Alpha-1 antitrypsin modulators

Abstract

Novel compounds, compositions, and methods of their use and manufacture, which compounds and compositions are useful in the treatment of alpha-1 antitrypsin deficiency (AATD).

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 004,713, 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 compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) for the treatment of AATD, 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. For example, a compound of formula (I), its tautomers, deuterated derivatives of these compounds or tautomers, or a pharmaceutically acceptable salt of any of the foregoing can be described as follows:

[0009]

[0010] in:

[0011] V 1 and V 2 Each is independently N or -CR 2 ;

[0012] U is -OH or -NH2;

[0013] X does not exist or is a key, -(CR) a R a ) p -or-R a’ C = CR a’ -;

[0014] Y does not exist or is a key, -(CR) b R b ) q -or-R b’ C = CR b’ -;

[0015] T is -CR c R c COOH, -CR c =CR c COOH, -CN or

[0016] R a and R b Each of these elements is independently hydrogen, halogen, -OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0017] R a’ and R b’ Each of these elements is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy, each when it appears.

[0018] R c Each time it appears, it is independently hydrogen, halogen, -OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0019] Ring A is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, C6 or C6 10 Aryl or 5 to 10-membered heteroaryl;

[0020] Z represents -CN. in:

[0021] When T is not -CN, the ring C is C3-C. 12 cycloalkyl, C6 or C 10 Aryl, 3- to 12-membered heterocyclic or 5- to 10-membered heteroaryl;

[0022] When T is -CN, the ring C is C3-C. 12 Cycloalkyl or 3 to 12-membered heterocyclic groups;

[0023] R E R F and R G Each of these can be independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(=O)R s -C(=O)OR s -C(=O)NR p R q -CR p (=N)OR s -NR p R q -NR p C(=O)R s -NR p C(=O)OR s -NR p C(=O)NR q R r -OR s -OC(=O)R s or -OC(=O)NR p R q ;in:

[0024] R E R F and R G The C1-C6 alkyl or C2-C6 alkenyl group of any one of them is optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R s-C(=O)OR s -C(=O)NR p R q -NR p C(=O)R s -NR p C(=O)OR s -NR p C(=O)NR q R r -NR p S(=O) r R s -OR s -OC(=O)R s -OC(=O)OR s -OC(=O)NR p R q -S (=O) r R s and -S (=O) r NR p R q The groups are substituted; wherein:

[0025] R p R q and R r Each of these groups, when appearing independently, is hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3- to 6-membered heterocyclic group; wherein:

[0026] R p R q and R r The C1-C4 alkyl group of any one of them is optionally substituted with one to three groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH (C1-C2 alkyl) and -C(=O)N (C1-C2 alkyl)2; and

[0027] R p R q and R r The C3-C6 cycloalkyl or 3- to 6-membered heterocyclic group of any of them is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O (C1-C2 alkyl), -C(=O)NH (C1-C2 alkyl) and -C(=O)N (C1-C2 alkyl)2;

[0028] R s Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl; wherein:

[0029] R s The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0030] R s The C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0031] R 1 It can be halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or -O- (C3-C6 cycloalkyl);

[0032] R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NR h R i , phenyl or 5 or 6-membered heteroaryl; wherein:

[0033] R 2 The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl groups are optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R k -C(=O)OR k -C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k -NR h C(=O)NR i R j -NR h S(=O) sR k -OR k -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) s R k and S (=O) s NR h R i The groups are substituted; wherein:

[0034] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0035] R h R i and R j The C1-C4 alkyl group of any one of them is optionally substituted with one to three groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0036] R h R i and R j The C3-C6 cycloalkyl group of any one of them is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0037] R k Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl; wherein:

[0038] -OR k It cannot be -OH;

[0039] R kThe C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0040] R k The C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0041] R 3 and R 4 Each time it appears, it is independently a halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)R y -C(=O)OR y -C(=O)NR v R w -C(=O)NR v OR y -C(=O)NR v S(=O) t R y -NR v R w -NR v C(=O)R y -NR v C(=O)OR y -NR v C(=O)NR w R x -NR v S(=O) t R y -OR y -OC(=O)R y -OC(=O)OR y -OC(=O)NR v Rw -S (=O) t R y -S (=O) t NR v R w -S (=O) t NR v C(=O)R y -P(=O)R z R z , phenyl or 5 or 6-membered heteroaryl; wherein:

[0042] R 3 and R 4 The C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups of any of them are optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R y -C(=O)OR y -C(=O)NR v R w -NR v R w -NR v C(=O)R y -NR v C(=O)OR y -NR v C(=O)NR w R x -NR v S(=O) r R y -OR y -OC(=O)R y -OC(=O)OR y -OC(=O)NR v R w -S (=O) t R y and -S (=O) t NR v R w The groups are substituted; wherein:

[0043] R v R w and R x Each of these groups, when appearing independently, is hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocyclic group, or a 5- or 6-membered heteroaryl group; wherein:

[0044] R v R w and R xThe C1-C4 alkyl group of any one of them is optionally substituted with one to three groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0045] R v R w and R x The C3-C6 cycloalkyl, 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl groups of any of them are optionally substituted by 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0046] R y Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclic, or 5- or 6-membered heteroaryl; wherein

[0047] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0048] R y The C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, NH (C1-C2 alkyl), -N (C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O (C1-C2 alkyl), -C(=O)NH2, -C(=O)NH (C1-C2 alkyl) and -C(=O)N (C1-C2 alkyl)2;

[0049] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0050] k, m, and n are each independently an integer selected from 0, 1, 2, and 3; and

[0051] p, q, r, s, and t are each an integer selected from 1 and 2.

[0052] Compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) are AAT activity modifiers. In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, when tested in an AAT function assay, have an EC50 of 2.0 μM or less. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, when tested in an AAT functional assay, have an EC50 of less than 0.5 μM. 50 .

[0053] In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, when tested in a Z-AAT elastase activity assay, have an IC50 of 5.0 μM or less. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, when tested in a Z-AAT elastase activity assay, have an IC50 concentration of 2.0 μM.50 .

[0054] In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, have an EC50 of 2.0 μM or less when tested in an AAT functional assay. 50 And when tested in the Z-AAT elastase activity assay, it has an IC50 of 5.0 μM or less. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, when tested in an AAT functional assay, have an EC50 of less than 0.5 μM. 50 Furthermore, it exhibits an IC50 of less than 5.0 μM when tested in the Z-AAT elastase activity assay. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, when tested in an AAT functional assay, have an EC50 of less than 2.0 μM or less. 50 Furthermore, it exhibited an IC50 of less than 2.0 μM when tested in the Z-AAT elastase activity assay. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, when tested in an AAT functional assay, have an EC50 of less than 0.5 μM. 50 Furthermore, it exhibited an IC50 of less than 2.0 μM when tested in the Z-AAT elastase activity assay. 50 .

[0055] In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) for treating AATTD are provided, 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. In one aspect of this disclosure, the compounds of formula I for treating AATTD are selected from compounds 1-203 and 206-227, 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 of this disclosure for treating AATTD are selected from compounds 1-227, tautomers of compounds 1-227, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0056] In some embodiments, this disclosure provides pharmaceutical compositions comprising at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions may comprise compounds selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0057] Another aspect of this disclosure provides a method for treating AATD, comprising administering to a subject in need at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method comprises administering a compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0058] In some embodiments, the treatment method comprises administering at least one additional active agent to a subject in need, in the form of at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, as part of the same pharmaceutical composition or as a single composition. In some embodiments, the method comprises administering a compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in the form of at least one additional active agent, as part of the same pharmaceutical composition or as a single 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.

[0059] In some embodiments, the treatment method includes administering at least one additional active agent to a subject in need, in the form of at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, as part of the same pharmaceutical composition or a single composition, wherein the additional active agent is α-1 antitrypsin protein (AAT) derived from plasma from a healthy human donor. In some embodiments, the method includes administering a compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in the form of at least one additional active agent, as part of the same pharmaceutical composition or a single composition, wherein the additional active agent is α-1 antitrypsin protein (AAT) derived from plasma from a healthy human donor.

[0060] In some embodiments, the treatment method comprises administering to a subject in need at least one additional active agent in the form of at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, either as part of the same pharmaceutical composition or as a single composition, wherein the additional active agent is recombinant AAT. In some embodiments, the method comprises administering to a subject in need at least one additional active agent in the form of the same pharmaceutical composition or as a single composition, wherein the additional active agent is recombinant AAT.

[0061] A method for modulating AAT is also provided, comprising administering to a subject in need at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives and tautomers of these compounds, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method for modulating AAT comprises administering at least one compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives and tautomers of these compounds, 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.

[0062] Compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) for therapeutic use are also provided, 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 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided for therapeutic use.

[0063] Also provided are pharmaceutical compositions for therapeutic purposes comprising compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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, a pharmaceutical composition for therapeutic purposes is provided comprising a compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0064] I. Definition

[0065] As used herein, the term “AAT” refers to α-1 antitrypsin or a mutation thereof, including but not limited to AAT gene mutations such as the Z mutation. As used herein, “Z-AAT” refers to an AAT mutant with a Z mutation.

[0066] 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.

[0067] As used in this article, patients with a specific gene mutation who are "homozygous" have the same mutation on each allele.

[0068] As used in this article, patients with the PiZZ genotype are those who are homozygous for the Z mutation in the AAT protein.

[0069] As used in this article, the term “AATD” refers to α-1 antitrypsin deficiency, a genetic disorder characterized by low circulating levels of AAT.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] "Stereoisomers" refers to both enantiomers and diastereomers.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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 8-14 Hydrocarbons 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.

[0082] 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.

[0083] 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).

[0084] 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.

[0085] 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.

[0086] As used in this article, “=O” refers to an oxo group.

[0087] As used in this article, the "cyano" or "nitrile" group refers to -C≡N.

[0088] As used in this article, "hydroxyl group" refers to -OH.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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-toluenesulfonamides (OTs). 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).

[0093] 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).

[0094] 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).

[0095] 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.

[0096] 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.

[0097] 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.

[0098] Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1-4Alkyl)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.

[0099] The terms “patient” and “subject” are used interchangeably and refer to animals including humans.

[0100] 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).

[0101] 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.

[0102] 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.

[0103] Compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered once, twice, or three times daily for the treatment of AATD. In some embodiments, any one or more compounds are selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily, twice daily, or three times daily. In some embodiments, a compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily. In some embodiments, a compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily. In some embodiments, at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily. In some embodiments, a compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily.

[0104] Any one or more of the compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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 1-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0105] 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.

[0106] 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 compounds of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc) and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once, twice or three times daily. In some embodiments, 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, or 400 mg to 600 mg of a compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once, twice, or three times daily. In some embodiments, 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, or 400 mg to 600 mg of a compound selected from compounds 1-227 are administered once, twice, or three times daily.

[0107] 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 equivalent to the amount of the free base concentration 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 compounds of formula (I) and their pharmaceutically acceptable salts” includes 10 mg of the compound of formula (I) and the concentration of a pharmaceutically acceptable salt of the compound of formula (I) equivalent to 10 mg of the compound of formula (I).

[0108] As used in this article, the term "environmental conditions" refers to room temperature, outdoor conditions, and uncontrolled humidity conditions.

[0109] It should be understood that the use of one or more compounds (e.g., compounds of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe)) as mentioned herein, as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds) in treatment methods (e.g., methods for treating AATD) should also be interpreted as referring to: - methods for treating, for example, AATD using one or more compounds (e.g., compounds of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe)), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds); and / or

[0110] Use of one or more compounds (e.g., compounds of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc) and (VIIa)-(VIIe), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds) in the manufacture of a medicament for treating, for example, AATD.

[0111] Example implementation plan:

[0112] Without restrictions, some embodiments of this disclosure include:

[0113] 1. A compound represented by the following structural formula:

[0114]

[0115] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0116] V 1 and V 2 Each is independently N or -CR 2 ;

[0117] U is -OH or -NH2;

[0118] X does not exist or is a key, -(CR) a R a ) p -or-R a’ C = CR a’ -;

[0119] Y does not exist or is a key, -(CR) b R b ) q -or-R b’ C = CR b’ -;

[0120] T is -CR c R c COOH, -CR c =CR c COOH, -CN or

[0121] R a and R b Each of these elements is independently hydrogen, halogen, -OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0122] R a’ and R b’ Each of these elements is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy, each when it appears.

[0123] R c Each time it appears, it is independently hydrogen, halogen, -OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0124] Ring A is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, C6 or C6 10 Aryl or 5 to 10-membered heteroaryl;

[0125] Ring B is C4-C 12 cycloalkyl, C6 or C10 aryl, benzyl, or 5 to 10-membered heteroaryl;

[0126] Z represents -CN. in:

[0127] When T is not -CN, the ring C is C3-C. 12 cycloalkyl, C6 or C 10 Aryl, 3- to 12-membered heterocyclic or 5- to 10-membered heteroaryl;

[0128] When T is -CN, the ring C is C3-C. 12 Cycloalkyl or 3 to 12-membered heterocyclic groups;

[0129] R E R F and R G Each of these can be independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(=O)R s -C(=O)OR s -C(=O)NR p R q -CR p (=N)OR s -NR p R q -NR p C(=O)R s -NR p C(=O)OR s -NR p C(=O)NR q R r -OR s -OC(=O)R s or -OC(=O)NR p R q ;in:

[0130] R E R F and R G The C1-C6 alkyl or C2-C6 alkenyl group of any one of them is optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R s -C(=O)OR s -C(=O)NR p R q -NR p C(=O)R s -NR p C(=O)OR s -NR p C(=O)NRq R r -NR p S(=O) r R s 、 -OR s -OC(=O)R s -OC(=O)OR s -OC(=O)NR p R q -S (=O) r R s and -S (=O) r NR p R q The groups are substituted; wherein:

[0131] R p R q and R r Each of these groups, when appearing independently, is hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3- to 6-membered heterocyclic group; wherein:

[0132] R p R q and R r The C1-C4 alkyl group of any one of them is optionally substituted with one to three groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH (C1-C2 alkyl) and -C(=O)N (C1-C2 alkyl)2; and

[0133] R p R q and R r The C3-C6 cycloalkyl or 3- to 6-membered heterocyclic group of any of them is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O (C1-C2 alkyl), -C(=O)NH (C1-C2 alkyl) and -C(=O)N (C1-C2 alkyl)2;

[0134] R s Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl; wherein:

[0135] R sThe C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0136] R s The C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0137] R 1 It can be halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or -O- (C3-C6 cycloalkyl);

[0138] R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NR h R i , phenyl or 5 or 6-membered heteroaryl; wherein:

[0139] R 2 The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl groups are optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R k -C(=O)OR k -C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k -NR h C(=O)NR i R j -NR h S(=O) s R k -ORk -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) s R k and S (=O) s NR h R i The groups are substituted; wherein:

[0140] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0141] R h R i and R j The C1-C4 alkyl group of any one of them is optionally substituted with one to three groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0142] R h R i and R j The C3-C6 cycloalkyl group of any one of them is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0143] R k Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl; wherein:

[0144] -OR k It cannot be -OH;

[0145] R kThe C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0146] R k The C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0147] R 3 and R 4 Each time it appears, it is independently a halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)R y -C(=O)OR y -C(=O)NR v R w -C(=O)NR v OR y -(=O)NR v S(=O) t R y -NR v R w -NR v C(=O)R y -NR v C(=O)OR y -NR v C(=O)NR w R x -NR v S(=O) t R y -OR y -OC(=O)R y -OC(=O)OR y -OC(=O)NR v Rw -S (=O) t R y -S (=O) t NR v R w -S (=O) t NR v C(=O)R y -P(=O)R z R z , phenyl or 5 or 6-membered heteroaryl; wherein:

[0148] R 3 and R 4 The C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, or 5- or 6-membered heteroaryl groups of any of them are optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R y -C(=O)OR y -C(=O)NR v R w -NR v R w -NR v C(=O)R y -NR v C(=O)OR y -NR v C(=O)NR w R x -NR v S(=O) r R y -OR y -OC(=O)R y -OC(=O)OR y -OC(=O)NR v R w -S (=O) t R y and -S (=O) t NR v R w The groups are substituted; wherein:

[0149] R v R w and R x Each of these groups, when appearing independently, is hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocyclic group, or a 5- or 6-membered heteroaryl group; wherein:

[0150] R v R w and R xThe C1-C4 alkyl group of any one of them is optionally substituted with one to three groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0151] R v R w and R x The C3-C6 cycloalkyl, 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl groups of any of them are optionally substituted by 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0152] R y Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclic, or 5- or 6-membered heteroaryl; wherein

[0153] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0154] R y The C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, NH (C1-C2 alkyl), -N (C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O (C1-C2 alkyl), -C(=O)NH2, -C(=O)NH (C1-C2 alkyl) and -C(=O)N (C1-C2 alkyl)2;

[0155] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0156] k, n, and o are each independently an integer selected from 0, 1, 2, and 3; and

[0157] p, q, r, s, and t are each an integer selected from 1 and 2.

