and appropriate ketones or ketone equivalents.

[0738] Table 3. Preparation of compounds 32-63

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748] a Standard procedure A was modified by replacing DCE with dichloromethane in a closed container at 50°C.

[0749] b Standard procedure B was modified by replacing ammonium formate with hydrogen at room temperature and using MeOH and EtOAc as solvents.

[0750] c Standard procedure A was modified by replacing DCE with dichloromethane.

[0751] d Standard procedure B was modified by using EtOH and THF as solvents.

[0752] e Standard procedure B was modified by using the conditions for BBr3 in dichloromethane as described for the synthesis of compounds 5 and 6.

[0753] f Standard procedure B was modified by replacing ammonium formate with hydrogen at room temperature and using EtOH as the solvent.

[0754] 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.

[0755] h Standard procedure A has been modified by removing Et3SiH.

[0756] i Prior to the debenzylation step, the ester was hydrolyzed using the same procedure described for the synthesis of compound C55, with the following modifications: THF and MeOH were used as solvents, and 6M NaOH was used to maintain the solution at 50°C for 1 hour.

[0757] j Prior to the debenzylation step, the ester was hydrolyzed using the same procedure described for the synthesis of compound C55, with the following modifications: THF and MeOH were used as solvents, and 1M NaOH was used to maintain the solution at 50°C for 1 hour.

[0758] k Standard procedure B was modified by replacing ammonium formate with hydrogen.

[0759] j Prior to the debenzylation step, the ester was hydrolyzed using the same procedure described for the synthesis of compound C55, with the following modifications: dichloromethane and MeOH as solvents, LiOH as base, and kept at room temperature for 2 hours.

[0760] 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.

[0761] n Add 1 mL of TFA when the reductive alkylation reaction is complete and stir the mixture for 10 minutes.

[0762] Compound 64

[0763] 2-(5'-(3,4-difluorophenyl)-7'-fluoro-9'-hydroxy-4',4'-dimethyl-2-oxo-4',5'-dihydro-3'H-spiro[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)acetic acid (64)

[0764]

[0765] Step 1: Synthesis of methyl 2-(9'-(benzyloxy)-5'-(3,4-difluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)acetate (C76)

[0766] The reaction was carried out according to standard procedure A from S5, using methyl 2-(4-oxo-1-piperidinyl)acetate as the ketone component, to give C76 (120 mg, 44%). Dichloromethane was used instead of DCE as the solvent. 1H NMR (400MHz, chloroform-d) δ7.67-7.58(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),3.73(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).

[0767] 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[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)acetate (C77)

[0768] Molecular iodine (395 mg, 1.56 mmol) was added to a mixture of methyl 2-(9'-(benzyloxy)-5'-(3,4-difluorophenyl)-7'-fluoro-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)acetate (C76) (120 mg, 0.207 mmol) and sodium bicarbonate (2 mL, 1 M, 2 mmol) in THF (6 mL). The reaction mixture was stirred for 40 min and then quenched with saturated NaHCO3 and sodium thiosulfate (10 mL). Purification by column chromatography (12 g column; 10-50% EtOAc in heptane solution) yielded C77 (75 mg, 58%). 1 H NMR (400MHz, chloroform-d) δ7.56-7.34(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] + .

[0769] Step 3: Synthesis of 2-(9'-(benzyloxy)-5'-(3,4-difluorophenyl)-7'-fluoro-4',4'-dimethyl-2-oxo-4',5'-dihydro-3'H-spiro[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)acetic acid (C78)

[0770] LiOH (50 mg, 1.19 mmol) was added 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]indol-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), and the mixture was stirred at 25 °C for 2 h. The reaction was neutralized with an aqueous solution of HCl (630 μL of 2 M solution, 1.26 mmol) and extracted with dichloromethane and the organic matter was concentrated. Purification by column chromatography (12 g gold column; 0-60% EtOAc in heptane solution) gave C78 (63.5 mg, 51%). LCMS m / z 579.23 [M+H] + .

[0771] Step 4: Synthesis of 2-(5'-(3,4-difluorophenyl)-9'-hydroxy-4',4'-dimethyl-2-oxo-4',5'-dihydro-3'H-spiro[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)acetic acid (64)

[0772] The reaction was carried out from C78 according to standard procedure B, using EtOH and THF as solvents, to give product 64 (3.8 mg, 14%). 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.26–7.21 (m, 1H), 7.16 (dddd, J = 9.8, 7.2, 5.1, 2.5Hz, 1H), 7.12–7.04 (m, 1H), 6.22 (dd, J = 11.0, 2.2Hz, 1H), 5.90 (dd, J = 9.4, 2.2Hz, 1H), 4.36 (d, J = 17.4Hz, 1H). H),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] + .

[0773] Compounds 65-82

[0774] Compounds 65-82 were prepared from S5 and appropriate ketones or ketone equivalents.

[0775] Table 4. Preparation of compounds 65-82

[0776]

[0777]

[0778]

[0779]

[0780]

[0781] a Standard procedure A was modified by replacing DCE with dichloromethane.

[0782] b Standard procedure A has been modified by removing Et3SiH.

[0783] c Standard procedure B was modified by using EtOH and THF as solvents and heating to a temperature within the range of 40°C-60°C.

[0784] d Standard procedure B was modified by replacing ammonium formate with hydrogen at room temperature and using MeOH and EtOAc as solvents.

[0785] e Standard procedure B was modified by replacing ammonium formate with hydrogen at room temperature and using MeOH as the solvent.

[0786] f Prior to the debenzylation step, the ester was hydrolyzed using the same procedure described for the synthesis of compound C47, with the following modifications: THF as solvent, and 1M LiOH held at room temperature for 1 hour.

[0787] g Standard procedure B was modified by replacing ammonium formate with hydrogen at room temperature and using EtOH and THF as solvents.