[0158] 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1, represented by formula (IIa):

[0159]

[0160] in:

[0161] Y does not exist or is a key, -CR b R b -or-R b’ C = CR b’ -;

[0162] R b Each time it appears, it is independently hydrogen or C1-C2 alkyl;

[0163] Ring B can be arbitrarily selected by R 1 Substitution and ring B is C4-C6 cycloalkyl, phenyl, or 5 or 6-membered heteroaryl;

[0164] Furthermore, all other variables not specifically defined herein are defined as in Implementation Scheme 1.

[0165] 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1, represented by formula (IIb) or (IIc):

[0166]

[0167] in:

[0168] Y does not exist or is a key, -CR b R b -or-R b’ C = CR b’ -;

[0169] R b Each time it appears, it is independently hydrogen or C1-C2 alkyl;

[0170] Ring B can be arbitrarily selected by R 1 Substitution and ring B is C4-C6 cycloalkyl, phenyl, or 5 or 6-membered heteroaryl;

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

[0172] 4. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 3, wherein Y is absent or is a bond, -CH2, or

[0173] -HC = CH-; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0174] 5. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 4, represented by formula (III):

[0175]

[0176] in:

[0177] X does not exist, is a key, or -(CR) a R a ) p -;

[0178] R a Each of them is independently hydrogen or C1-C2 alkyl;

[0179] R c Each time it appears, it is independently hydrogen, F, -OH, benzyl, C1-C2 alkyl, or C1-C2 alkoxy;

[0180] Ring B can be arbitrarily selected by R 1 The ring B is substituted and is cyclobutyl, phenyl, pyridyl, or pyrimidinyl;

[0181] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0182] 6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 5, wherein:

[0183] X either does not exist or is a bond, -CH2-, -CHCH3-, -CH2CH2-, or -CHCH3CH2-;

[0184] Ring B can be arbitrarily selected by R 1 The ring B is substituted with cyclobutyl, phenyl, pyridin-4-yl or pyrimidin-4-yl;

[0185] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0186] 7. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 6, represented by formula (IV):

[0187]

[0188] in:

[0189] T is -CH2COOH, -CHCH3COOH, -CHC2H5COOH, -C(CH3)2COOH, -CF2COOH, -CH=CHCOOH, -C(CH3)(OH)COOH, -C(CH3)(OCH3)COOH, cyano, -CH(benzyl)COOH, or optionally R. 3 Replaced ring A;

[0190] When Z is a ring C, the ring C is arbitrarily bounded by R. 4 The ring C is substituted and is a C3-C6 cycloalkyl, a 4- to 8-membered heterocyclic group, a phenyl group, or a 5- or 6-membered heteroaryl group; and

[0191] R 1 It is a halogen, a C1-C2 alkyl, or a C1-C2 haloalkyl; and

[0192] k is an integer selected from 0, 1, and 2;

[0193] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0194] 8. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 7, wherein R 1 It is F, Cl, or -CH3; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0195] 9. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 8, wherein when T is ring A, ring A is optionally converted by R. 3 Substitution, and ring A is a C3-C7 cycloalkyl, a 4- to 6-membered heterocyclic group, a phenyl group, or a 5- or 6-membered heteroaryl group; and

[0196] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0197] 10. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 9, wherein when T is ring A, ring A is optionally converted by R. 3The substitution is performed, and ring A is a C3-C7 cycloalkyl, a 4- to 6-membered heterocyclic group, a phenyl group, or a 5- or 6-membered heteroaryl group containing one or two nitrogen atoms; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0198] 11. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 10, wherein when T is ring A, ring A is optionally converted by R. 3 Replacement, and ring A is selected from Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0199] 12. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 11, wherein when T is ring A, ring A is optionally converted by R. 3 Replacement, and ring A is selected from Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0200] 13. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 12, wherein when Z is ring C, ring C is optionally converted by R. 4 The substitution is performed, and the ring C is a C3-C4 cycloalkyl or a 4- to 6-membered heterocyclic group; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0201] 14. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 13, wherein when Z is ring C, ring C is optionally converted by R. 4 Replacement, and ring C is Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0202] 15. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 14, wherein when Z is ring C, ring C is optionally converted by R. 4 Replacement, and ring C is Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0203] 16. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 12, wherein Z is At that time, R E R F and R G Each can be independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)OR s -C(=O)NR p R q -CR p (=N)OR s -NR p R q or -OR s ;in:

[0204] R E R F and R G The C1-C6 alkyl group of any one of them is optionally surrounded by 1 to 3 groups selected from cyano and -OR s The groups are substituted; wherein:

[0205] R p and R q Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0206] R s Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0207] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0208] 17. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 12 and 16, wherein Z is At that time, R E R F and R G Each is independently hydrogen, halogen, C1-C2 alkyl, -NR p R q or -OR s ;in:

[0209] R E R F and R G The C1-C2 alkyl group of any one of them may optionally be substituted with 1 to 3 groups selected from cyano, -OH and -OCH3; wherein:

[0210] R p and R q Each time it appears, it is independently either hydrogen or a C1-C2 alkyl group; and

[0211] R sEach time it appears, it is independently hydrogen or C1-C2 alkyl;

[0212] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0213] 18. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 12, 16, and 17, wherein:

[0214] When Z is At that time, R E R F and R G Each can be independently hydrogen, F, -CH2CN, -OH, -OCH3, -CH3, -C2H5, or -CH2OCH3; and

[0215] When Z is At that time, R E and R F Each can be independently -CH3 or -NH2;

[0216] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0217] 19. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 18, represented by formula (Va), (Vb), or (Vc):

[0218]

[0219] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0220] 20. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 19, represented by formula (VIa), (VIb), or (VIc):

[0221]

[0222] 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.

[0223] 21. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 20, represented by formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe):

[0224]

[0225]

[0226] 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.

[0227] 22. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 21, wherein R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -NR. h R i Or cyclopropyl; wherein R h and R i Each occurrence is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0228] 23. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 22, wherein R 2 Each occurrence is independently hydrogen, F, Cl, -CH3, -NH2, or cyclopropyl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0229] 24. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 23, wherein R 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)OR y -C(=O)NR v S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R w -P(=O)R z R z Or 5 or 6-membered heteroaryl groups; among which:

[0230] R 3 The C1-C6 alkyl or 5-membered heteroaryl group is optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)OR y -OR y and -NR v R w The groups are substituted; wherein:

[0231] Rv and R w Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0232] R y Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0233] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0234] 25. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 24, wherein R 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)OR y -C(=O)NR v S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y Or 5-membered heteroaryl; among which:

[0235] R 3 The C1-C4 alkyl or 5-membered heteroaryl group is optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)OR y -OR y and -NR v R w The groups are substituted; wherein:

[0236] R v and R w Each time it appears, it is independently either hydrogen or a C1-C2 alkyl group; and

[0237] R y Each time it appears, it is independently hydrogen or C1-C2 alkyl;

[0238] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0239] 26. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 25, wherein R 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=O)OR y -C(=O)NR v S(=O)2R y-S(=O)2NR v R w -S(=O)2NR v C(=O)R y , tetrazolyl or oxadiazolyl; wherein:

[0240] R 3 The C1-C2 alkyl or oxadiazolyl group is optionally substituted with 1 to 3 groups selected from cyano, -COOH and -OH; wherein:

[0241] R v and R w Each time it appears, it is independently either hydrogen or -CH3; and

[0242] R y Each time it appears, it is independently hydrogen or

[0243] -CH3;

[0244] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0245] 27. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 26, wherein R 3 Each occurrence is independently F, cyano, =O, -CH3, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OCH3, -OCH3, -COOH, -CH2COOH, -C(=O)NHS(=O)2CH3, -S(=O)2NHCH3, -S(=O)2NHC(=O)CH3, tetrazol-5-yl, 1,2,4-oxadiazole-5(4H)-keto, or 1,3,4-oxadiazole-2(3H)-keto; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0246] 28. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 27, wherein R 4 Each time it appears, it is independently a halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, or -C(=O)R y -C(=O)OR y C(=O)NR v R w -NR v R w -OR y or -P(=O)R z R z ;in:

[0247] Rv and R w Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0248] R y Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0249] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0250] 29. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 28, wherein R 4 Each time it appears, it is independently a halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, or -C(=O)R. y -C(=O)OR y C(=O)NR v R w -NR v R w or -OR y ;in:

[0251] R v and R w Each time it appears, it is independently either hydrogen or a C1-C2 alkyl group; and

[0252] R y Each time it appears, it is independently hydrogen or C1-C4 alkyl;

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

[0254] 30. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 29, wherein R 4 Each time it appears, it is independently a halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or -C(=O)OR. y or -OR y ;in:

[0255] R y Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0256] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0257] 31. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 30, wherein R 4It is -C(=O)OC(CH3)3 each time it appears; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0258] 32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 31, wherein m is 0; and wherein all other variables not specifically defined herein are as defined in any of the preceding claims.

[0259] 33. A compound selected from compounds 1-227, their tautomers, deuterated derivatives of said compound or said tautomers, or a pharmaceutically acceptable salt of any of the foregoing.

[0260] 34. A pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33.

[0261] 35. 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 33, or a therapeutically effective amount of a pharmaceutical composition according to embodiment 34.

[0262] 36. 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 33, or a therapeutically effective amount of a pharmaceutical composition according to embodiment 34.

[0263] 37. The method according to embodiment 35 or embodiment 36, wherein a 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.

[0264] II. Compounds and Compositions

[0265] In some embodiments, the compounds disclosed herein are compounds of formula (I):

[0266]

[0267] Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0268] V 1 and V 2Each is independently N or -CR 2 ;

[0269] U is -OH or -NH2;

[0270] X does not exist or is a key, -(CR) a R a ) p -or-R a’ C = CR a’ -;

[0271] Y does not exist or is a key, -(CR) b R b ) q -or-R b’ C = CR b’ -;

[0272] T is -CR c R c COOH, -CR c =CR c COOH, -CN or

[0273] R a and R b Each of these elements is independently hydrogen, halogen, -OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0274] R a’ and R b’ Each of these elements is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy, each when it appears.

[0275] R c Each time it appears, it is independently hydrogen, halogen, -OH, benzyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0276] Ring A is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, C6 or C6 10 Aryl or 5 to 10-membered heteroaryl;

[0277] Ring B is C4-C 12 cycloalkyl, C6 or C 10 aryl, benzyl, or 5 to 10-membered heteroaryl;

[0278] Z represents -CN. in:

[0279] When T is not -CN, the ring C is C3-C. 12 cycloalkyl, C6 or C 10 Aryl, 3- to 12-membered heterocyclic or 5- to 10-membered heteroaryl;

[0280] When T is -CN, the ring C is C3-C. 12 Cycloalkyl or 3 to 12-membered heterocyclic groups;

[0281] R E R F and R G Each of these can be independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(=O)R s -C(=O)OR s -C(=O)NR p R q -CR p (=N)OR s -NR p R q -NR p C(=O)R s -NR p C(=O)OR s -NR p C(=O)NR q R r -OR s -OC(=O)R s or -OC(=O)NR p R q ;in:

[0282] R E R F and R G The C1-C6 alkyl or C2-C6 alkenyl group of any one of them is optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R s -C(=O)OR s -C(=O)NR p R q -NR p C(=O)R s -NR p C(=O)OR s -NR p C(=O)NR q R r -NR p S(=O) r R s -OR s -OC(=O)Rs -OC(=O)OR s -OC(=O)NR p R q -S (=O) r R s and -S (=O) r NR p R q The groups are substituted; wherein:

[0283] R p R q and R r Each of these groups, when appearing independently, is hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3- to 6-membered heterocyclic group; wherein:

[0284] R p R q and R r The C1-C4 alkyl group of any one of them is optionally substituted with one to three groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH (C1-C2 alkyl) and -C(=O)N (C1-C2 alkyl)2; and

[0285] R p R q and R r The C3-C6 cycloalkyl or 3- to 6-membered heterocyclic group of any of them is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O (C1-C2 alkyl), -C(=O)NH (C1-C2 alkyl) and -C(=O)N (C1-C2 alkyl)2;

[0286] R s Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl; wherein:

[0287] R s The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0288] R sThe C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0289] R 1 It can be halogen, -CN, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or -O-(C3-C6 cycloalkyl);

[0290] R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NR h R i , phenyl or 5 or 6-membered heteroaryl; wherein:

[0291] R 2 The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl groups are optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R k -C(=O)OR k -C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k -NR h C(=O)NR i R j -NR h S(=O) s R k 、 -OR k -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S (=O) s R k and S (=O) s NR h R iThe groups are substituted; wherein:

[0292] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0293] R h R i and R j The C1-C4 alkyl group of any one of them is optionally substituted with one to three groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0294] R h R i and R j The C3-C6 cycloalkyl group of any one of them is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0295] R k Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl; wherein:

[0296] -OR k It cannot be -OH;

[0297] R k The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0298] R kThe C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0299] R 3 and R 4 Each time it appears, it is independently a halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)R y -C(=O)OR y -C(=O)NR v R w -C(=O)NR v OR y -C(=O)NR v S(=O) t R y -NR v R w -NR v C(=O)R y -NR v C(=O)OR y -NR v C(=O)NR w R x -NR v S(=O) t R y -OR y -OC(=O)R y -OC(=O)OR y -OC(=O)NR v R w -S (=O) t R y -S (=O) t NR v R w -S (=O) t NR v C(=O)R y -P(=O)R z R z , phenyl or 5 or 6-membered heteroaryl; wherein:

[0300] R 3 and R 4 The C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl groups of any one thereof are optionally surrounded by 1 to 3 groups selected from cyano, -C(=O)R y -C(=O)OR y -C(=O)NR v R w -NR v R w -NR v C(=O)R y -NR v C(=O)OR y -NR v C(=O)NR w R x -NR v S(=O) r R y -OR y -OC(=O)R y -OC(=O)OR y -OC(=O)NR v R w -S (=O) t R y and -S (=O) t NR v R w The groups are substituted; wherein:

[0301] R v R w and R x Each of these groups, when appearing independently, is hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocyclic group, or a 5- or 6-membered heteroaryl group; wherein:

[0302] R v R w and R x The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano-OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2; and

[0303] R v R w and R xThe C3-C6 cycloalkyl, 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl groups of any of them are optionally substituted by 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and -C(=O)N(C1-C2 alkyl)2;

[0304] R y Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclic, or 5- or 6-membered heteroaryl; wherein

[0305] R y The C1-C4 alkyl group is optionally surrounded by 1 to 3 radicals selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl) and

[0306] Substitution of the -C(=O)N(C1-C2 alkyl)2 group; and

[0307] R y The C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl groups are optionally surrounded by 1 to 3 groups selected from halogen, cyano, -OH, -NH2, NH (C1-C2 alkyl), -N (C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O (C1-C2 alkyl), -C(=O)NH2, -C(=O)NH (C1-C2 alkyl) and

[0308] Substitution of the -C(=O)N(C1-C2 alkyl)2 group;

[0309] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0310] k, m, and n are each independently an integer selected from 0, 1, 2, and 3; and

[0311] p, q, r, s, and t are each an integer selected from 1 and 2.

[0312] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIa):

[0313]

[0314] in:

[0315] Y does not exist or is a key, -CR b R b -or-R b’ C = CR b’ -;

[0316] R b Each time it appears, it is independently hydrogen or C1-C2 alkyl;

[0317] Ring B can be arbitrarily selected by R 1 Substitution and ring B is C4-C6 cycloalkyl, phenyl, or 5 or 6-membered heteroaryl;

[0318] And all other variables therein are defined as in equation (I).

[0319] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIb) or formula (IIc):

[0320]

[0321]

[0322] in:

[0323] Y does not exist or is a key, -CR b R b -or-R b’ C = CR b’ -;

[0324] R b Each time it appears, it is independently hydrogen or C1-C2 alkyl;

[0325] Ring B can be arbitrarily selected by R 1 Substitution and ring B is C4-C6 cycloalkyl, phenyl, or 5 or 6-membered heteroaryl;

[0326] And all other variables therein are defined as in equation (I).

[0327] In some embodiments, Y is absent or is a bond in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of formulas (I), (IIa), (IIb) or (IIc) of this disclosure, or is selected from -CH2- and -HC=CH-; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0328] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (III):

[0329]

[0330] in:

[0331] X does not exist, is a key, or -(CR) a R a ) p -;

[0332] R a Each of them is independently hydrogen or C1-C2 alkyl;

[0333] R c Each time it appears, it is independently hydrogen, F, -OH, benzyl, C1-C2 alkyl, or C1-C2 alkoxy;

[0334] Ring B can be arbitrarily selected by R 1 The ring B is substituted and is cyclobutyl, phenyl, pyridyl, or pyrimidinyl;

[0335] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0336] In some embodiments, in compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of any of formulas (I), (IIa), (IIb), (IIc), or (III), X is absent or is a bond, or is selected from -CH2-, -CHCH3-, CH2CH2-, and -CHCH3CH2-; ring B is optionally separated by R 1 The substitution is performed, and ring B is selected from cyclobutyl, phenyl, pyridin-4-yl and pyrimidin-4-yl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0337] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IV):

[0338]

[0339] in:

[0340] T is -CH2COOH, -CHCH3COOH, -CHC2H5COOH, -C(CH3)2COOH, -CF2COOH, -CH=CHCOOH, -C(CH3)(OH)COOH, -C(CH3)(OCH3)COOH, -CN, -CH(benzyl)COOH, or ring A is optionally replaced by R. 3 replace;

[0341] When Z is a ring C, the ring C is arbitrarily bounded by R. 4 The ring C is substituted and is a C3-C6 cycloalkyl, a 4- to 8-membered heterocyclic group, a phenyl group, or a 5- or 6-membered heteroaryl group; and

[0342] R 1 It is a halogen, a C1-C2 alkyl, or a C1-C2 haloalkyl; and

[0343] k is an integer selected from 0, 1, and 2;

[0344] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0345] In some embodiments, R is in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any of formulas (I), (IIa), (IIb), (IIc), (III), or (IV). 1 It is F, Cl, or -CH3; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0346] In some embodiments, T is ring A in compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of any of formulas (I), (IIa), (IIb), (IIc), (III), or (IV), and ring A is optionally separated by R. 3 The substitution is performed, and ring A is a C3-C7 cycloalkyl, a 4- to 6-membered heterocyclic group, a phenyl group, or a 5- or 6-membered heteroaryl group; and all other variables are as defined in any of the foregoing embodiments.

[0347] In some implementations, ring A is optionally R 3 The substitutions are as follows: ring A is a C3-C7 cycloalkyl, a 5- or 6-membered heterocyclic group, a phenyl group, or a 4- to 6-membered heteroaryl group containing one or two nitrogen atoms; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0348] In some embodiments of formulas (I), (IIa), (IIb), (IIc), (III), or (IV), T is optionally replaced by R. 3 Replace ring A, and ring A is selected from:

[0349]

[0350] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0351] In some embodiments of formulas (I), (IIa), (IIb), (IIc), (III), or (IV), T is optionally replaced by R. 3 Replace ring A, and ring A is selected from: Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0352] In some embodiments of formulas (I), (IIa), (IIb), (IIc), (III), or (IV), Z is optionally replaced by R. 4 The substituted ring C, wherein the ring C is a 3- or 4-membered cycloalkyl or a 4- to 6-membered heterocyclic group; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0353] In some embodiments of formulas (I), (IIa), (IIb), (IIc), (III), or (IV), Z is optionally replaced by R. 4 The ring C is replaced, and the ring C is selected from:

[0354] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0355] In some embodiments of formulas (I), (IIa), (IIb), (IIc), (III), or (IV), Z is optionally replaced by R. 4 The ring C is replaced, and the ring C is selected from:

[0356] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0357] In some embodiments of formulas (I), (IIa), (IIb), (IIc), (III), or (IV), Z is R E R F and R G Each can be independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)OR s -C(=O)NR p R q -CR p(=N)OR s -NR p R q or -OR s ;in:

[0358] R E R F and R G The C1-C6 alkyl group of any one of them is optionally surrounded by 1 to 3 groups selected from cyano and -OR s The groups are substituted; wherein:

[0359] R p and R q Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0360] R s Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0361] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0362] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, wherein when Z is At that time, R E R F and R G Each is independently hydrogen, halogen, C1-C2 alkyl, -NR p R q or -OR s ;in:

[0363] R E R F and R G The C1-C6 alkyl group of any one of them is optionally substituted with 1 to 3 groups selected from cyano, -OH and -OCH3; wherein:

[0364] R p and R q Each time it appears, it is independently either hydrogen or a C1-C2 alkyl group; and

[0365] R s Each time it appears, it is independently hydrogen or C1-C2 alkyl;

[0366] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0367] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, wherein:

[0368] When Z is At that time, R E R F and R G Each can be independently represented as hydrogen, F, -CH2CN, -OH, or -OCH. 3、 -CH3, -C2H5, or -CH2OCH3; and

[0369] When Z is At that time, R E and R F Each can be independently -CH3 or -NH2;

[0370] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0371] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (Va), formula (Vb), or formula (Vc):

[0372]

[0373] All other variables are defined as in equation (I) or any of the above-described implementation schemes.

[0374] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (VIa), formula (VIb), or formula (VIc):

[0375]

[0376] Where n is an integer selected from 0, 1, and 2; and all other variables not specifically defined herein are defined as in equation (I) or any of the above-described implementation schemes.

[0377] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe):

[0378]

[0379]

[0380] Where n is an integer selected from 0, 1, and 2; and all other variables not specifically defined herein are defined as in equation (I) or any of the embodiments described above.

[0381] Following some implementations of equations (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), R 2 Each time it appears, it is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -NR h R i and cyclopropyl; wherein R h and R i Each occurrence is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0382] In some embodiments of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), R 2 Each occurrence is independently selected from F, Cl, -CH3, -NH2, and cyclopropyl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0383] In some embodiments of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), R 2 Each time it appears, it is independently selected from hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted by 1 to 3 groups selected from -CN, -OH, -OCH3 and -NH2), C1-C2 haloalkyl and C3-C4 cycloalkyl; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0384] 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 selected from halogen, cyano, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)OR y -C(=O)NR v S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y -P(=O)R z R z And 5- and 6-membered heteroaryl groups;

[0385] Where R3 The C1-C6 alkyl or 5-membered heteroaryl group is optionally surrounded by 1 to 3 groups selected from cyano, -OR y and -NR v R w The groups are substituted; wherein:

[0386] R v and R w Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0387] R y Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0388] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0389] 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 selected from halogen, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)OR y -C(=O)NR v S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y And 5-membered heteroaryl groups;

[0390] Where R 3 The C1-C4 alkyl or 5-membered heteroaryl group is optionally surrounded by 1 to 3 groups selected from cyano, -OR y and -NR v R w The groups are substituted; wherein:

[0391] R v and R w Each time it appears, it is independently either hydrogen or a C1-C2 alkyl group; and

[0392] R y Each time it appears, it is independently hydrogen or C1-C2 alkyl;

[0393] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0394] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 3Each time it appears, it is independently selected from halogen, cyano, =O, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=O)OR y -C(=O)NR v S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y Tetrazolyl and oxadiazolyl;

[0395] Where R 3 The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from cyano and -OH; wherein:

[0396] R v and R w Each time it appears, it is independently either hydrogen or -CH3; and

[0397] R y It is either hydrogen or -CH3 each time it appears;

[0398] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0399] 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 selected from F, cyano, =O, -CH3, -CH2F, -CHF2, -CF3, -CH2OH, -CH2OCH3, -OCH3, -COOH, -CH2COOH, -C(=O)NHS(=O)2CH3, -S(=O)2NHCH3, -S(=O)2NHC(=O)CH3, tetrazol-5-yl, 1,2,4-oxadiazole-5(4H)-keto, and 1,3,4-oxadiazole-2(3H)-keto; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0400] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 4 Each time it appears, it is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)R y -C(=O)OR y -OR y and -S(=O)2R y ;in:

[0401] Where R 4The C1-C6 alkyl group is optionally surrounded by 1 to 3 groups selected from cyano, -OR y -C(=O)OR y and -NR v R w The groups are substituted; wherein:

[0402] R v and R w Each time it appears, it is independently either hydrogen or a C1-C6 alkyl group; and

[0403] R y Each occurrence is independently of hydrogen and C1-C4 alkyl; wherein:

[0404] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3 and -NH2;

[0405] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0406] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 4 Each time it appears, it is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -C(=O)R y -C(=O)OR y C(=O)NR v R w -NR v R w -OR y and -P(=O)R z R z ;

[0407] Where R v and R w Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0408] R y Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0409] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0410] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 4 Each time it appears, it is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, -C(=O)R y -C(=O)ORy C(=O)NR v R w -NR v R w and -OR y ;in:

[0411] R v and R w Each time it appears, it is independently either hydrogen or a C1-C2 alkyl group; and

[0412] R y Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0413] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0414] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 4 Each time it appears, it is independently selected from halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, -C(=O)OR y and -OR y ;in:

[0415] R y Each time it appears, it is independently hydrogen or C1-C4 alkyl;

[0416] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0417] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 4 It is C(=O)OC(CH3)3 each time it appears; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0418] In some embodiments, m is 0 in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0419] In some embodiments, the compounds of any one of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) are selected from compounds 1-227 (Table I below), tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of any of the foregoing.

[0420] Table I. Compounds 1-227

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440] Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0441] Some embodiments of this disclosure include derivatives of compounds 1-227 or compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), or their tautomers. In some embodiments, the derivative is a silicon derivative, wherein at least one carbon atom selected from compounds 1-227 or compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) has been substituted with silicon. In some embodiments, the derivative is a boron derivative, wherein at least one carbon atom selected from compounds 1-227 or compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), or their tautomers, has been substituted with boron. In other embodiments, the derivative is a phosphate ester derivative, wherein at least one carbon atom in a compound selected from compounds 1-227 or compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), or their tautomers, is substituted with phosphorus. Since the general properties of silicon, boron, and phosphorus are similar to those of carbon, substituting carbon with silicon, boron, or phosphorus can produce compounds with similar biological activities to the original carbon-containing compound.

[0442] In some embodiments, the derivative is a silicon derivative wherein one carbon atom of a compound selected from compounds 1-227 or compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) and their tautomers is substituted with silicon. In other embodiments, two carbon atoms are 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 derivative of this disclosure may contain one or more deuterium-substituted hydrogen atoms. For example, one or more hydrogen atoms of the tert-butyl moiety (wherein the carbon has been substituted with silicon) may be substituted with deuterium. In other embodiments, the silicon derivative of a compound selected from compounds 1-227 or compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) and their tautomers may have silicon incorporated into the heterocycle.

[0443] Examples of silicon derivatives of compounds 1-227 or of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds:

[0444] Undefined variables are defined by any one of the terms in equations (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0445] Examples of silicon derivatives of compounds 1-227 or of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds:

[0446] Undefined variables are defined by any one of the terms in equations (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0447] Examples of boron derivatives of compounds 1-227 or of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds:

[0448] Undefined variables are defined by any one of the terms in equations (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0449] Examples of boron derivatives of compounds 1-227 or of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds:

[0450] Undefined variables are defined by any one of the terms in equations (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0451] Examples of phosphate ester derivatives of compounds 1-227 or of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds:

[0452] Undefined variables are defined by any one of the terms in equations (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0453] Examples of phosphate ester derivatives of compounds 1-227 or of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe) include the following compounds:

[0454] Undefined variables are defined by any one of the terms in equations (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe).

[0455] Another aspect of this disclosure provides a pharmaceutical composition comprising a compound selected from any of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), compounds 1-227, 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 comprising at least one compound selected from formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered to a patient in need.

[0456] 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.

[0457] It should also be understood that the pharmaceutical compositions of this disclosure can be used in combination therapies; that is, the pharmaceutical compositions described herein may further comprise at least one other active agent. Alternatively, a pharmaceutical composition comprising at least one compound of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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 1-227, 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.

[0458] In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one additional active agent for simultaneous, separate, or sequential treatment of AATD. In some embodiments, when used concurrently, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one additional active agent are in a separate pharmaceutical composition. In some embodiments, when used concurrently, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, pharmaceutically acceptable salts of any of the foregoing, and at least one additional active agent are contained together in the same pharmaceutical composition. In some embodiments, the compounds are selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0459] In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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 compounds and an additional active agent. In some embodiments, the compounds and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compounds and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compounds and the additional active agent are co-administered simultaneously. In some embodiments, the compounds and the additional active agent are co-administered sequentially. In some embodiments, the compounds are selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0460] In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, are provided in combination with an additional active agent for the treatment of 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 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0461] In some embodiments, a method of treating AATD with an additional active agent is provided, wherein the method comprises co-administering the additional active agent and compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0462] In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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 said compounds are prepared for administration in combination with an additional active agent. In some embodiments, the compounds and additional active agents are prepared for administration in the same pharmaceutical composition. In some embodiments, the compounds and additional active agents are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compounds and additional active agents are prepared for simultaneous administration. In some embodiments, the compounds and additional active agents are prepared for sequential co-administration. In some embodiments, the compounds are selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0463] In some embodiments, compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, are provided in combination with an additional active agent for use in a method of treating AATD. In some embodiments, the compounds and additional active agents are prepared for administration in the same pharmaceutical composition. In some embodiments, the compounds and additional active agents are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compounds and additional active agents are prepared for simultaneous administration. In some embodiments, the compounds and additional active agents are prepared for sequential co-administration. In some embodiments, the compounds are selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0464] In some embodiments, a method of providing an additional active agent for treating AATD is provided, wherein the additional active agent is prepared for combined administration with compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential co-administration. In some embodiments, the compound is selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0465] 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.

[0466] 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, etc.). The ingredients include: cellulose (including 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, flavoring agents, aroma agents, preservatives, and antioxidants.

[0467] 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.

[0468] In some embodiments, the method of this disclosure includes administering to a patient in need a compound selected from any one of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), 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 1-227, 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.

[0469] Another aspect of this disclosure provides a method for modulating α-1-antitrypsin activity, comprising contacting the α-1-antitrypsin with at least one compound of formula (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the method for modulating α-1-antitrypsin activity comprises contacting the α-1-antitrypsin with at least one compound selected from compounds 1-227, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt of any of the foregoing.

[0470] 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.

[0471] III. Preparation of Compounds

[0472] All genera, subgenera and specific compound formulas disclosed herein are considered part of this disclosure.