[0788] h Prior to the debenzylation step, the ester was hydrolyzed using the same procedure described for the synthesis of compound C47, with the following modifications: dichloromethane and MeOH as solvents, LiOH as base, and kept at room temperature for 2 hours.

[0789] iStandard procedure A was modified by replacing DCE with dichloromethane and heating the reaction in a closed container at 55°C.

[0790] j Add 1 mL of TFA when the reductive alkylation reaction is complete and stir the mixture for 10 minutes.

[0791] Compound 83

[0792] 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)

[0793]

[0794] 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)

[0795] The reaction was carried out from S6 according to standard procedure A. Dichloromethane was used as the solvent to give product C79 (428 mg, 82%). LCMS m / z 444.24 [M+H] + .

[0796] 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'-thiapyran]1'-oxide (C80)

[0797] Add (diacetoxyiodine)-benzene (218 mg, 0.677 mmol) and ammonium carbamate (84 mg, 1.08 mmol) to a solution of C79 (150 mg, 0.308 mmol) in dichloromethane (3 mL) and stir the mixture overnight at room temperature. Dilute the mixture with water and extract twice with dichloromethane, separating the phases using a phase separator. Concentrate the organic matter. Purify by column chromatography (C18 50 g column; TFA / MeCN aqueous solution). Concentrate the pure fraction under vacuum, dilute with dichloromethane, and neutralize with NaHCO3 aqueous solution. Pass the organic phase through a phase separator and concentrate the resulting filtrate under vacuum to give product C80 (220 mg, 47%). 1H NMR (400MHz, DMSO-d6) δ7.60-7.52(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] + .

[0798] 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)

[0799] The reaction was carried out from C80 according to standard procedure B, with the following modification: Pd(OH)2 was used as the catalyst. This yielded product 83 (46 mg, 25%). 1 H NMR (400MHz, DMSO-d6) δ10.05(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=8.3,1.3Hz,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] + .

[0800] Compound 84

[0801] 2-(((1S,4S)-5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indole]-4-yl)oxy)acetic acid (84)

[0802]

[0803] Step 1. Synthesize (1S,4S)-9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indole]-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]indole]-4-ol (C82).

[0804] The reaction was carried out according to standard procedure A. Using dichloromethane as a solvent, the cis product C81 (860 mg, 41%) was given, LCMS m / z 485.43 [M+H]. + And the trans product C82 (920 mg, 47%), LCMS m / z 485.48 [M+H] + .

[0805] Step 2. Synthesis of ethyl acetate 2-(((1S,4S)-9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[4,3-b]indole]-4-yl)oxy) (C83)

[0806] Over 10 minutes, ethyl 2-diazoethyl acetate (13% w / v, 350 μL, 0.399 mmol) was added dropwise to a mixture of C81 (200 mg, 0.370 mmol) and rhodium diacetoxy (25 mg, 0.113 mmol) in dichloromethane (5 mL), and the reaction was stirred for 2 hours. The product C83 (140 mg, 59%) was purified by column chromatography (40 g gold column, eluted with heptane solution of 0-100% ethyl acetate). LCMS m / z 572.38 [M+H] + .

[0807] 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]indole]-4-yl)oxy)acetic acid (C84)

[0808] NaOH (2M, 1mL, 2mmol) was added to a solution of C83 (140mg, 0.217mmol) in MeOH (3mL) and THF (2mL). The reaction was stirred at room temperature for 1 hour. DMSO (2mL) and TFA (250μL, 3.25mmol) were added, and the mixture was partially concentrated. Purification was performed by reversed-phase chromatography (50g column, C18 column, eluted with 10-100% ACN aqueous solution containing 0.1% TFA) to give product C84 (105mg, 81%). LCMS m / z 543.36 [M+H] + .

[0809] 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]indole]-4-yl)oxy)acetic acid (84)

[0810] The 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) δ7.39-7.30(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] + .

[0811] Compound 85

[0812] 4-(5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-yl)benzoic acid (85)

[0813]

[0814] 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

[0815] Methanesulfonic acid (35 μL, 0.54 mmol) was added to a mixture of 2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-prop-1-ol S6 (100.0 mg, 0.257 mmol) and 3-bromocyclobutanone (80.0 mg, 0.537 mmol) in dichloroethane (1.5 mL), followed by the addition of triethylsilane (89 μL, 0.557 mmol). The resulting dark solution was stirred at room temperature for 16 hours. The solution was quenched with a saturated aqueous solution of NaHCO3 and extracted with dichloromethane. The solution was filtered through a phase separator and concentrated to give product C85 (60.0 mg, 41%) as a mixture of isomers. LCMS m / z 519.94 [M+H] + .

[0816] 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]indole]-3-yl)benzoate (C86)

[0817] The following were added to a vial: photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (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-trimethylsilane (112 μL, 0.363 mmol), toluene (960 μL), and 1,4-dioxane (4 mL). Add 2,6-dimethylpyridine (195 mg, 1.82 mmol) and 100 μL of NiCl2·dtbppy (prepared using nickel dichloroethylene; 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)) to the above mixture. The mixture was irradiated with nitrogen for 10 min and then irradiated in a photoreactor for 16 h. The reaction was quenched with water and extracted with dichloromethane (3 x 20 mL). The organic layer was dried, concentrated, and purified by column chromatography to give product C86 (63.7 mg, 31%). 1¹H NMR (400 MHz, 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 = 8.3 Hz, 2H), 7.07–6.97 (m, 2H), 6.83 (t, J = 8.0 Hz, 1H), 6.53 (dd, J = 7.9, 0.8 Hz) ,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),3.24-3.1 0(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).

[0818] Step 3: Synthesis of 4-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutane]-1'-yl]benzoic acid (C87)

[0819] LiOH monohydrate (50 mg, 1.19 mmol) was added to a solution of C86 (70 mg, 0.118 mmol) in MeOH (0.7 mL), THF (0.3 mL), and water (200 μL), and the mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum, neutralized with HCl (0.6 mL, 2 M, 1.19 mmol), and back-extracted with dichloromethane (3 x 10 mL). The organic layer was dried (Na₂SO₄) and concentrated to give 4-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutane]-1'-yl]benzoic acid C87 (50.0 mg, 72%). LCMS m / z 561.82 [M+H] + .

[0820] Step 4: Synthesis of 4-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutane]-1'-yl]benzoic acid (85)

[0821] Add 10% Pd / C (20 mg, Degussa humectant) and NH4CO2H (50.0 mg, 0.79 mmol) to a solution of 4-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,3'-cyclobutane]-1'-yl]benzoic acid C87 in EtOH (1 mL) and THF (0.3 mL). Heat the mixture at 50 °C for 1 hour. The reaction mixture was filtered, concentrated, and purified using a 15.5 g HP C18 column (formic acid modifier) ​​to give 85 (30 mg, 70%) of ethyl 4-(9'-(benzyloxy)-5'-(4-fluorophenyl)-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[cyclobutane-1,1'-pyrano[4,3-b]indole]-3-yl)benzoate. 1 H NMR (400MHz, methanol-d4) δ8.01(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=7.9H z, 1H), 6.56 (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]+

[0822] Compound 86

[0823] 2-(5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)oxazol-4-carboxylic acid (86)

[0824]

[0825] 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)

[0826] Methanesulfonic acid (210 μL, 3.24 mmol) was added to a mixture of 2-[4-benzyloxy-1-(4-fluorophenyl)indol-2-yl]-2-methyl-prop-1-ol S6 (600.0 mg, 1.541 mmol) and piperidin-4-one hydrochloride (272 mg, 2.02 mmol) in dichloroethane (9 mL), and the resulting dark solution was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with dichloromethane (3 x 30 mL), filtered through a phase separator, and concentrated to give product C88 (740 mg, 91%). LCMS m / z 471.21 [M+H]+.

[0827] Step 2: Synthesis of 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,4'-piperidin]-1'-yl]oxazol-4-carboxylate (C89)

[0828] 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), methyl 2-chlorooxazol-4-carboxylate (105 mg, 0.650 mmol) and N-ethyl-N-isopropyl-propyl-2-amine (140 μL, 0.804 mmol) were added. The mixture was microwaved at 120 °C for 30 min and then diluted with dichloromethane (20 mL). It was washed with brine, and the layers were separated using a phase separator. The organic matter was concentrated to give crude product C89 (300 mg, 83%) as a dark solid. LCMS m / z 596.11 [M+H] + .

[0829] Step 3: Synthesis of 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,4'-piperidin]-1'-yl]oxazol-4-carboxylic acid (C90)

[0830] To a solution of methyl 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,4'-piperidin]-1'-yl]oxazol-4-carboxylate C89 (270.0 mg, 0.382 mmol) in MeOH (2 mL), THF (3 mL), and water (600 μL), lithium hydroxide hydrate (163 mg, 3.84 mmol) was added, and the mixture was heated in a microwave at 100 °C for 3 hours. The mixture was evaporated, neutralized with HCl (1.9 mL, 2 M, 3.8 mmol), and back-extracted with dichloromethane (3 x 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]indol-1,4'-piperidin]-1'-yl]oxazol-4-carboxylic acid C90 (30 mg, 13%). LCMS m / z 582.07 [M+H]+

[0831] Step 4: Synthesis of 2-(5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)oxazol-4-carboxylic acid (86)

[0832] 1,2,3,4,5-pentamethylbenzene (152 mg, 1.03 mmol) and trichloroborane (1.5 mL, 1 M, 1.5 mmol) were added to a solution of 2-[9-benzyloxy-5-(4-fluorophenyl)-4,4-dimethyl-spiro[3H-pyrano[4,3-b]indol-1,4'-piperidin]-1'-yl]oxazol-4-carboxylic acid C90 (30 mg, 0.0516 mmol) in dichloromethane (6 mL), 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 by a phase separator. The organic layer was concentrated and purified by reversed-phase chromatography (acetonitrile, formic acid modifier) ​​to give product 86 (6.1 mg, 23%). 1 HNMR (400MHz, methanol-d4) δ7.82(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,1H),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 / z492.09[M+H]+

[0833] Compound 87

[0834] 2-(5'-(4-fluorophenyl)-9'-hydroxy-4',4'-dimethyl-4',5'-dihydro-3'H-spiro[piperidin-4,1'-pyrano[4,3-b]indole]-1-yl)oxazol-5-carboxylic acid (87)

[0835]

[0836] In step 2, ethyl 2-bromooxazol-5-carboxylate was used to synthesize compound 87 in the same manner as 86. 1 H NMR(400MHz,DMSO-d6)δ9.69(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] +

[0837] Compounds 88-177

[0838] Compounds 88-177 were prepared from S6 and appropriate ketones or ketone equivalents.

[0839] Table 5. Preparation of compounds 88-177

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863] a Standard procedure A was modified by replacing DCE with dichloromethane.

[0864] b Standard procedure B was modified by replacing ammonium formate with hydrogen and Pd / C with Pd(OH)2, and using MeOH or EtOAc as a solvent or using MeOH and EtOAc as a co-solvent.

[0865] c Standard procedure A has been modified by removing Et3SiH.

[0866] d Prior to the debenzylation step, the ester is hydrolyzed using the same procedure described for the synthesis of compound C55, with the following modifications: THF, MeOH, and water are used as solvents, and LiOH is used as a base. The mixture is kept on a hot plate or in a microwave at a temperature between room temperature and 70°C for 2 hours.

[0867] e Standard procedure B was modified by using MeOH as the sole solvent and heating to a temperature within the range of 40°C–60°C.