[0473] A. Compound of Formula I

[0474] The compounds disclosed herein may be prepared according to standard chemical practice or as described herein. The following abbreviations are used in the following synthetic schemes and in the descriptions of the preparation of compounds of formulas (I), (IIa)-(IIc), (III), (IV), (Va)-(Vc), (VIa)-(VIc), and (VIIa)-(VIIe), compounds 1-227, tautomers of these compounds, deuterated derivatives and tautomers of these compounds, and pharmaceutically acceptable salts of any of the foregoing:

[0475] abbreviation

[0476] 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

[0477] DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-2-amino

[0478] DMA = dimethylacetamide

[0479] DMAP = dimethylaminopyridine

[0480] DME = dimethoxyethane

[0481] DMF = dimethylformamide

[0482] DMSO = dimethyl sulfoxide

[0483] EtOH = ethanol

[0484] EtOAc = Ethyl acetate

[0485] HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphine hexafluoride ion)

[0486] MeOH = methanol

[0487] MP-TMT cleaner resin = macroporous polystyrene-bonded trithiotriazine, resin-bonded 2,4,6-trithiotriazine (TMT) equivalent.

[0488] MTBE = Methyl tert-butyl ether

[0489] NMM = N-methylmorpholine

[0490] NMP = N-methylpyrrolidine

[0491] Pd(dppf)₂Cl₂=[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0492] PdCl2 = Palladium(II) dichloride

[0493] PdCl2(PPh3)2=bis(triphenylphosphine)palladium(II) dichloride

[0494] SFC = Supercritical Fluid Chromatography

[0495] SPhos Pd G3=(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

[0496] TBAF = Tetrabutylammonium fluoride

[0497] 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

[0498] tBuXPhos Pd G3=[(2-di-tert-butylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

[0499] tBuXPhos Pd G4=di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine; dichloromethane; methanesulfonic acid; N-methyl-2-phenyl-aniline palladium(II)

[0500] TFA = Trifluoroacetic acid

[0501] THF = Tetrahydrofuran

[0502] 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.

[0503] In some embodiments, the method for preparing a compound of formula (I), 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 (I), its tautomers, deuterated derivatives, or a pharmaceutically acceptable salt with a deprotecting agent, as shown in Schemes 1 to 11 below (wherein all variables are as defined above for formula (I)):

[0504] Option 1

[0505]

[0506] Scheme 1 illustrates a method for preparing compounds of formula (I). PG 1 It is an alcohol protecting group, such as benzyl (Bn), methoxymethyl (MOM), or methyl. In some instances, in PG... 1 In the case of a benzyl group, compounds of formula 1-2 can be prepared by hydrogenolysis of the compound of formula 1-1 using a palladium / carbon catalyst under a hydrogen atmosphere. The reaction can be carried out under high pressure. Solvents such as methanol, EtOH, or EtOAc can be used. 1 In the case of groups such as MOM, compounds of formula (I) can be prepared by treatment with an acid such as HCl. In which PG 1 In the case of a methyl group, the group can be removed by treatment with AlCl3 in the presence of octylthiol. In some instances, reagents such as BBr3 can be used. Compounds of Formula 1-2 can be prepared from compounds of Formula 1-1 using any other standard method suitable for removing the alcohol group.

[0507] Option 2

[0508]

[0509] Scheme 2 illustrates a method for preparing compounds of formulas 2-5. Q 1 It is a halogen, such as Br, I, or Cl. Compounds of formula 2-3 are those having R... 20 Alkyl (Me) or hydrogen borate or ester. All other variables are as defined above. Compounds of Formula 2-1 can be converted to compounds of Formula 2-2 using any suitable method for halogenation reactions. For example, solvents such as N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS) in dichloromethane can be used. Compounds of Formula 2-4 are prepared from 2-2 and 2-3 using standard Suzuki coupling conditions. In some instances, Suzuki coupling conditions may involve a catalyst such as Pd(dppf)Cl2 and a base such as Na2CO3. In some instances, catalysts such as Pd2(dba)3 in the presence of ligands such as XPhos can be used. Solvents such as DMF or DME can be used. The reaction can be carried out in the presence of additional heat (e.g., 90°C). Compounds of Formula 2-5 can be prepared from compounds of Formula 2-4 using a suitable method for removing the alcohol protecting group.

[0510] Option 3

[0511]

[0512] The method for preparing compounds of formulas 3-4 is shown in scheme 3. PG2 It can be any suitable carboxylic acid protecting group. For example, PG 2 It can be Me, Et, benzyl, or tert-butyl. All other variables are as defined above. Compounds of Formula 3-2 can be prepared from compounds of Formula 3-1 using any suitable method for Suzuki coupling. For example, Pd(dppf)Cl2 in the presence of Na2CO3 can be used. Compounds of Formula 3-3 can be prepared from compounds of Formula 3-2 using a suitable method for removing the alcohol protecting group. For example, in PG... 2 In the case of methyl esters, hydrolysis can be performed using solvents such as THF and bases such as LiOH or NaOH in water. In PG... 2 In the case of a group such as tert-butyl, treatment with an acid such as TFA or HCl provides a compound of formula 3-3. In some instances, when PG 1 and PG 2 When both are benzyl groups, compounds of formula 3-4 can be prepared directly from compounds of formula 3-2 by hydrogenation.

[0513] Option 4

[0514]

[0515] Scheme 4 illustrates a method for preparing compounds of formula 4-4. All variables are as defined above. Compounds of formula 4-2 can be prepared by reductive alkylation of an indole of formula 2-1 with a ketone of formula 4-1. In some instances, reductive alkylation can be carried out in the presence of reagents such as triethylsilane and acids (such as trifluoroacetic acid or methanesulfonic acid). The reaction can be carried out in a solvent such as dichloromethane.

[0516] Option 5

[0517]

[0518] Scheme 5 describes a method for preparing compounds of formula 5-4. All variables are as defined above. Compounds of formula 5-2 can be prepared from a ketone or aldehyde of formula 5-1 and an indole of formula 2-1 under any conditions suitable for reductive alkylation. In some instances, the reaction can be carried out in the presence of triethylsilane and trifluoroacetic acid. Solvents such as dichloromethane can be used. The reaction can be carried out in the presence of additional heat (e.g., 40 °C).

[0519] Option 6

[0520]

[0521] Scheme 6 illustrates a method for preparing indole of formula 2-1. Q 2 and Q 3 It is a halogen, such as Br, Cl, or I. E 1It is hydrogen or SiMe3. For example, in some methods, Q 2 It is iodine, and Q 3 It is bromine. In some instances, the compound of formula 6-3 can be prepared from the compound of formula 6-1 and the alkyne of formula 6-2 under any suitable conditions for Sonagashira coupling. In some instances, a catalyst in the presence of CuI, such as Pd(PPh3)2Cl2, can be used. Bases such as triethylamine or diisopropylethylamine can be used. The reaction can be carried out in a solvent such as DMF in the presence of additional heat. In some instances, where E 1 The reaction is carried out in the presence of TBAF, specifically SiMe3. Compounds of Formula 6-5 can be prepared from compounds of Formula 6-3 by transition metal-catalyzed amination with an amine of Formula 6-4. Amination can be carried out in the presence of palladium catalysts such as tBuXPhos Pd G3, tBuXPhos Pd G, or any other suitable catalyst for Buchwald amination. Bases, such as NaOtBu, can be used. The reaction can be carried out in a solvent such as xylene. The reaction can be carried out at room temperature or in the presence of additional heat. In some instances, spontaneous cyclization to compounds of Formula 2-1 occurs during the amination reaction. In some instances, compounds of Formula 2-1 are prepared from 6-5 by treatment with PdCl2 in a solvent such as MeCN. The reaction can be carried out in the presence of additional heat (e.g., 50°C).

[0522] Option 7

[0523]

[0524] Scheme 7 illustrates a method for preparing compounds of formula 6-5. Q 4 It is a halogen, such as Br or I. R 21 It is hydrogen or an alkyl group such as ethyl. The N-aniline of Formula 7-1 can be arylated with boric acid or ester 7-2 under any suitable N-arylation conditions to give the compound of Formula 7-3. In some instances, a Cu(OAc)₂ catalyst can be used. The reaction can be carried out in the presence of a base such as K₂CO₃. A solvent such as DMSO can be used. The compound of Formula 6-5 can be prepared by a Sonagashira coupling reaction of the compound of Formula 7-3 with an alkyne of Formula 7-4 to give the compound of Formula 6-5.

[0525] Option 8

[0526]

[0527] Scheme 8 describes a method for preparing compounds of general formula 8-7 from dihaloaryl groups of general formula 8-1. Q 5It is a halogen such as Cl, Br, or I. In some embodiments, group A is an aromatic or heteroaromatic ring. Amination of the compound of formula 8-1 with an amine of formula 8-2 yields the compound of formula 8-3. Amination of aryl halides with amines can be carried out using any suitable method. For example, the reaction can be carried out in the presence of a catalyst such as Pd(OAc)2 and a ligand such as dppf. In some instances, the reaction can be carried out in the presence of tBuXPhos Pd G1. The reaction can be carried out in the presence of a base such as NaOtBu. The indole of formula 8-5 can be prepared by reacting the compound of formula 8-3 with a disubstituted alkyne of formula 8-4 in the presence of a suitable palladium catalyst. For example, a catalyst such as Pd(tBu3P)2 or JackiePhos Pd G3 can be used. In some alternative embodiments, Pd(OAc)2 can be used. The reaction is carried out in the presence of a suitable ligand. For example, dicyclohexylmethylamine (cHx)2NMe can be used. The reaction can be carried out in a solvent such as 1,4-dioxane and in the presence of additional heat (e.g., 60 °C).

[0528] Option 9

[0529]

[0530] As shown in Scheme 9, any suitable conditions for Chan-Lam coupling of the compound of Formula 9-1 with the iodide of Formula 9-2 can be used to prepare the compound of Formula 9-3. The compound of Formula 9-4 can be prepared from the compound of Formula 9-3 using any suitable method for brominating the indole at the C2 position. In some embodiments, the reaction is carried out in the presence of tert-butyllithium, followed by quenching with an electrophilic bromide source such as 1,2-dibromotetrachloroethane. The sp2-sp3 coupling from the indole of Formula 9-4 to the compound of Formula 9-5 can be carried out using photoredox cross-coupling conditions. For example, trifluoroborate and an iridium-based photocatalyst are used in a flow reactor, irradiated with a Vaportech LED 124-watt lamp at 450 nM. The compound of Formula 9-6 can be prepared from the compound of Formula 9-5 using standard methods for alcohol deprotection.

[0531] Option 10

[0532]

[0533] As shown in Scheme 10, any suitable conditions for the formation of indole from benzoquinone with amines of Formula 8-2 and ketone esters of Formula 10-1 (Nenitzescu) can be used to prepare compounds of Formula 10-2. In some embodiments, the reaction is carried out in the presence of zinc chloride and acetic acid. Compounds of Formula 10-3 can be prepared from compounds of Formula 10-2 using standard methods with alcohol protection.

[0534] Option 11

[0535]

[0536] As shown in Scheme 11, any suitable conditions for the Stille cross-coupling reaction of vinyl-stanane with the iodide of Formula 2-2 can be used to prepare compounds of Formula 11-1. In some embodiments, the reaction is carried out in the presence of tetrapalladium and tetraethylammonium chloride with a solvent such as dimethylformamide. Cyclopropanization is carried out in the presence of (R,R)-PyBox with a reagent such as ethyl 2-diazolate. The reaction can be carried out in a solvent such as toluene and in the presence of additional heat (e.g., 50°C). Compounds of Formula 11-3 can be prepared from compounds of Formula 11-2 using the standard method of ester hydrolysis described above. Compounds of Formula 11-4 can be prepared from compounds of Formula 11-3 using the standard method of alcohol deprotection. Example

[0537] 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.

[0538] Example 1. Synthesis of the compound

[0539] All specific and general compounds, methods for preparing those compounds, and intermediates disclosed for preparing those compounds are considered part of this disclosure.

[0540] A. Synthetic starting materials

[0541] The preparation of S1-S22 describes the synthetic route for the intermediates used to synthesize compounds 1-227.

[0542] Preparation of S1-S6

[0543] 5-(benzyloxy)-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indole (S1)

[0544]

[0545] Step 1. Synthesis of 4-(benzyloxy)-1-bromo-2-iodobenzene (C2)

[0546] To a solution of 4-bromo-3-iodophenol (88.1 g, 291.9 mmol) in acetone (840 mL), K₂CO₃ (48.4 g, 350.3 mmol) and NaI (13.1 g, 87.6 mmol) were added. The resulting suspension was heated to 45–50 °C. Benzyl bromide (36.7 mL, 306.5 mmol) was added dropwise, and the reaction mixture was heated overnight at 50 °C. The reaction mixture was cooled to room temperature. The solids were removed by filtration and washed with acetone. The resulting filtrate was concentrated under vacuum, diluted with dichloromethane (400 mL), and washed with 1 M NaOH (2 x 200 mL). The aqueous phase was extracted with dichloromethane (200 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give 112 g of the desired product: 4-benzyloxy-1-bromo-2-iodophenol (99%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.50–7.32 (m, 7H), 6.84 (dd, J = 8.8, 2.9 Hz, 1H), 5.02 (s, 2H).

[0547] Step 2. Synthesis of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-pyran (C3)

[0548] Water (13.0 mL, 721.6 mmol) was added to a solution of 4-benzyloxy-1-bromo-2-iodobenzene C2 (141.1 g, 344.6 mmol) and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (75.0 g, 407.2 mmol) in triethylamine (900 mL), followed by the addition of cuprous iodide (8.0 g, 42.0 mmol) and palladium dichloroisocyanurate; triphenylphosphine (12.0 g, 17.1 mmol). The reaction mixture was purged with nitrogen for 2 min and then cooled to 0 °C for 5 min. Tetrabutylammonium fluoride (430 mL, 1 M solution in THF, 430.0 mmol) was added to the mixture. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The resulting residue was diluted with dichloromethane and filtered through a silica gel pad. The filtrate was concentrated under vacuum to give a black oily substance, which crystallized upon standing to give 320 g of solid. The solid was diluted again in dichloromethane and purified through a silica gel stopper using heptane (100%) and then using a gradient purification with (1:9 EtOAc-CH2Cl2) / heptane (0-40%) until all products appeared. The major homogeneous fraction was concentrated under vacuum and dried under vacuum to give a solid, which was ground with heptane and filtered. After drying, 81.6 g of beige solid was obtained. The mother liquor was concentrated and purified by MPLC-0-15% EtOAc / heptane on an 880 g silica gel column; the pure fraction gave an oily substance, which, after standing, crystallized to give another 49.6 g of the desired product. 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-pyran (95%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.38–7.04 (m, 6H), 6.88 (d, J = 3.0 Hz, 1H), 6.59 (dd, J = 8.9, 3.1 Hz, 1H), 4.83 (s, 2H), 3.81 (m, 2H), 3.41 (m, 2H), 2.75 (dt, J = 7.8, 3.7 Hz, 1H), 1.94–1.42 (m, 4H). ESI-MS m / z calculated value 370.06, measured value 372.36 (M+H). + .