[0868] fStandard procedure B was modified by using EtOH and THF as solvents and heating to a temperature within the range of 40°C-60°C.

[0869] g Standard procedure B was modified by using MeOH and THF as solvents and heating to a temperature within the range of 40°C-60°C.

[0870] h Standard procedure B was modified by using EtOH as the sole solvent.

[0871] i Standard procedure B was modified by using the conditions for BBr3 in dichloromethane as described for the synthesis of compounds 5 and 6.

[0872] j Standard procedure B was modified by replacing ammonium formate with hydrogen and using MeOH as a solvent or using MeOH and EtOAc as a co-solvent.

[0873] k Standard procedure B was modified by replacing ammonium formate with hydrogen and using EtOH or THF as a solvent or using EtOH and THF as a co-solvent.

[0874] l Standard procedure B was modified by replacing ammonium formate with hydrogen and using THF as the solvent.

[0875] 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.

[0876] n Prior to the debenzylation step, the ester is hydrolyzed using the same procedure described for the synthesis of compound C55, with the following modifications: THF as solvent or THF and MeOH as co-solvent, and 3M NaOH at a temperature between room temperature and 50°C.

[0877] o Standard procedure B was modified by replacing ammonium formate with hydrogen gas.

[0878] p Use methylamine (2M THF solution) instead of ammonium hydroxide.

[0879] q Add 1 mL of TFA when the reductive alkylation reaction is complete and stir the mixture for 10 minutes.

[0880] rEnantiomers of the racemic products from the reduction alkylation step are separated by chiral SFC and each is used individually in the benzyl deprotection step.

[0881] s Use dimethylamine (40% aqueous solution) instead of ammonium hydroxide.

[0882] t Prior to the debenzylation step, the ester is hydrolyzed using the same procedure described for the synthesis of compound C55, with the following modifications: dichloromethane and MeOH as solvents, and LiOH as base, at room temperature.

[0883] u Prior to the debenzylation step, the ester was hydrolyzed using the same procedure described for the synthesis of compound C55, with the following modifications: MeOH as solvent, 6M NaOH, in a microwave at 120°C.

[0884] Compound 178

[0885] (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)

[0886]

[0887] (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) were added to a flask, followed by 2 mL of THF, and the mixture was stirred at room temperature. After 4 hours, ammonium hydroxide (500 μL, 28% w / v, 4.0 mmol) was added at room temperature. After 40 minutes, brine and EtOAc were added, and the layers were separated. The combined organic matter was dried (Na2SO4), filtered, and concentrated. Ether was added, the mixture was sonicated, and a white solid was filtered off. Further purification was performed by column chromatography (C18 AQ 40 g column; TFA / MeCN aqueous solution). The pure fraction was concentrated, water was added, and the mixture was extracted with EtOAc. The layers were separated. The aqueous layer was extracted again with EtOAc, and the combined organic matter was concentrated. EtOAc was added, and product 178 (27.9 mg, 28%) was filtered off. 1H NMR(400MHz, DMSO-d6)δ9.87(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 / z409.13[M+H] + .

[0888] Compound 179

[0889] (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)

[0890]

[0891] To a 2-dela solution of (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), 1.5 mL of NaOH (1 M, 1.5 mmol) dissolved in it was added. Within 1 minute, sodium hypochlorite (300 μL, 5% w / v, 0.202 mmol) was added, and the reaction immediately turned brown. After 10 minutes, water (3 mL) was added, followed by HCl (3 mL of 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 organic matter was concentrated. Purification was completed by column chromatography (C18 50 g column; TFA / MeCN aqueous solution). The pure fraction was concentrated and the mixture was extracted with dichloromethane. The layers were separated using a phase separator. The aqueous layer was extracted again with dichloromethane and the combined organic matter was concentrated. The mixture was ground with EtOAc to give a white solid, which was dried on a glass 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%). 1HNMR(400MHz,DMSO-d6)δ11.90(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 the presence of orthochlorination.

[0892] Compounds 180-185

[0893] Compounds 180-185 were prepared from S7 and appropriate ketones.

[0894] Table 6. Preparation of compounds 180-185

[0895]

[0896]

[0897]

[0898] a Standard procedure A was modified by replacing DCE with dichloromethane.

[0899] b Standard procedure A has been modified by removing Et3SiH.

[0900] c Standard procedure B was modified by using EtOH and THF as solvents and heating at a temperature in the range of 50°C to 55°C.

[0901] Compounds 186-189

[0902] Compounds 186-189 were prepared from S8 and appropriate ketones.

[0903] Table 7. Preparation of compounds 186-189

[0904]

[0905]

[0906] a Standard procedure A was modified by removing Et3SiH and heating at 45°C.

[0907] iStandard procedure B was modified by using the conditions for BBr3 in dichloromethane as described for the synthesis of compounds 7 and 8.

[0908] Compounds 190 and 191

[0909] Compounds 190-191 were prepared from S9 and appropriate ketones.

[0910] Table 8. Preparation of compounds 190-191

[0911]

[0912] a Perform standard procedure A at 50°C.

[0913] b Using the same procedure described for the synthesis of compound C47, the product from standard procedure A was hydrolyzed with the following modifications: 1M LiOH as base in a microwave at 160°C.