[0549] Step 3. 5-(benzyloxy)-1-(4-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indole (S1)

[0550] Sodium tert-butoxide (8.5 mL 2 M solution, 17.0 mmol) was added to a mixture of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-pyran C3 (3.3 g, 8.1 mmol), 4-fluoroaniline (1.0 g, 9.0 mmol), and tBuXxPhos Pd G3 (0.34 g, 0.43 mmol) in dioxane (30 mL). The resulting material was stirred at 50 °C for 1 h. After cooling to room temperature, the mixture was diluted with CH2Cl2, filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (80 g ISCO column) with a 0-10% EtOAc / CH2Cl2 gradient elution to give 4-benzyloxy-N-(4-fluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline, which was used without further purification. PdCl2 (0.20 g, 1.13 mmol) was added to a solution of 4-benzyloxy-N-(4-fluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline in CH3CN (30 mL). The reaction mixture was heated at 50 °C. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (80 g ISCO column) with 0–30% CH2Cl2 / heptane elution to give 1.2 g of product: 5-benzyloxy-1-(4-fluorophenyl)-2-tetrahydropyran-4-yl-indole (37%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.50 (d, J = 7.0Hz, 2H), 7.45–7.22 (m, 7H), 7.21–7.11 (m, 1H), 6.96–6.81 (m, 2H), 6.39 (d, J = 0.9Hz, 1H), 5.14 (s, 2H), 4.08–3.92 (m, 2H), 3.35 (td, J = 11.8, 2.1Hz, 2H), 2.79 (ddd, J = 11.6, 7.6, 3.8Hz, 1H), 1.94–1.64 (m, 4H). ESI-MS m / z calculated value 401.18, measured value 402.0 (M+H). + .

[0551] Compounds S2-S6 (Table 1) were prepared by substituting appropriate aniline into the Buchwald amination reaction in a similar manner to S1.

[0552] Table 1. Structural and physicochemical data of intermediates S2-S6

[0553]

[0554]

[0555] Preparation of S7

[0556] 5-(methoxymethoxy)-1-(2-methylpyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indole (S7)

[0557]

[0558] Step 1. Synthesis of 1-bromo-2-iodo-4-(methoxymethoxy)benzene (C4)

[0559] Add 4-bromo-3-iodophenol (300.7 g, 1.006 mol) to CH2Cl2 (2.5 L) at cold (0 °C) i Pr2NEt (185.0 mL, 1.062 mol) was added, followed by the addition of chloromethyl methyl ether (80 mL, 1.053 mol) at a controlled rate to maintain the temperature below 10 °C. After the addition, the reactants were removed from the cooling bath and stirred overnight at room temperature. The resulting deep red-brown solution was poured into a separatory funnel and washed with 1N citric acid. The organic layer was separated and washed with 1N NaOH. The organic layer was separated, dried (MgSO4), and filtered through a short silica gel stopper. The stopper was eluted with CH2Cl2 and the filtrate was evaporated under vacuum to give 309.5 g of product. 1-Bromo-2-iodo-4-(methoxymethoxy)benzene (90%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.55 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.90 (dd, J = 8.8, 2.9 Hz, 1H), 5.12 (s, 2H), 3.46 (s, 3H).

[0560] Step 2. 4-((2-bromo-5-(methoxymethoxy)phenyl)ethynyl)tetrahydro-2H-pyran (C5)

[0561] Water (0.21 mL, 11.68 mmol) was added to a solution of 1-bromo-2-iodo-4-(methoxymethoxy)benzene C4 (2.0 g, 5.8 mmol) and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (1.4 g, 7.6 mmol) in triethylamine (14 mL). Copper iodide (0.12 g, 0.65 mmol) and palladium dichloroisocyanurate (0.21 g, 0.29 mmol) were added to the mixture. The mixture was purged with nitrogen for 2 min and tetrabutylammonium fluoride (7.6 mL, 1 M solution, 7.6 mmol) was added. The resulting black mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was diluted with CH2Cl2 and filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum, and the resulting crude material was purified by silica gel chromatography (80 g ISCO column) using a 0–50% EtOAc / heptane gradient to give 1.8 g of product. 4-[2-[2-bromo-5-(methoxymethoxy)phenyl]ethynyl]tetrahydropyran (95%). 1 HNMR (300MHz, chloroform-d) δ7.46(d,J=8.9Hz,1H),7.15(d,J=3.0Hz,1H),6.86(dd,J=8.8,3.0Hz,1H),5.16(s,2H),4.01(ddd,J=11.6,6.5,3.5Hz ,2H),3.62(ddd,J=11.3,7.6,3.3Hz,2H),3.48(s,3H),2.96(tt,J=8.0,4.2Hz,1H),1.97(ddt,J=13.8,7.1,3.8Hz,2H),1.89-1.71(m,2H).

[0562] Step 3. 5-(methoxymethoxy)-1-(2-methylpyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indole (S7)

[0563] 2-Methylpyridin-4-amine (1.70 g, 15.72 mmol) was added to a solution of 4-((2-bromo-5-(methoxymethoxy)phenyl)ethynyl)tetrahydro-2H-pyran C5 (5.02 g, 15.44 mmol) in tert-BuOH (50 mL), followed by the addition of NaOtBu (4.41 g, 45.89 mmol). tBuXPhos Pd G1 (0.59 g, 0.86 mmol) was added, and the mixture was heated and stirred under reflux overnight to drive the reaction to completion. The crude reactant was poured into water. The mixture was extracted with CH2Cl2. The organic phase was dried (MgSO4), filtered, and evaporated under vacuum to give a deep red oil. The oil was dissolved in CH2Cl2 and filtered through a silica gel stopper. The stopper was eluted with 25% EtOAc / CH2Cl2, and the filtrate was evaporated under vacuum to give a crude product as a pale red solid. The obtained solid was dissolved in CH2Cl2 and purified by silica gel chromatography (330 g ISCO silica gel column) using 10% EtOAc / CH2Cl2 as elution of impurities. The product, appearing as a pale yellow solid, was then eluted with 25% EtOAc / CH2Cl2. The solid was ground with pentane, filtered, and concentrated under vacuum to give 6.0 g of product. 5-(methoxymethoxy)-1-(2-methyl-4-pyridyl)-2-tetrahydropyran-4-yl-indole (110%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.69 (d, J = 5.3Hz, 1H), 7.28 (d, J = 2.2Hz, 1H), 7.18 (d, J = 1.9Hz, 1H), 7.12 (dd, J = 5.3, 1.6Hz, 1H), 7.03 (d, J = 8.9Hz, 1H), 6.88 (dd, J = 8.9, 2.4Hz, 1H). (H), 6.43(s,1H), 5.19(s,2H), 3.98(dd,J=11.7,2.5Hz,2H), 3.51(s,3H), 3.36(td,J=11.8,2.4Hz,2H), 2.90(tt,J=11.4,3.9Hz,1H), 2.67(s,3H), 1.88-1.65(m,4H). ESI-MS m / z calculated value 352.18, measured value 353.33(M+1). + .

[0564] Preparation of S8-S11

[0565] 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S8)

[0566]

[0567] Step 1. Synthesis of 4-(benzyloxy)-1-bromo-2-(3-methylbut-1-yn-1-yl)benzene (C6)

[0568] To a 3 L round-bottom flask, 4-benzyloxy-1-bromo-2-iodobenzene (172.0 g, 442.1 mmol) in a solution of triethylamine (1.5 L) was reacted with 3-methylbut-1-yne (40.0 g, 563.7 mmol), followed by CuI (12.0 g, 63.0 mmol) and PdCl2(PPh3)2 (17.4 g, 24.8 mmol). The solution was stirred overnight at room temperature. During this time, a solid precipitated. The solvent was removed from the reactants and the mixture was suspended in 20% CH2Cl2 / heptane; it was loaded onto a silica gel stopper (approximately 1.5 kg) and eluted with heptane (2 x 1 L) followed by 20% CH2Cl2 / heptane until no more pure product was eluted. The pure fractions were combined to give a waxy, brownish-red solid, which was dried to give 140 g of product. 4-Benzyloxy-1-bromo-2-(3-methylbut-1-ynyl)benzene (92%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.51–7.31 (m, 6H), 7.08 (d, J = 3.0 Hz, 1H), 6.78 (dd, J = 8.9, 3.1 Hz, 1H), 5.04 (s, 2H), 2.85 (septet, J = 6.9 Hz, 1H), 1.33 (d, J = 6.9 Hz, 6H). ESI-MS m / z calculated value 328.04, measured value 338.56 (M+1). + .

[0569] Step 2. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S8)

[0570] Add 4-fluoro-3-methylaniline (25.0 g, 199.8 mmol) to a solution of 4-benzyloxy-1-bromo-2-(3-methylbut-1-ynyl)benzene C6 (57.4 g, 165.6 mmol) in tert-BuOH (1 L) to a 1 L round-bottom flask. Heat the mixture to 80 °C and add NaOtBu (49.0 g, 494.6 mmol). Purge the mixture with nitrogen for 10 min and then add t-BuXPhos PdG1 (5.3 g, 7.7 mmol) and heat the reaction mixture to reflux overnight. Remove most of the solvent by first passing the reaction mixture through nitrogen to cool it; then reduce the volume to about 200 mL by rotary evaporation. Dissolve the residue in CH2Cl2 (500 mL) and filter through a 500 g silica gel pad. Wash the silica gel pad with CH2Cl2 (about 3 x 500 mL). Concentrate the filtrate under vacuum to give 72 g of dark brown solid. 1¹H NMR revealed the material to be a 2:1 mixture of an uncyclized intermediate and closed indole S8. The residue was dissolved in DMSO (116 mL) to give approximately 0.7 M solution, which was heated to 150 °C for 30 min and then cooled to room temperature. The reaction mixture was partitioned between a saturated aqueous NaCl solution and 10% EtOAc / CH₂Cl₂. The aqueous phase was extracted multiple times with CH₂Cl₂ until no further UV material was observed. The organic extracts were combined, dried (Na₂SO₄), filtered, and concentrated under vacuum. The resulting crude material was milled between 1 L of 5% CH₂Cl₂ / heptane. The filtered solid was washed with heptane and then air-dried for 30 min by passing air through it. After drying, 36.2 g of a gray solid was obtained. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (62%). 1 ¹H NMR (300MHz, DMSO-d⁶) δ 7.37 (ddt, J = 21.3, 11.8, 7.2Hz, 9H), 7.12 (s, 1H), 6.77 (q, J = 8.8Hz, 2H), 6.32 (s, 1H), 5.10 (s, 2H), 3.01–2.78 (m, 1H), 2.31 (s, 3H), 1.14 (d, J = 6.6Hz, 6H). ESI-MS m / z calculated value 373.18, measured value 374.41 (M+1). + .

[0571] Compounds S9-S11 (Table 2) were prepared by substituting appropriate aniline into the amination step in a manner similar to that used for S8.

[0572] Table 2. Structural and physicochemical data of intermediates S9-S11

[0573]

[0574] Preparation of S12

[0575] 2-Isopropyl-5-(methoxymethoxy)-1-(2-methylpyridin-4-yl)-1H-indole (S12)

[0576]

[0577] S12 was prepared using a method similar to S8, with OMOM as a substitute for OBn and 2-methylpyridin-4-amine as a substitute for 4-fluoro-3-methyl-aniline. The core was prepared via Sonagashira, Buchwald, and cyclization. 1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-(methoxymethoxy)-1H-indole. 1H NMR (300MHz, chloroform-d) δ8.67(dd,J=5.3,0.7Hz,1H),7.31-7.24(m,1H),7.22-7.15(m,1H),7.13(ddd,J=5.3,2.0,0.6Hz,1H),7.03(dt,J=8.8,0.7Hz, 1H),6.85(dd,J=8.8,2.4Hz,1H),6.41(t,J=0.8Hz,1H),5.19(s,2H),3.5 1(s,3H),3.03(pd,J=6.8,0.8Hz,1H),2.66(s,3H),1.20(d,J=6.8Hz,6H). ESI-MS calculated m / z value: 310.17; measured value: 311.35 (M+1). + .

[0578] Preparation of S13-S15

[0579] 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indole (S13)

[0580]

[0581] Step 1. Synthesis of 4-(5-(benzyloxy)-2-bromophenyl)-2,2-dimethylbut-3-yne-1-ol (C7)

[0582] To a solution of 4-benzyloxy-1-bromo-2-iodobenzene C2 (13.3 g, 34.2 mmol) and 2,2-dimethylbut-3-yn-1-ol (4.0 g, 40.8 mmol) in dioxane (75 mL), iPr2NEt (15.0 mL, 86.1 mmol) was added. The reaction mixture was purged with nitrogen for 5–10 min. PdCl2(PPh3)2 (1.2 g, 1.7 mmol) was added, followed by CuI (0.7 g, 3.7 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen and foil. The reactants were filtered using EtOAc and then concentrated under vacuum. Purification was performed by silica gel chromatography (330 g ISCO column) using a 0–100% EtOAc / heptane gradient to give 7.2 g of the product 4-(5-benzyloxy-2-bromo-phenyl)-2,2-dimethylbut-3-yn-1-ol (81%). 1¹H NMR (400MHz, chloroform-d) δ 7.45 (d, J = 8.9 Hz, 1H), 7.44–7.34 (m, 5H), 7.09 (d, J = 3.0 Hz, 1H), 6.82 (dd, J = 8.9, 3.0 Hz, 1H), 5.05 (s, 2H), 3.55 (d, J = 7.2 Hz, 2H), 2.10 (d, J = 7.1 Hz, 1H), 1.35 (s, 6H). ESI-MS m / z calculated value 358.06, measured value 359.17 (M+1). + .

[0583] Step 2. Synthesis of 4-(benzyloxy)-1-bromo-2-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)benzene (C8)

[0584] At room temperature, NaH (0.8 g 60% w / w, 20.9 mmol) was added to a solution / suspension of 4-(5-benzyloxy-2-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol C7 (7.2 g, 19.9 mmol) and 1-(bromomethyl)-4-methoxy-benzene (3.2 mL, 21.9 mmol) in 2-MeTHF (40 mL). The temperature of the reaction mixture was increased to approximately 35 °C. Water and EtOAc were added, and the layers were separated. The aqueous layer was re-extracted with EtOAc, and the combined organic phases were concentrated under vacuum. The residue was purified by silica gel chromatography (220 g ISCO column) using a 0-100% EtOAc / heptane gradient to give 1.71 g of product. The methylated product was obtained: 4-benzyloxy-1-bromo-2-(4-methoxy-3,3-dimethyl-but-1-yn-yl)benzene (23%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.45–7.33 (m, 7H), 7.09 (d, J = 3.1 Hz, 1H), 6.78 (dd, J = 8.9, 3.0 Hz, 1H), 5.04 (s, 2H), 3.47 (s, 3H), 3.40 (s, 2H), 1.36 (s, 6H). ESI-MS m / z calculated value 372.07, measured value 375.24 (M+1). + .

[0585] Step 3. Synthesis of 4-(benzyloxy)-N-(4-fluoro-3-methylphenyl)-2-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)aniline (C8)

[0586] A solution of 4-benzyloxy-1-bromo-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzene C7 (1.71 g, 4.58 mmol) and 4-fluoro-3-methylaniline (0.64 g, 5.08 mmol) in dioxane (5 mL) and tert-BuOH (5 mL) was purged with nitrogen for 5–10 min. During purging, tBuXphos Pd G1 (0.20 g, 0.29 mmol) was added sequentially, followed by sodium tert-butoxide (1.00 g, 10.41 mmol). The reaction mixture was stirred under nitrogen at room temperature for 4 h. The reaction mixture was filtered through diatomaceous earth using EtOAc and then concentrated under vacuum. Purification was performed by silica gel chromatography (80g GOLD column) using a 0-100% EtOAc / heptane gradient to yield 1.91g of the product 4-(benzyloxy)-N-(4-fluoro-3-methylphenyl)-2-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)aniline (100%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.46–7.38 (m, 4H), 7.37–7.32 (m, 1H), 7.05 (d, J = 8.9 Hz, 1H), 7.01 (d, J = 2.9 Hz, 1H), 6.97–6.90 (m, 3H), 6.84 (dd, J = 9.0, 3.0 Hz, 1H), 5.02 (s, 2H), 3.43 (s, 3H), 3.34 (s, 2H), 2.29–2.24 (m, 3H), 1.34 (s, 6H). ESI-MS m / z calculated value 417.21, measured value 418.41 (M+1). + .