[0914] Compound 192

[0915] 4-(9-(4-fluorophenyl)-5-hydroxy-1,1,4-trimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-4-yl)benzoic acid 192

[0916] Standard synthesis sequence A

[0917]

[0918] Standard synthesis sequence A

[0919] 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)

[0920] Methyl 4-[1-[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) was added dropwise at -10 °C. The reaction was stirred at -10 °C for 30 min. LC / MS indicated the presence of the desired epoxide ring-opening product, which was quenched with saturated NaHCO3 aqueous solution and extracted with dichloromethane, concentrated, and washed with an ISCO (40 g gold column) to give crude methyl 4-[1-[4-benzyloxy-1-(4-fluorophenyl)indole-3-yl]-2-hydroxy-1-methyl-ethyl]benzoate (305 mg, 17%). LC / MS m / z 510.08 (M+H) + 2,2-Dimethoxypropane (300.0 μL, 2.440 mmol) and methanesulfonic acid (30.0 μL, 0.4623 mmol) were added 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). The mixture was stirred at 25 °C for 16 hours. The mixture was quenched with a saturated aqueous solution of NaHCO3, extracted with dichloromethane, concentrated, and purified using ISCO (24 g gold column; 0-60% ethyl acetate in heptane solution) 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%). 1 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 = 8.0 Hz, 1H), 6.84–6.69 (m, 2H), 6.48–6.13 (m, 2H), 4.72 (d, J = 11.8 Hz, 1H), 4.46 (d, J = 11.7 Hz, 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) +

[0921] 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)

[0922] 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), lithium hydroxide hydrate (132 mg, 3.15 mmol) was added, and the mixture was heated at 80 °C for 2 h. The mixture was evaporated, neutralized with HCl (2 M, 1.6 mL, 3.2 mmol), and back-extracted with dichloromethane (3 x 40 mL). The dichloromethane layer was dried (Na₂SO₄) and concentrated to give product C92 (165 mg, 81%). LCMS m / z 536.43 [M+H] + .

[0923] 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)

[0924] 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), 10% Pd / C (70 mg, Degussa type, wettable) and NH4CO2H (180 mg, 2.86 mmol) were added. The mixture was heated at 50 °C for 1 hour. The reaction mixture was filtered, concentrated, and purified by reversed-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 ¹H 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, 1H), 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] +

[0925] Compounds 193-199

[0926] Compounds 193-199 were prepared from S10 or S11, as well as suitable epoxides and ketone / ketone equivalents.

[0927] Table 9. Preparation of compounds 193-199

[0928]

[0929]

[0930]

[0931] Compound 200

[0932] Compound 200 was prepared from S12 and a suitable ketone.

[0933] Table 10. Preparation of Compound 200

[0934]

[0935] a Standard procedure A was performed in dichloromethane in a sealed vial at 60°C.

[0936] b Standard procedure B was modified by replacing ammonium formate with hydrogen and using EtOH as the solvent.

[0937] Compound 201

[0938] 9-(4-Fluorophenyl)-5-hydroxy-1,1-dimethyl-2-oxo-1,2,3,9-tetrahydrospiro[carbazole-4,1'-cyclobutane]-3'-carboxylic acid (201)

[0939]

[0940] Step 1: Synthesis of 2-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-2-methylpropanal (C93)

[0941] Add Desmond-Martin periodane (10 g, 23.6 mmol) to a mixture of S6 (7.24 g, 18.6 mmol) in dichloromethane (100 mL) while cooling in an ice bath. After a few minutes, remove the reaction mixture from the cooling bath. After 3 hours, concentrate the reaction mixture and then purify it with dichloromethane through a silica stopper (200 g) to give product C93 (6.3 g, 87%). 1H NMR (400MHz, chloroform-d) δ9.55(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, 1H), 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).

[0942] Step 2: Synthesis of dimethyl (3-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl]-3-methyl-2-oxobutyl)phosphonate (C94)

[0943] 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 minutes. After 45 minutes, a solution of THF (11 mL) in C93 (3 g, 7.74 mmol) was added over 15 minutes at -78 °C. After stirring for another 5 minutes at -78 °C, the reaction mixture was placed in an ice bath. After 45 minutes, the reaction was quenched with a saturated aqueous solution of NH4Cl. Ethyl acetate was added and the reaction mixture was allowed to stand overnight. The next day, water and EtOAc were added, and a white, insoluble material was filtered off. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic matter was dried (Na2SO4), filtered, and concentrated.

[0944] To the residue in a solution of dichloromethane (80 mL) cooled in an ice bath, NaHCO3 (780 mg, 9.29 mmol) was added, followed by the addition of Des Martin periodane (4.3 g, 10.1 mmol). After 75 minutes, saturated aqueous sodium bicarbonate solution (100 mL) and 1 M sodium thiosulfate (50 mL) were added, and the mixture was vigorously stirred for 15 minutes. The layers were separated using a phase separator. The aqueous layer was re-extracted with dichloromethane, and the layers were again separated by a phase separator, and the combined organic matter was concentrated. Purification was performed by column chromatography (120 g gold column; 20–75% EtOAc in heptane solution) to give product C94 (2.14 g, 54%). 1H NMR (400MHz, chloroform-d) δ7.58-7.53(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, 1H), 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] + .

[0945] Step 3: Synthesis of benzyl 3-(3-(4-(benzyloxy)-1-(4-fluorophenyl)-1H-indol-2-yl)-3-methyl-2-oxobutylene)cyclobutane-1-carboxylate (C95)

[0946] Over 5 minutes, a solution of C94 (1.13 g, 2.21 mmol) in THF (6 mL) was added to a suspension of NaH (60% w / w, 97 mg, 2.43 mmol) in THF (5 mL). A solution of 3-oxocyclobutanecarboxylic acid benzyl ester (454 mg, 2.22 mmol) in THF (2 mL) was added, and the mixture was heated overnight at 50 °C. A saturated aqueous NH4Cl solution was added, and the mixture was extracted twice with EtOAc. The combined organic compounds were concentrated and then purified by column chromatography (C18 AQ 100 g column; TFA / MeCN aqueous solution) to give product C95 (524 mg, 40%) as a pale yellow viscous solid. 1 ¹H 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 = 8.0 Hz, 1H), 6.82 (d, J = 0.8 Hz, 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] + .

[0947] 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)

[0948] At room temperature, bismuth trifluoromethanesulfonate (130 mg, 0.210 mmol) was added to a solution of C95 (479 mg, 0.815 mmol) in deuterated MeCN (10 mL). After 2 hours, the reaction was concentrated. The residue was purified by column chromatography (C18 150 g column; TFA / MeCN aqueous solution), and the relevant fractions were concentrated. MeOH was added, and the product C96 (397 mg, 83%) was filtered off as a pale yellow solid. LCMS m / z 588.41 [M+H] + .

[0949] 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)

[0950] The procedure was performed from C96 according to standard procedure B, but with hydrogen gas instead of ammonium formate and with MeOH, EtOAc, and THF as solvents. A mixture of isomers was obtained. Note: One isomer: 1 H NMR (400MHz, DMSO-d6) δ7.51(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=7.7Hz,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 / z408.27[M+H] + .

[0951] Compound 202

[0952] 9-(4-Fluorophenyl)-2,5-dihydroxy-1,1-dimethyl-1,2,3,9-tetrahydrospiro[carbazole-4,1'-cyclobutane]-3'-carboxylic acid (202)

[0953]

[0954] 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)

[0955] Sodium borohydride (80 mg, 2.12 mmol) was added to a solution of C96 (307 mg, 0.522 mmol) in 9 mL of 2-MeTHF at room temperature. After 5 hours, 250 mg of reducing agent was added, and stirring continued overnight. Water and EtOAc were added, and the layers were separated. The aqueous layer was extracted again with EtOAc, and the combined organic matter was dried (Na₂SO₄), filtered, and concentrated to give product C97 (308 mg, 100%) as a straw-colored oil. LCMS m / z 590.93 [M+H] + .

[0956] 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)

[0957] The procedure was performed from C97 according to standard procedure B, but with hydrogen gas instead of ammonium formate and with MeOH, EtOAc and THF as solvents, to obtain two isomers of 202 with biological activity (31 mg, 14%). 1 H NMR (400MHz, methanol-d4) δ7.42-7.24(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). LCMSm / z 410.3[M+H] + .

[0958] Compound 203

[0959] (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)

[0960]

[0961] Step 1: Synthesis of 5-(2-benzyloxy)-6-bromophenyl)-2-methylpentan-4-yne-2-ol (C98)

[0962] 1-Benzyloxy-3-bromo-2-iodobenzene C2 (3.51 g, 9.02 mmol), 2-methylpentan-4-yn-2-ol (930 mg, 9.48 mmol), and then DMF (14 mL) were added sequentially to a 20 mL vial with a red vacuum cap. Nitrogen gas was bubbled through the mixture for 15–20 min. Pd(PPh3)2Cl2 (410 mg, 0.584 mmol) was added to the solution. 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 and maintained for 60 h. The reaction mixture was then directly loaded onto a reversed-phase column for purification (C18 275 g column; 5–95% MeCN solution in aqueous TFA). The purified fractions were combined and partially concentrated under reduced pressure. The mixture was extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, then concentrated under reduced pressure to obtain product C98 (2.01 g, 62%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.40–7.20 (m, 5H), 7.11 (dd, J = 8.1, 1.0 Hz, 1H), 6.98 (t, J = 8.2 Hz, 1H), 6.77 (dd, J = 8.4, 1.0 Hz, 1H), 5.06 (s, 2H), 2.61 (s, 2H), 2.20 (s, 1H), 1.27 (s, 6H).

[0963] Step 2: Synthesis of 5-(2-(benzyloxy)-6-((4-fluoro-3-methylphenyl)amino)phenyl)-2-methylpent-4-yne-2-ol (C99)

[0964] Nitrogen gas was bubbled through a solution of 5-(2-benzyloxy-6-bromo-phenyl)-2-methyl-pentan-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 minutes. Sodium tert-butyrate (915 mg, 9.52 mmol) and tBuXphosPalladacycle (195 mg, 0.284 mmol) were added, and bubbling continued for another 5 minutes, after which the vial was placed on a heating block set to 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 was performed by column chromatography (80 g column; 0-25% EtOAc in heptane solution) to give product C99 (2.26 g, 100%). 1HNMR (400MHz, chloroform-d) δ7.58-7.54(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).

[0965] Step 3: Synthesis of 1-(4-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)-2-methylprop-2-ol (C100)

[0966] Potassium tert-butoxide (5.6 mL, 1 M, 5.60 mmol) was added to a solution of C99 (2.26 g, 5.60 mmol) in 2-MeTHF (20 mL) at room temperature, and the reaction mixture was stirred overnight. Ethyl acetate, water, brine, and saturated ammonium chloride were added, and the layers were separated. 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 solution). The fractions were combined 10-13 to give 980 mg of indole product C100 (980 mg, 43%). 1 H NMR (400MHz, chloroform-d) δ7.56-7.51(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] + .

[0967] 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)

[0968] From C100, following standard procedure A, using 3-oxocyclobutanecarboxylic acid as the ketone, product C101 (58 mg, 49%) was obtained. LCMS m / z 500.58 [M+H] + .

[0969] 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)

[0970] BBr3 (290 μL, 1 M, 0.290 mmol) was added dropwise over 3 minutes to a solution of C101 (58 mg, 0.116 mmol) in 3.5 mL of dichloromethane at 0–5 °C. The reaction was quenched with water after 15 minutes. Dichloromethane was added, and the layers were separated using a phase separator. The organic matter was concentrated. Purification was performed by column chromatography (4 g gold column; 0–10% MeOH in dichloromethane solution) to give product 203 (10.7 mg, 21%). 1 H NMR (400MHz, methanol-d4) δ7.23-7.17(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] + .

[0971] Compound 204

[0972] Compound 204 was prepared from C2 and a suitable alkyne using the same procedure as compound 203.

[0973] Table 11. Preparation of compound 204

[0974]

[0975] a For step 5, standard procedure B is used instead of the BBr3-based method.