[0587] Step 4. 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indole (S13)

[0588] Add KOt-Bu (3.25 mL 1 M solution, 3.25 mmol) to a solution of N-[4-benzyloxy-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)phenyl]-4-fluoro-3-methyl-aniline C8 (1.23 g, 2.946 mmol) in 2-MeTHF (20 mL). Heat the reaction mixture at 50 °C until the reaction is complete.

[0589] Water and CH2Cl2 were added, and the layers were separated using a phase separator. The aqueous phase was re-extracted with CH2Cl2, and the layers were separated again using a phase separator. The combined organic matter was concentrated. MTBE was added, and the off-white solid was filtered off to give 800 mg of product. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indole (65%).1 ¹H NMR (400 MHz, chloroform-d) δ 7.48 (ddt, J = 7.5, 1.4, 0.7 Hz, 2H), 7.42–7.37 (m, 2H), 7.35–7.30 (m, 1H), 7.21 (tq, J = 7.5, 2.1 Hz, 2H), 7.16–7.13 (m, 1H), 7.12 (d, J = 2.3 Hz, 1H), 6 0.79 (dd, J = 8.8, 2.4 Hz, 1H), 6.57 (dt, J = 8.9, 0.6 Hz, 1H), 6.43 (d, J = 0.8 Hz, 1H), 5.11 (s, 2H), 3.25 (s, 3H), 3.19 (s, 2H), 2.35 (d, J = 2.0 Hz, 3H), 1.30 (s, 3H), 1.28 (s, 3H). ESI-MS m / z calculated value: 417.21, measured value: 418.41 (M+1). + .

[0590] Compounds S14-S15 (Table 3) were prepared by substituting appropriate alkynes into the Sonagashira coupling step in a similar manner to S13.

[0591] Table 3. Structural and physicochemical data of intermediates S14-S15

[0592]

[0593]

[0594] Preparation of S16

[0595] Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indole (S16)

[0596]

[0597] CuI (0.5 g, 2.6 mmol) and Cs₂CO₃ (25.0 g, 76.7 mmol) were added to a solution of 5-benzyloxy-1H-indole (10.0 g, 44.8 mmol) and 1-fluoro-4-iodo-2-methyl-benzene (12.0 g, 50.8 mmol) in DMF (50 mL). The mixture was purged with nitrogen for 5 min in a pressure-resistant bottle (Qian cap), then the bottle was sealed and heated at 130 °C for 24 h. The solution was diluted with EtOAc (200 mL) and the solid was filtered off. The filtrate was washed with water (200 mL) and the organic layer was separated and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (80 g ISCO column) with elution of 0–15% EtOAc / heptane to give 7.8 g of the product as a white solid. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)indole (51%). ESI-MS m / z calculated value 331.14, measured value 326.11 (M+1). + .

[0598] Preparation of S17

[0599] 5-(benzyloxy)-4-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S17)

[0600]

[0601] Step 1. Synthesis of 3-(benzyloxy)-6-bromo-2-fluoroaniline (C10)

[0602] NH₄Cl (4.09 g, 76.46 mmol) was added to a solution of 1-benzyloxy-4-bromo-2-fluoro-3-nitrobenzene (4.96 g, 15.21 mmol) and Fe (4.25 g, 76.10 mmol) in methanol (150 mL). The reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the mixture was filtered through a diatomaceous earth mat and the resulting solid was washed with methanol. The filtrate was concentrated under vacuum and then diluted to H₂O and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO₄), filtered, and concentrated under vacuum. The resulting crude material was purified by silica gel chromatography (330 g ISCO column) using a 0–15% EtOAc / heptane gradient to give 4.02 g of product, which, upon drying, formed a white solid: 3-benzyloxy-6-bromo-2-fluoroaniline (88%). 1¹H NMR (400MHz, chloroform-d) δ 7.48–7.29 (m, 5H), 7.06 (dd, J = 8.9, 1.3Hz, 1H), 6.38–6.28 (m, 1H), 5.11 (s, 2H), 4.12 (s, 2H). ESI-MS m / z calculated 295.0, measured 296.5 (M+1). + .

[0603] Step 2. Synthesis of 1-(benzyloxy)-4-bromo-2-fluoro-3-iodobenzene (C11)

[0604] A solution of NaNO2 (1.51 g, 21.89 mmol) and KI (4.53 g, 27.29 mmol) in water (7.0 mL) was added dropwise to a cold (-5 °C) suspension of 3-benzyloxy-6-bromo-2-fluoroaniline C10 (3.28 g, 10.92 mmol) and TsOH-H2O (6.24 g, 32.80 mmol) in acetonitrile (100 mL) at a rate of 0.20 mL / min using a syringe pump. The internal temperature was maintained <-5 °C throughout the addition. Over time, the reaction mixture turned yellow, then black, and finally deep orange. The reaction mixture was slowly heated to room temperature overnight. The solvent was removed under reduced pressure, and the resulting crude product was diluted in water and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (80g ISCO column) using a 0-10% EtOAc / heptane gradient, yielding an impure material. A second purification was performed by silica gel chromatography (80g ISCO column) using 0-40% CHCl3 / heptane, yielding a clear, colorless oily product. 1-(benzyloxy)-4-bromo-2-fluoro-3-iodobenzene 1 ¹H NMR (300MHz, chloroform-d) δ 7.45–7.29 (m, 6H), 6.88 (dd, J = 8.8, 8.3 Hz, 1H), 5.13 (s, 2H).

[0605] Step 3. Synthesis of 1-(benzyloxy)-4-bromo-2-fluoro-3-(3-methylbut-1-yn-1-yl)benzene (C12)

[0606] Add Pd(PPh3)2Cl2 (0.09 g, 0.13 mmol), CuI (0.03 g, 0.13 mmol), and 3-methylbut-1-yne (0.33 mL, 3.18 mmol) to a solution of 1-benzyloxy-4-bromo-2-fluoro-3-iodo-benzene C11 (1.08 g, 2.63 mmol) purged with nitrogen for 5 min in triethylamine (7.0 mL). Heat the reaction mixture overnight at 40 °C. LC-MS showed that the reaction did not complete. Add additional 3-methylbut-1-yne (0.33 mL, 3.18 mmol), Pd(PPh3)2Cl2 (0.09 g, 0.13 mmol), and CuI (0.03 g, 0.13 mmol) to the reaction mixture. Heat the reaction mixture again overnight at 40 °C. Remove the solvent under vacuum. Add H2O and extract with EtOAc. The combined organic phases were washed with 1M HCl and then with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (120g ISCO column) using a CHCl3 / heptane gradient to give 548 mg of the desired product: 1-benzyloxy-4-bromo-2-fluoro-3-(3-methylbut-1-ynyl)benzene (60%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.43–7.29 (m, 5H), 7.2 (dd, J = 8.9, 1.9 Hz, 1H), 6.77 (dd, J = 8.9, 8.3 Hz, 1H), 5.12 (s, 2H), 2.87 (double septuplet, J = 6.9, 0.9 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H). ESI-MS m / z calculated value 346.0, measured value 346.9 (M+1). + .

[0607] Step 4. Synthesis of 5-(benzyloxy)-4-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S17)

[0608] Add 0.23 g, 1.84 mmol of 4-fluoro-3-methylaniline to a solution of 1-benzyloxy-4-bromo-2-fluoro-3-(3-methylbut-1-ynyl)benzene C12 (0.55 g, 1.58 mmol) in dioxane (7 mL). Degas the mixture with nitrogen for 10 min. Add tBuXPhos Pd G3 (0.06 g, 0.08 mmol) and NaOtBu (0.46 g, 4.74 mmol) to the mixture, and then purge it again with nitrogen. Seal the reaction mixture and heat to 80 °C. After 10 min, cool the reaction mixture to room temperature. Filter the mixture through a fluorosilicic acid pad and wash with CH2Cl2 / EtOAc. Concentrate the filtrate under vacuum. Dilute the resulting residue in water and extract with EtOAc. Wash the combined organic phases with brine, dry (MgSO4), filter, and concentrate under vacuum. The residue was purified by silica gel chromatography (40g ISCO column) using a 0-20% EtOAc / heptane gradient to give 515 mg of the desired product: 5-benzyloxy-4-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (82%). ESI-MS m / z calculated value 391.17, found value 391.36 (M+1). + .

[0609] Compounds S18-S20 were prepared by a method similar to that of S17, using appropriate iodoaniline (Table 4) via Sonagashira coupling with isopropyne, followed by N-arylation with 4-bromo-2-methylbromobenzene.

[0610] Table 4. Structural and physicochemical data of intermediates S18-S20

[0611]

[0612]

[0613] Preparation of S21

[0614] Synthesis of 5-(benzyloxy)-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S21)

[0615]

[0616] Add BBr3 (5.0 mL 1 M solution, 5.0 mmol) to a cold (0 °C) solution of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole S19 (0.8 g, 2.5 mmol) in CH2Cl2 (25 mL). Heat the reaction mixture to room temperature and stir for 120 min. Wash the mixture with a saturated aqueous solution of NaHCO3. Dry the organic phase over Na2SO4, filter, and concentrate under vacuum to give 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-5-ol. Dissolve the crude product in acetone (25 mL) and add benzyl bromide (0.35 mL, 2.94 mmol) and CS2CO3 (1.6 g, 4.911 mmol), stirring the resulting solution at room temperature for 24 h. Dilute the mixture to water (25 mL) and extract with EtOAc (3 x 25 mL). The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-50% EtOAc / heptane gradient to give 781 mg of the product as a white solid. 5-Benzyloxy-6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (81%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.51 (d, J = 7.5Hz, 2H), 7.41 (t, J = 7.4Hz, 2H), 7.34 (t, J = 7.3Hz, 1H), 7.20–7.05 (m, 4H), 6.75 (d, J = 11.5Hz, 1H), 6.31 (s, 1H), 5.17 (s, 2H), 2.99–2.85 (m, 1H), 2.46–2.33 (m, 3H), 1.20 (d, J = 6.8Hz, 7H). ESI-MS m / z calculated value 391.17, measured value 390.69 (M+1). + .

[0617] Preparation of S22

[0618] Synthesis of 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)tetrahydro-2H-thiaran 1,1-dioxide (S22)

[0619]

[0620] Step 1. Synthesis of 4-ethynyltetrahydro-2H-thiaran 1,1-dioxide (C13)

[0621] K₂CO₃ (5.00 g, 36.18 mmol) was added to a solution of 1,1-dioxocyclopentane-4-carboxaldehyde (2.93 g, 18.06 mmol) and 1-diazo-1-dimethoxyphosphoryl-prop-2-one (5.20 g, 27.07 mmol) in methanol (20 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the resulting residue was diluted with EtOAc and washed with water. The organic phase was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (4 g ISCO column) using a 10–40% EtOAc / heptane gradient to give 2.28 g of the desired product: 4-ethynylcyclopentane-1,1-dioxide (80%). 1 ¹H NMR (400MHz, methanol-d⁴) δ 4.92–4.76 (m, 1H), 3.14–3.04 (m, 4H), 2.44–2.33 (m, 2H), 2.10 (dtd, J = 14.2, 10.1, 3.7 Hz, 2H).

[0622] Step 2. Synthesis of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-thiaran 1,1-dioxide (C14)

[0623] Pd(PPh3)2Cl2 (0.61 g, 0.87 mmol) and CuI (0.31 g, 1.62 mmol) were added to a solution of 4-benzyloxy-1-bromo-2-iodobenzene (3.50 g, 8.99 mmol) and 4-ethynyltetrahydro-2H-thiaran 1,1-dioxide C13 (1.98 g, 12.51 mmol) in trimethylamine (15 mL) and dioxane (15 mL). The reaction mixture was heated at 60 °C overnight. The reaction mixture was cooled to room temperature and then filtered through a diatomaceous earth stopper. The filtrate was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 10-90% EtOAc / heptane gradient to give 2.1 g of product. 4-[2-(5-benzyloxy-2-bromo-phenyl)ethynyl]cyclopentane sulfide 1,1-dioxide (51%) ESI-MS m / z calculated value 418.02, measured value 419.35 (M+1) + .

[0624] Step 3. Synthesis of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-thiaran 1,1-dioxide (C15)

[0625] To a solution of 4-((5-(benzyloxy)-2-bromophenyl)ethynyl)tetrahydro-2H-thiaran-1,1-dioxide C14 (2.09 g, 4.98 mmol) and 4-fluoro-3-methylaniline (0.65 g, 5.19 mmol) in t-BuOH (8 mL) and dioxane (8 mL), tBuXPhos Pd G3 (0.20 g, 0.25 mmol) and NaOtBu (1.25 g, 13.01 mmol) were added. The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, and the resulting residue was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 10–40% EtOAc / heptane gradient to give 2.12 g of product. N-[4-benzyloxy-2-[2-(1,1-dioxocyclopentan-4-yl)ethynyl]phenyl]-4-fluoro-3-methylaniline (61%). ESI-MS m / z calculated value 463.16, measured value 464.23 (M+1). + .

[0626] Synthesis of 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-2-yl)tetrahydro-2H-thiaran 1,1-dioxide (S22)

[0627] KOtBu (0.27 g, 2.40 mmol) was added to a solution of N-[4-benzyloxy-2-[2-(1,1-dioxocyclopentan-4-yl)ethynyl]phenyl]-4-fluoro-3-methylaniline C15 (1.12 g, 2.42 mmol) in THF (20 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, diluted with EtOAc, and washed with water. The organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 10-40% EtOAc / heptane gradient to give 820 mg of product: 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-2-yl]cyclopentane 1,1-dioxide (43%). ESI-MS calculated m / z value: 463.16; measured value: 464.23 (M+1) + .

[0628] Preparation of S23

[0629] Synthesis of 2-isopropyl-5-methoxy-1-(2-methylpyrimidin-4-yl)-1H-indole (S23)

[0630]

[0631] Step 1. Synthesis of N-(2-iodo-4-methoxyphenyl)-2-methylpyrimidin-4-amine (C16)

[0632] A mixture of 2-iodo-4-methoxy-aniline (2.52 g, 10.12 mmol), 4-chloro-2-methylpyrimidine e (1.80 g, 14.00 mmol), and iPr2NEt (4.0 mL, 22.9 mmol) in DMSO (10 mL) was irradiated with microwaves at 180 °C for 20 min. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with H2O, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–60% EtOAc / CH2Cl2 gradient to give 1.0 g of product. N-(2-iodo-4-methoxy-phenyl)-2-methylpyrimidine-4-amine (29%). ESI-MS m / z calculated value 341.0, found value 342.0 (M+1). + .

[0633] Step 2. Synthesis of N-(2-iodo-4-methoxyphenyl)-2-methylpyrimidin-4-amine (S23)

[0634] Pd(PPh3)2Cl2 (0.20 g, 0.28 mmol) and CuI (0.15 g, 0.79 mmol) were added to a solution of N-(2-iodo-4-methoxy-phenyl)-2-methylpyrimidin-4-amine C16 (1.00 g, 2.93 mmol) and 3-methylbut-1-yne (0.40 g, 5.87 mmol) in trimethylamine (10 mL). The reaction mixture was heated at 50 °C for 1 hour. The mixture was concentrated under vacuum and diluted with EtOAc, filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-100% EtOAc / heptane gradient to give 420 mg of product: N-[4-methoxy-2-(3-methylbut-1-yneyl)phenyl]-2-methylpyrimidin-4-amine (51%). ESI-MS calculated m / z value: 281.2; measured value: 282.0 (M+1) + .