[0976] Compounds 205 and 206

[0977] Preparation of compounds 205-206 from S14 and suitable ketones

[0978] Table 12. Preparation of compounds 205-206

[0979]

[0980] a Standard procedure A is performed in dichloromethane instead of DCE.

[0981] b Standard procedure B was modified by replacing ammonium formate with hydrogen and using MeOH as the solvent.

[0982] Compounds 207 and 208

[0983] Preparation of compounds 207-208 from S16 and suitable ketones

[0984] Table 13. Preparation of compounds 207-208

[0985]

[0986] a Standard procedure A is performed in dichloromethane instead of DCE.

[0987] b Standard procedure B was modified by replacing ammonium formate with hydrogen and using EtOH as the solvent. b This is a byproduct observed from overreduction during the synthesis of compound 208.

[0988] Compounds 209 and 210

[0989] Compounds 209-210 were prepared from S15 and appropriate ketones.

[0990] Table 14. Preparation of compounds 209-210

[0991]

[0992]

[0993] a Standard procedure A is performed in dichloromethane instead of DCE.

[0994] b Standard procedure B was modified by replacing ammonium formate with hydrogen and using EtOH as the solvent.

[0995] b This is a byproduct observed from overreduction during the synthesis of compound 209.

[0996] Determination of the properties of AAT modifiers for detecting and measuring compounds

[0997] A. AAT function assay (MSD assay of NL20-SI cell line)

[0998] α-1 antitrypsin (AAT) is a SERPIN (serine protease inhibitor) that inactivates the enzyme by covalent binding. This assay measures the amount of functionally active AAT in a sample in the presence of the disclosed compounds 1-210 by determining the ability of AAT to form an irreversible complex with human neutrophil elastase (hNE). In practice, the sample (cell supernatant, blood sample, or others) is incubated with an excess of hNE to allow for the formation of an AAT-elastase complex with all functional AAT in the sample. This complex is then captured onto a microplate coated with an anti-AAT antibody. The captured complex is 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, sulfonated labeling, and microplates are used to provide high sensitivity and a wide dynamic range.

[0999] Material :

[1000]

[1001] instrument :

[1002] Meso Sector S600

[1003] Bravo

[1004] Washer dispenser

[1005] Multidrop Combi

[1006] Measurement scheme

[1007] Day 1 Cell Culture

[1008] 1. Harvesting in OptiMEM containing Pen / Strep (P / S) TM NL20 human bronchial epithelial cells expressing human Z-AAT

[1009] 2. Seed at 16,000 cells / well (384-well plate) in 30 μL.

[1010] 3. Briefly centrifuge the plate (1200 rpm) and incubate overnight at 37°C.

[1011] Day 2: Compound addition and plate coating with capture antibodies

[1012] Compound addition:

[1013] 1. Using Multidrop Combi in a fume hood, dispense 40 μL of OptiMEM containing doxycycline (1:1000 stock solution = 0.1 μM final). TM (P / S) Dispensed into each well of the compound plate

[1014] 2. Remove the cell plate from the incubator, invert / absorb the dry material, and immediately transfer it to Bravo for compound transfer.

[1015] 3. Place the plate back in the incubator overnight.

[1016] Coated MSD board

[1017] 1. Dilute the capture antibody (polyclonal goat anti-AAT) with PBS (BSA-free) to 5 μg / mL (1:200).

[1018] 2. Using a Multidrop kit equipped with a standard kit, dispense 25 μL of diluted capture antibody into all wells of an MSD384-well high-binding plate.

[1019] 3. Incubate overnight at 4°C.

[1020] Preparation of sealing agent A (BSA) solution

[1021] 1. Follow the manufacturer’s instructions to prepare a 5% MSD blocking agent A (BSA) solution.

[1022] 2. If necessary, further dilute the 5% MSD blocking agent A in PBS to 1% (blocking agent A).

[1023] Day 3: Run MSD measurement

[1024] Enclosed panel

[1025] 1. Wash the plate 1x with 50 μL of wash buffer (PBS + 0.5% Tween 20) and add 35 μL of 5% blocking agent A buffer to block the nonspecific binding on the washer dispenser.

[1026] 2. Rotate the plate at 600 rpm for 1 hour on the vibrator.

[1027] Prepare M-AAT standard products

[1028] 1. Dilute the M-AAT stock solution to 1.6 μg / mL with 1% BSA blocking agent A (stored at -70°C); then prepare 12x1:2 series dilutions with 1% blocking agent A.

[1029] 2. The highest starting concentration on the MSD plate is 320 ng / mL. These dilutions correspond to concentrations of 320, 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.312, and 0.156 ng / mL.

[1030] dilution plate

[1031] 1. Using Multidrop Combi, add 80 μL of 1% assay buffer to all wells except for columns 1 / 24 (standards).

[1032] 2. Add diluted standards to columns 1 and 24.

[1033] 3. Briefly centrifuge the dilution plate at 1200 rpm.

[1034] Cell plate

[1035] 1. Use a 16-needle aspirator in a fume hood to aspirate from the cell plate containing the standard.

[1036] Preparation of human neutrophil elastase (hNE)

[1037] 1. Prepare 1 μg / mL human neutrophil elastase by dilution in 1% blocking agent A.

[1038] a. Small 100μg tube – Add 1mL PBS (100μg / mL)

[1039] i. This can then be diluted 1:100 in 1% assay buffer to a final concentration of 1 μg / mL.

[1040] MSD - Add hNE (20 μL / well)

[1041] 1. After blocking the MSD plate for at least 1 hour, wash the plate 1x with 50 μL of wash buffer (PBS + 0.5% Tween 20) and then add 20 μL of hNE to each well.