[0635] To a solution of N-[4-methoxy-2-(3-methylbut-1-ynyl)phenyl]-2-methylpyrimidin-4-amine (0.42 g) in THF (20 mL), KOtBu (0.40 g, 3.57 mmol) was added. The reaction mixture was heated to reflux and maintained at that temperature overnight. The mixture was cooled, concentrated under vacuum, and diluted with water. The aqueous phase was extracted with CH2Cl2, and the organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (12 g ISCO column) using a 0–30% EtOAc / CH2Cl2 gradient to give 320 mg of product 2-isopropyl-5-methoxy-1-(2-methylpyrimidin-4-yl)indole (39%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.75 (d, J = 5.4Hz, 1H), 7.44 (dt, J = 9.0, 0.6Hz, 1H), 7.33–7.23 (m, 1H), 7.06 (d, J = 2.4Hz, 1H), 6.83 (dd, J = 8.9, 2.5Hz, 1H), 6.49 (t, J = 0.8Hz, 1H), 3.87 (s, 3H), 3.62 (pd, J = 6.8, 0.9Hz, 1H), 2.81 (d, J = 0.5Hz, 3H), 1.27 (d, J = 6.8Hz, 6H). ESI-MS m / z calculated value 281.2, measured value 282.0 (M+1). + .

[0636] Preparation of S24

[0637] Synthesis of 5-(benzyloxy)-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (S24)

[0638]

[0639] N-iodosuccinimide (2.98 g, 12.58 mmol) was added to a cold (0 °C) solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (4.00 g, 10.50 mmol) in CH₂Cl₂ (70 mL). The solution was stirred at 0 °C for 2.5 h. The mixture was washed with saturated aqueous NaHCO₃ solution and 1N Na₂S₂O₃ solution, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (80 g ISCO column) using a 0-30% EtOAc / heptane gradient to obtain the desired product: 5-(benzyloxy)-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole (87%). 1¹H NMR (400MHz, chloroform-d) δ 7.52–7.47 (m, 2H), 7.43–7.36 (m, 2H), 7.36–7.29 (m, 1H), 7.18–7.06 (m, 3H), 7.01 (dd, J = 2.4, 0.5Hz, 1H), 6.84 (dd, J = 8.8, 2.4Hz, 1H), 6.74 (dd, J = 8.8, 0.5Hz, 1H), 5.14 (s, 2H), 3.13–3.01 (m, 1H), 2.34 (d, J = 2.1Hz, 3H), 1.34 (dd, J = 7.2, 3.2Hz, 6H). ESI-MS m / z calculated value 499.08, measured value 499.59 (M+1). + .

[0640] Compounds S25-S26 (Table 5) were prepared from suitable indole intermediates by a method similar to that used for S24.

[0641] Table 5. Structural and physicochemical data of compounds S25-S29

[0642]

[0643]

[0644] Preparation of S30 and S31

[0645] Synthesis of 6-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carboxynitrile (S30) and 7-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carboxynitrile (S31)

[0646]

[0647] Step 1. Synthesis of 3-((4-fluoro-3-methylphenyl)amino)but-2-enonitrile (C17)

[0648] Zinc trifluoromethanesulfonate (1.08 g, 2.97 mmol) was added to a solution of 3-oxobutyronitrile (4.93 g, 59.33 mmol) and 4-fluoro-3-methylaniline (7.42 g, 59.29 mmol). The reaction mixture was stirred overnight at room temperature, at which point the mixture solidified. The solid was dissolved in CH2Cl2 and purified by silica gel chromatography (330 g ISCO column) using a 0-100% CH2Cl2 / heptane gradient to give 7.9 g of the product as a possible mixture of the E and Z constructs. (Z) isomer: (Z)-3-(4-fluoro-3-methylaniline)but-2-enonitrile (68%). 1¹H NMR (400MHz, chloroform-d) δ 7.06–6.83 (m, 3H), 5.70 (s, 1H), 4.21 (s, 1H), 2.26 (d, J = 2.1 Hz, 3H), 2.24 (s, 3H). ESI-MS m / z calculated 190.09, measured 191.29 (M+1). + .

[0649] Step 2. Synthesis of 6-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carboxynitrile (C18) and 7-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carboxynitrile (C19)

[0650] A solution of 3-(4-fluoro-3-methyl-phenyl)-but-2-enyl nitrile C17 (7.91 g, 41.58 mmol) in CH2Cl2 (33 mL) was added dropwise to a reflux solution of 2-bromo-1,4-benzoquinone (9.07 g, 43.65 mmol) and zinc diiodophosphate (1.33 g, 4.17 mmol) in CH2Cl2 (120 mL). The mixture was heated under reflux for 1 hour and then cooled to room temperature. The sample was aliquoted and purified in two batches. The residue was purified by silica gel chromatography using a 0-10% EtOAc / CH2Cl2 gradient to give 1.5 g of the first product. 6-Bromo-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-methyl-indole-3-carboxynitrile (20%). 1 HNMR (400MHz, DMSO-d6) δ 10.15 (s, 1H), 7.54–7.45 (m, 1H), 7.45–7.36 (m, 2H), 7.16 (s, 1H), 7.10 (s, 1H), 2.35 (s, 3H), 2.34–2.27 (m, 3H). ESI-MS m / z calculated value 358.01, measured value 359.02 (M+1). + The second product separated: 7-bromo-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-methyl-indole-3-carboxynitrile (1.04 g, 14%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.69 (s, 1H), 7.48–7.38 (m, 1H), 7.38–7.29 (m, 2H), 7.00–6.86 (m, 2H), 2.34–2.26 (m, 3H), 2.23 (s, 3H). ESI-MS m / z calculated value 358.01, measured value 359.07 (M+1). + .

[0651] Step 3a. Synthesis of 6-bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carboxynitrile (S30)

[0652] Benzyl bromide (0.35 mL, 2.94 mmol) was added to a suspension of 6-bromo-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-methyl-indole-3-carboxynitrile C18 (0.94 g, 2.57 mmol) and K₂CO₃ (0.71 g, 5.15 mmol) in DMF (6 mL). The reaction mixture was heated to 70°C for 4 hours. The mixture was cooled to room temperature, diluted with water, and stirred for 30 minutes. A brown precipitate was filtered off. The precipitate was ground with heptane and filtered. The brown solid was purified by silica gel chromatography (120 g ISCO column) using CH₂Cl to give 1.12 g of product: 5-benzyloxy-6-bromo-1-(4-fluoro-3-methyl-phenyl)-2-methyl-indole-3-carboxynitrile (95%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.55–7.48 (m, 3H), 7.46–7.37 (m, 5H), 7.37–7.30 (m, 1H), 7.28 (s, 1H), 5.31 (s, 2H), 2.37 (s, 3H), 2.32 (d, J = 1.4Hz, 3H). ESI-MS m / z calculated value 448.06, measured value 449.1 (M+1). + .

[0653] Synthesis of step 3b. 7-Bromo-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-methyl-1H-indole-3-carboxynitrile (S31)

[0654] Benzyl bromide (0.35 mL, 2.94 mmol) was added to a suspension of 7-bromo-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-methyl-indole-3-carboxynitrile C19 (0.54 g, 1.47 mmol) and K2CO3 (0.61 g, 4.41 mmol) in DMF (3.5 mL). The reaction mixture was heated to 70°C for 1 hour. The mixture was cooled to room temperature and diluted with water and EtOAc. The organic phase was washed, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–50% CH2Cl2 / heptane gradient to give 620 mg of product: 5-benzyloxy-7-bromo-1-(4-fluoro-3-methyl-phenyl)-2-methyl-indole-3-carboxynitrile (94%). 1¹H NMR (400MHz, chloroform-d) δ 7.51–7.31 (m, 5H), 7.19 (d, J = 2.3 Hz, 1H), 7.18–7.05 (m, 4H), 5.11 (s, 2H), 2.35 (d, J = 2.1 Hz, 3H), 2.30 (s, 3H).

[0655] Preparation of S32

[0656] Synthesis of 5-(benzyloxy)-2-bromo-1-(4-fluorophenyl)-1H-indole-3-carboxynitrile (S32)

[0657]

[0658] Step 1. Synthesis of 1-(4-fluorophenyl)-5-methoxy-1H-indole-3-carboxynitrile (C20)

[0659] To a solution of 5-methoxy-1H-indole-3-carboxynitrile S32 (1.25 g, 7.28 mmol), 1-fluoro-4-iodo-benzene (1.76 g, 7.93 mmol), purged with nitrogen, in 12 mL of DMF, copper iodide (0.28 g, 1.45 mmol) and Cs2CO3 (3.56 g, 10.92 mmol) were added. The reaction mixture was sealed and heated at 120 °C for 15 hours. The mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were washed with water, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–50% EtOAc / heptane gradient to give 1.03 g of product: 1-(4-fluorophenyl)-5-methoxy-indole-3-carboxynitrile (53%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.72 (d, J = 1.9Hz, 1H), 7.58–7.40 (m, 2H), 7.38–7.11 (m, 4H), 6.99 (dd, J = 9.1, 2.4Hz, 1H), 3.93 (d, J = 2.0Hz, 3H). ESI-MS m / z calculated value 266.08, measured value 267.12 (M+1). + .

[0660] Step 2. Synthesis of 2-bromo-1-(4-fluorophenyl)-5-methoxy-1H-indole-3-carboxynitrile (C21)

[0661] A solution of tert-butyllithium (31 mL of 1.7 M solution in pentane, 52.70 mmol) was added dropwise to a cold (-10 °C) solution of 1-(4-fluorophenyl)-5-methoxy-indole-3-carboxynitrile C20 (12.05 g, 45.25 mmol) in THF (280 mL). After 1 hour, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (19.0 g, 58.0 mmol) in THF (60 mL) was added dropwise. After 1 hour, the cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (220 g ISCO column) using a 0–20% EtOAc / heptane gradient to give 14.7 g of product. 2-Bromo-1-(4-fluorophenyl)-5-methoxy-indole-3-carboxynitrile (94%). ESI-MS m / z calculated value 344.0, measured value 345.1 (M+1). + .

[0662] Step 3. Synthesis of 2-bromo-1-(4-fluorophenyl)-5-hydroxy-1H-indole-3-carboxynitrile (C22)

[0663] Tribromoborane (90.0 mmol, 1 M solution in CH2Cl2) was added to a cold (0 °C) solution of 2-bromo-1-(4-fluorophenyl)-5-methoxy-indole-3-carboxynitrile C21 (13.2 g, 38.2 mmol) in CH2Cl2 (250 mL). After 90 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 1 h. Water was carefully added. The mixture was extracted three times with CH2Cl2. A white solid was present in the aqueous phase and collected by filtration. The combined organic phases were evaporated. The residue and solid were dissolved in 20% MeOH / CH2Cl2 and the mixture was purified by silica gel chromatography (220 g ISCO column) using a 0–4% MeOH / CH2Cl2 gradient to give 11.9 g of product: 2-bromo-1-(4-fluorophenyl)-5-hydroxy-indole-3-carboxynitrile (94%). 1 ¹H NMR (300MHz, DMSO-d⁶) δ 9.57 (s, 1H), 7.83–7.58 (m, 2H), 7.57–7.34 (m, 2H), 6.95 (dd, J = 5.4, 3.1Hz, 2H), 6.80 (dd, J = 9.0, 2.3Hz, 1H). ESI-MS m / z calculated value 329.98, measured value 330.65 (M+1). + .

[0664] Step 4. Synthesis of 5-(benzyloxy)-2-bromo-1-(4-fluorophenyl)-1H-indole-3-carboxynitrile (S32)

[0665] Benzyl bromide (0.75 mL, 6.31 mmol) was added to a solution of 2-bromo-1-(4-fluorophenyl)-5-hydroxy-indole-3-carboxynitrile C22 (1.10 g, 3.32 mmol) and CS2CO3 (3.50 g, 10.74 mmol) in acetone (25 mL). The reaction mixture was heated at 70 °C for 18 hours at room temperature. The solvent was removed under reduced pressure, and the resulting residue was dissolved in EtOAc (10 mL) and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a 0–50% EtOAc / heptane gradient to give 870 mg of product. 5-Benzyloxy-2-bromo-1-(4-fluorophenyl)indole-3-carboxynitrile (60%). ESI-MS m / z calculated value 420.02, found value 420.98 (M+1). + .

[0666] Preparation of S33

[0667] 2-Bromo-1-(4-fluorophenyl)-5-(methoxymethoxy)-1H-indole-3-carboxynitrile (S33)

[0668]

[0669] S33 uses OMOM as a substitute for OBn to prepare 2-bromo-1-(4-fluorophenyl)-5-(methoxymethoxy)-1H-indole-3-carboxynitrile via a similar method to S32. 1 ¹H NMR (300MHz, DMSO-d⁶) δ 7.77–7.60 (m, 2H), 7.58–7.40 (m, 2H), 7.31 (dd, J = 2.1, 0.7Hz, 1H), 7.11–6.89 (m, 2H), 5.27 (s, 3H), 3.40 (s, 3H). ESI-MS calculated m / z 374.00, measured 375.01 (M+1). + .

[0670] Preparation of S34

[0671] 2-Bromo-1-(4-fluorophenyl)-5-methoxy-1H-indole-3-carboxynitrile (S34)

[0672]

[0673] S34 was prepared using a similar method to S32, employing OMe as a substitute for OBn to prepare 2-bromo-1-(4-fluorophenyl)-5-methoxy-1H-indole-3-carboxynitrile. The calculated ESI-MS m / z value was 344.0, and the observed value was 345.1 (M+1). + .

[0674] Preparation of S35

[0675] 5-(benzyloxy)-2-bromo-1-phenyl-1H-indole-3-carboxynitrile (S35)

[0676]

[0677] S35 uses iodobenzene to prepare 5-(benzyloxy)-2-bromo-1-phenyl-1H-indole-3-carboxynitrile via a method similar to that of S30. The calculated ESI-MS m / z value is 402.04, and the observed value is 403.09 (M+1). + .

[0678] Preparation of S36

[0679] Synthesis of 2-(1-(4-fluorophenyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (S36)

[0680]

[0681] Step 1. Synthesis of 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (C23)

[0682] To a cold (0°C) solution of 5-methoxy-2-methyl-1H-indole (6.45 g, 40.01 mmol) in THF (80 mL), n-butyllithium (16 mL of 2.5 M solution in hexane, 40 mmol) was added dropwise, while maintaining the internal temperature below 10°C using an ice / ethanol bath. After 0.25 hours, zinc chloride (80 mL of 0.5 M solution in THF, 40 mmol) was added dropwise, while maintaining the internal temperature between 0 and 2°C. The cooling bath was removed, and the mixture was stirred for 2 hours and then concentrated under reduced pressure to obtain a waxy substance, which was dissolved in toluene (80 mL). Bromoacetonitrile (2.75 mL, 40.01 mmol) was added to this solution, and the mixture was stirred at room temperature for 24 hours. Additional bromoacetonitrile (2.75 mL, 40.01 mmol) was added, and the mixture was stirred for another 1 hour. The reaction mixture was quenched with 1 M HCl (30 mL), and the layers were separated. The organic phase was washed with brine. The aqueous layer was extracted once more with EtOAc, followed by washing once with brine. The combined organic phases were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was then subjected to silica gel chromatography using 0–5% EtOAc / CH₂Cl₂.

[0683] The product was purified using a gradient method to yield 4.1 g of 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (51%). 1 HNMR (400MHz, DMSO-d6) δ 10.86 (s, 1H), 7.17 (d, J = 8.7Hz, 1H), 7.02 (d, J = 2.4Hz, 1H), 6.68 (dd, J = 8.7, 2.4Hz, 1H), 3.93 (s, 2H), 3.76 (s, 3H), 2.35 (s, 3H). ESI-MS m / z calculated value 200.1, measured value 201.0 (M+1). + .

[0684] Step 2. Synthesis of 2-(1-(4-fluorophenyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile (S36)

[0685] To a suspension of 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetonitrile C23 (1.32 g, 6.59 mmol) degassed with nitrogen for 10 min in toluene (13.2 mL), K3PO4 (4.2 g, 19.8 mmol), copper iodide (0.75 g, 3.96 mmol), N,N'-dimethylethane-1,2-diamine (0.42 mL, 3.956 mmol), and 1-fluoro-4-iodobenzene (approximately 2.93 g, 13.18 mmol) were added. The pressure flask was sealed with a screw cap, and the reaction mixture was heated at 110 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth filter, followed by further washing with CH2Cl2. The filtrate was concentrated under reduced pressure to a black oil, and the crude material was purified by silica gel chromatography using a 0–20% EtOAc / CH2Cl2 gradient to give 845 mg of product. 2-[1-(4-fluorophenyl)-5-methoxy-2-methyl-indol-3-yl]acetonitrile (44%). ESI-MS m / z calculated value 294.1, measured value 295.2 (M+1). + .