[1042] Bravo – Cell Plate – Dilution Plate – MSD Plate

[1043] Aspirate 10 μL from the cell plate using Bravo and transfer it to a dilution plate (9-fold dilution).

[1044] 1. Mix 25 μL of 3x solution, then aspirate 5 μL and transfer to an MSD plate (5-fold dilution).

[1045] 2. Mix 10 μL of 3x solution. The total dilution is 45-fold.

[1046] 3. Shake the plate at 600 rpm for 1.5 hours.

[1047] Add function to detect hNE antibodies

[1048] 1. Wash the plate 1X with washing buffer.

[1049] 2. Using a washer / dispenser, add 25 μL of sulfonated antielastase (monoclonal mouse antielastase) diluted to 0.45 μg / mL (1:2000) in 1% blocking agent A to all wells of the functionally active MSD plate.

[1050] Note: The dilution required to produce a sufficient signal for each new batch of labeled antibody must be determined.

[1051] 3. Incubate at room temperature with shaking at 600 rpm for 1 hour.

[1052] Final wash and MSD imager readings

[1053] 1. Wash the plate 1x and add 25 μL of wash buffer to the plate.

[1054] 2. Prepare 2x read buffer

[1055] 3. Remove the washing buffer from the MSD plate.

[1056] 4. Use Bravo to transfer 35 μL of 2x read buffer to the MSD plate and immediately read the MSD.

[1057] Data analysis and EC in MSD Discovery Workbench 4.0 software 50 The value is determined using Genedata.

[1058] B. Biochemical analysis (Z-AAT elastase activity assay)

[1059] This assay measured the regulation of Z-AAT SERPIN activity by compound 1-210 using purified Z-AAT and purified human neutrophil elastase (hNE). Normally, when the active monomer Z-AAT encounters a protease such as trypsin or elastase, it forms a 1:1 covalent “suicide” complex in which both AAT and the protease are irreversibly inactivated. However, the binding of a compound to Z-AAT can lead to decreased SERPIN activity. In such cases, when the protease encounters Z-AAT bound to the compound, the protease cleaves and inactivates Z-AAT without being inactivated itself.

[1060] Material

[1061] reagents

[1062] PBS buffer (for culture medium preparation) + 0.01% BRIJ35 detergent (Calbiochem catalog number 203728)

[1063] Opti-MEM medium (Fisher 11058-021)

[1064] Human neutrophil elastase (hNE, Athens Research #16-14-051200)

[1065] A 3.4 μM stock solution (0.1 mg / mL) prepared with 50 mM sodium acetate, pH 5.5, and 150 mM NaCl was stored at -80 °C.

[1066] Elastase substrate V (ES V, fluorescent peptide substrate MeOSuc-Ala-Ala-Pro-Val-AMC, Calbiochem catalog number 324740)

[1067] The 20mM stock solution in DMSO is stored at -20°C.

[1068] Z-AAT protein purified from human plasma;

[1069] 12.9 μM (0.67 mg / mL) Z-AAT Vertex Cambridge sample 4942 from patient #061-SSN, stored at -80°C.

[1070] plate

[1071] Corning 4511 (384-hole black low capacity)

[1072] instrument

[1073] EnVision TM

[1074] Measurement scheme

[1075] Z-AAT pre-incubation with the compound

[1076] 1. Incubate 7.5 μL of Z-AAT (20 nM) with compound 1-210 in a GCA plate at room temperature for 1 hour.

[1077] Adding hNE

[1078] 1. Add 7.5 μL of HNE solution (3 nM in PBS + 0.01% BRIJ35) to the GCA plate.

[1079] 2. Incubate the plate for 30 minutes to allow the Z-AAT / HNE suicide complex to form.

[1080] Add substrate to PE Envision and read the board.

[1081] 1. Dispense 7.5 μL of substrate (300 μM solution of elastase substrate (ESV) in PBS + 0.01% BRIJ35) into each well of a GCA plate.

[1082] 2. Read immediately on Envision.

[1083] C. EC50 and Z-AAT elastase activity data of compounds 1-210

[1084] Compounds of formula (I) can be used as modifiers of AAT activity. Table 15 below shows the EC values ​​of compounds 1-210 obtained using the procedure described in section A above. 50 Table 15 below also provides the Z-AAT elastase activities obtained using the procedures described in Section B above. In Table 15 below, the following meanings apply: for EC... 50 and IC 50 "+++" means <1.2μM; "++" means between 1.2μM and 3.0μM; "+" means greater than 3.0μM; "N / A" means activity not evaluated. For IC 50 "ND" means that no activity was detected at 30 μM.

[1085] Table 15. EC5 of compounds 1-210 50 data

[1086]

[1087]

[1088]

[1089]

[1090]

[1091] Other implementation plans

[1092] This description provides only exemplary embodiments of the disclosed subject matter. Those skilled in the art will readily recognize from this disclosure and the appended claims that various changes, modifications, and variations may be made therein without departing from the spirit and scope of this disclosure as defined in the following claims.

Claims

1. A compound selected from: ， And pharmaceutically acceptable salts of the compound.

2. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating alpha-1 antitrypsin (AAT) deficiency in patients in need.

4. Use of a therapeutically effective amount of the pharmaceutical composition according to claim 2 in the manufacture of a medicament for treating α-1 antitrypsin (AAT) deficiency in patients in need.

5. Use of at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating the activity of α-1 antitrypsin (AAT) in patients in need.

6. Use of a therapeutically effective amount of the pharmaceutical composition according to claim 2 in the manufacture of a medicament for modulating the activity of α-1 antitrypsin (AAT) in patients in need.

7. The use according to claim 4 or claim 6, wherein the therapeutically effective amount of the pharmaceutical composition is administered in combination with AAT intensification therapy.

8. The use according to claim 4 or claim 6, wherein the therapeutically effective amount of the pharmaceutical composition is administered in combination with an AAT replacement therapy.

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