[0686] Preparation of S37

[0687] Synthesis of 1-(4-fluoro-3-methylphenyl)-3-iodo-5-methoxy-1H-indole-2-carboxynitrile (S37)

[0688]

[0689] Step 1. Synthesis of 1-(4-fluoro-3-methylphenyl)-5-methoxy-1H-indole-2-carboxynitrile (C24)

[0690] A 3 Å molecular sieve (0.235 g) was added to a solution of 5-methoxy-1H-indole-2-carboxynitrile (0.133 g, 0.704 mmol), (4-fluoro-3-methyl-phenyl)boronic acid (0.219 g, 1.423 mmol), copper(II) acetate (0.270 g, 1.487 mmol), and potassium carbonate (0.225 g, 1.628 mmol) in dimethyl sulfoxide (2 mL). The reaction mixture was stirred overnight at room temperature in open air. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed twice with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reversed-phase rapid chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 88 mg of product. 1-(4-Fluoro-3-methylphenyl)-3-iodo-5-methoxy-1H-indole-2-carboxynitrile (44%). 1¹H NMR (400MHz, DMSO-d⁶) δ 7.63–7.52 (m, 2H), 7.50–7.37 (m, 2H), 7.28–7.17 (m, 2H), 7.06 (dd, J = 9.1, 2.5Hz, 1H), 3.80 (s, 3H), 2.34 (d, J = 2.1Hz, 3H). ESI-MS m / z calculated value 280.10, measured value 281.47 (M+1). + .

[0691] Step 2. Synthesis of 1-(4-fluoro-3-methylphenyl)-3-iodo-5-methoxy-1H-indole-2-carboxynitrile (S37)

[0692] N-iodosuccinimide (0.077 g, 0.342 mmol) was added to a cold (0 °C) solution of 1-(4-fluoro-3-methyl-phenyl)-5-methoxy-indole-2-carboxynitrile (0.088 g, 0.306 mmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at 0 °C for 1 h. The ice bath was removed and the mixture was warmed to room temperature and stirred for 36 h. The reaction mixture was quenched with water and extracted twice with CH2Cl2. The combined organic phases were washed with 1N sodium thiosulfate, passed through a phase separator, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (24 g ISCO column) using a 0-100% EtOAc / CH2Cl2 gradient to give 52 mg of product: 1-(4-fluoro-3-methyl-phenyl)-3-iodo-5-methoxy-indole-2-carboxynitrile (39%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.33–7.25 (m, 2H), 7.22 (t, J = 8.7 Hz, 1H), 7.17 (dd, J = 9.1, 0.6 Hz, 1H), 7.08 (dd, J = 9.1, 2.4 Hz, 1H), 6.89 (dd, J = 2.3, 0.5 Hz, 1H), 3.94 (s, 3H), 2.40 (d, J = 2.1 Hz, 3H). ESI-MS m / z calculated value 406.0, measured value 407.3 (M+1). + .

[0693] Preparation of S38

[0694] Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydrofuran-2-yl)-3-vinyl-1H-indole (S38)

[0695]

[0696] Step 1. Synthesis of ethyl 1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydrofuran-2-yl)-1H-indole-3-carboxylate (C25)

[0697] A suspension of 4-fluoro-3-methylaniline (2.00 g, 15.98 mmol) and ethyl 3-oxo-3-tetrahydrofuran-2-yl propionate (approximately 2.97 g, 15.98 mmol) in AcOH (0.09 mL, 1.59 mmol) in a sealed Teflon-septum vial was heated at 90 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with CH₂Cl₂, and then concentrated under reduced pressure, repeated twice. The residue was then further dried under high vacuum for 1 h, and then dissolved in anhydrous CH₂Cl₂ (62 mL) under nitrogen atmosphere. 1,4-Benzoquinone (1.73 g, 15.98 mmol) was added, followed by zinc diiodide (0.51 g, 1.59 mmol), and the reaction mixture was then heated under reflux for 24 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-20% EtOAc / heptane gradient. The resulting fractions were combined and concentrated under vacuum, and the solid was ground with Et2O / hexane to give 350 mg of product. Ethyl 1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydrofuran-2-yl-indole-3-carboxylate (5%). Separation of enantiomers was obtained by SFC chiral chromatography. 1 H NMR (400MHz, DMSO-d6) δ9.07 (s, 1H), 7.42 (d, J = 2.2Hz, 1H), 7.41-7.19 (m, 3 H),6.66(dd,J=8.9,1.8Hz,1H),6.58(d,J=8.5Hz,1H),5.79-5.70(m,1H),4. 31(q,J=7.1Hz,2H),3.55-3.47(m,1H),3.06-2.97(m,1H),2.30(s,3H),2.2 7-2.17(m,1H),1.98-1.71(m,2H),1.61-1.50(m,1H),1.37(t,J=7.1Hz,3H). ESI-MS calculated m / z value: 383.1533; measured value: 384.5 (M+1). + .

[0698] Step 2. Synthesis of (5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydrofuran-2-yl)-1H-indol-3-yl)methanol (C26)

[0699] Ethyl 1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-[(2R)-tetrahydrofuran-2-yl]indole-3-carboxylate C25 (0.63 g, 1.65 mmol) was added to a solution of DMF (6.5 mL) with K2CO3 (0.71 g, 5.10 mmol) and the reaction mixture was cooled to 0 °C. Bromomethylbenzene (0.26 mL, 2.14 mmol) was slowly added under a nitrogen atmosphere. The reaction mixture was gradually heated to room temperature and stirred for 4 hours. The mixture was diluted with water and diethyl ether. The aqueous phase was washed with diethyl ether. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a 0–60% EtOAc / heptane gradient to give 725 mg of product. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indole-3-carboxylic acid ethyl ester (93%). 1 H NMR(400MHz,DMSO-d6)δ7.59(d,J=2.5Hz,1H),7.52-7.19(m,8H),6.95-6.83(m,1H) ,6.70(dd,J=8.9,2.0Hz,1H),5.76(q,J=8.2Hz,1H),5.16(s,2H),4.31(q,J=7.1Hz,2 The calculated m / z values ​​are: 3.52 (dt, J = 7.9, 4.1 Hz, 1H), 3.00 (p, J = 7.0 Hz, 1H), 2.37-2.16 (m, 4H), 1.92 (dt, J = 12.1, 8.7 Hz, 1H), 1.79 (dt, J = 20.1, 8.1 Hz, 1H), 1.56 (s, 1H), 1.35 (t, J = 7.1 Hz, 3H). The calculated m / z value from ESI-MS is 473.20, and the measured value is 474.37 (M+1). + .

[0700] Ethyl 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indol-3-carboxylate (0.70 g, 1.48 mmol) was added to a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indol-3-yl]carboxylate (18 mL). The reaction mixture was stirred overnight at room temperature. Rochelle salt and CH2Cl2 were added. The residue was purified by silica gel chromatography (40 g ISCO column) using an EtOAc / heptane gradient to give 533 mg of product. [5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indol-3-yl]methanol (84%). ESI-MS m / z calculated value 431.19, found value 430.78 (M+1). + .

[0701] Step 3. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydrofuran-2-yl)-1H-indole-3-carboxaldehyde (C27)

[0702] Add (1,1-diacetoxy-3-oxo-) to a cold (0°C) solution of [5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indol-3-yl]methanol C26 (0.44 g, 1.02 mmol) in CH2Cl2 (12 mL) A solution of 5,2-benzyl-1-yl)acetate (0.43 g, 1.02 mmol) in CH2Cl2 (12 mL). After 30 minutes, the mixture was diluted in 2N NaOH and CH2Cl2. The phases were separated by passing through a phase separator. The residue was purified by silica gel chromatography using an EtOAc / heptane gradient to give 113 mg of product. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indole-3-carboxaldehyde (18%). 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),7.87(d,J=2.4Hz,1H),7.59-7.24(m,8H),6.94(dd,J=9.0,2.5Hz,1H),6.83(d,J=8.9Hz,1H),5.15(s,2H),4 .99(dt,J=12.7,7.6Hz,1H),3.86(dq,J=13.5,6.9Hz,1H),3.69(q,J=7.1 Hz, 1H), 2.32 (d, J = 2.3Hz, 3H), 2.17 (d, J = 7.0Hz, 1H), 2.04-1.79 (m, 3H). ESI-MS calculated m / z value: 429.17; measured value: 430.31 (M+1) + .

[0703] Step 4. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydrofuran-2-yl)-3-vinyl-1H-indole (S38)

[0704] n-BuLi (0.165 mL, 2.5 M, 0.413 mmol) was added under nitrogen atmosphere to a cold (0 °C) solution of methyl-(triphenyl)phosphonium bromide (0.131 g, 0.367 mmol) in THF (2.4 mL). The resulting yellow solution was stirred at 0 °C for 2 hours, and 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]indol-3-carboxaldehyde C27 (0.113 g, 0.182 mmol) was added dropwise to THF (0.6 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with a saturated aqueous solution of NH4Cl. The solvent was removed under reduced pressure, and the crude product was dissolved in EtOAc (200 mL) and washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography on neutral alumina using EtOAc / heptane to give 79 mg of product. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-[(2R)-tetrahydrofuran-2-yl]-3-vinyl-indole (100%). ESI-MS m / z calculated value 427.19, found value 428.33 (M+1). + .

[0705] Compounds S39-S44 (Table 6) were prepared from suitable indole intermediates as described for the preparation of S38.

[0706] Table 6. Structural and physicochemical data of compounds S39-S44

[0707]

[0708]

[0709] Compounds 1 and 2

[0710]

[0711] Step 1. Synthesis of ethyl 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohex-3-en-1-carboxylate (C28)

[0712] A solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole S5 (0.35 g, 0.84 mmol), ethyl 4-oxocyclohexanecarboxylate (0.60 g, 3.53 mmol), trifluoroacetic acid (0.30 mL, 3.89 mmol), and triethylsilane (0.54 mL, 3.38 mmol) in CH2Cl2 (7 mL) was stirred at 50 °C for 3 days. The reaction mixture was washed with water and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography with 0-50% EtOAc / heptane elution to give 226 mg of product. Ethyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole-3-yl]cyclohex-3-en-1-carboxylate (47%). Retention time: 0.9 min 1H NMR (400MHz, chloroform-d) δ 7.53-7.47 (m, 2H), 7.45-7.39 (m, 2H), 7.34 (d, J = 7.3Hz, 1H), 7.19-7.06 (m, 3H), 6.98 (d, J = 2.3Hz, 1H), 6.84 (dd, J = 8.8, 2.4Hz, 1H), 6.79-6.66 (m, 1H), 5.81 (s, 1H), 5.11 (s, 1H), 4.27-4.23 ( m, 2H), 3.97 (d, J = 11.4 Hz, 2H), 3.30 (t, J = 12.0 Hz, 2H), 2.87-2.69 (m, 2H), 2.56-2.53 (m, 2H), 2.43 (m, 2H), 2.37 (d, J = 2.0 Hz, 3H), 2.19-2.17 (m, 1H), 2.11-1.92 (m, 3H), 1.64-1.62 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H). ESI-MS m / z calculated value: 567.28, measured value: 568.53 (M+1). + .

[0713] Step 2. Synthesis of trans-4-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexane-1-carboxylic acid (1) and cis-4-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexane-1-carboxylic acid (2)

[0714] Pd(OH)₂ (0.10 g, 0.1424 mmol) was added to a solution of ethyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexane-1-carboxylate C28 (0.20 g, 0.35 mmol) purged with nitrogen in 10 mL of MeOH. The system was evacuated and purged with hydrogen (balloon) for 3 hours. The mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-80% EtOAc / heptane gradient to give 168 mg of the product as a mixture of cis isomer (major) and trans isomer (minor). ethyl 4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexane-carboxylate (100%). ESI-MS calculated m / z value: 479.25; measured value: 480.56 (M+1) + LiOH (0.10 g, 4.18 mmol) was added to a solution of ethyl 4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexane-formate (168 mg) in MeOH (5 mL), THF (1 mL), and water (1 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. The crude residue was acidified with 10% HCl and extracted twice with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum.

[0715] The residue was purified by silica gel chromatography using a 0-80% EtOAc / heptane gradient to give 110 mg (63%) of major product 1 and 10 mg (6%) of minor product 2. Major product 1 is trans-4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanecarboxylic acid. 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.25–7.13 (m, 2H), 7.13–7.02 (m, 2H), 6.59 (d, J = 8.7 Hz, 1H), 6.53 (dd, J = 8.7, 2.3 Hz, 1H), 3.95 (dd, J = 11.6, 4.1 Hz, 2H), 3.30–3.28 (m, 2H), 3.06 (m, 1H), 2.83–2.81 (m, 2H), 2.42–2.27 (m, 7H), 2.18–1.96 (m, 2H), 1.80–1.60 (m, 6H). ESI-MS m / z calculated value 451.22, measured value 452.56 (M+1). +The minor product is 2-cis-4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanecarboxylic acid. 1 HNMR (400MHz, methanol-d4) δ7.26-7.14(m,2H),7.10(dd,J=8.5,2.6Hz,2H),6.61(d,J=8.7Hz,1H),6.55(dd,J=8.7,2.3Hz,1H),3.96(dd,J=11.5,4.1Hz,2H) ,3.30-3.30(m,2H),3.05(m,1H),2.90-2.74(m,1H),2.55-2.45(m,1H),2.3 4(d,J=1.9Hz,3H),2.23-1.98(m,7H),1.88-1.86(m,2H),1.70-1.55(m,4H). ESI-MS calculated m / z value: 451.22; measured value: 452.56 (M+1) + .

[0716] Compounds 3-104 were prepared as described for compounds 1 and 2 by reductive alkylation with a suitable aldehyde or ketone reagent and a relevant indole intermediate.

[0717] Table 7. Preparation methods, structure, and physicochemical data of compound 3-104

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740] 1. Reduction alkylation of Et3SiH, TFA, CH2Cl2 at 50℃.

[0741] 2. Hydrogenation: H2, Pd(OH)2

[0742] 3. Hydrolysis conditions: LiOH, THF, MeOH, H2O

[0743] 4. Hydrogenation: H2, Pd / C, MeOH, or EtOAc

[0744] 5. Hydrolysis conditions: NaOH, MeOH

[0745] 6. SFC chiral separation yields a single stereoisomer.

[0746] 7. Hydrogenation: H2, Pd / C (charcoal), EtOAc

[0747] 8. BBr3, CH2Cl2

[0748] 9. Reduction alkylation of Et3SiH, MeSO3H, CH2Cl2 at 50℃.

[0749] 10. Hydrolysis conditions: KOH, MeOH, THF, H2O, 70℃

[0750] 11. Note: Overreduction of the N-3-chloro-4-fluorophenyl intermediate under hydrogenation conditions yields N-monofluorophenyl substituted products.

[0751] 12. The final compound is a racemic mixture of isomers.

[0752] 13. Reduction conditions: Mg, MeOH

[0753] 14. The final compound is a single stereoisomer with an unknown absolute configuration.

[0754] 15. The final compound is a mixture of cis and trans isomers.

[0755] Compound 105

[0756] Synthesis of cis-2-(3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexyl)acetic acid (105)

[0757]

[0758] Step 1. Synthesis of 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexyl-1-one (C29)

[0759] Bismuth was added to a suspension of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole S5 (0.30 g, 0.69 mmol) and cyclohexyl-2-en-1-one (0.10 mL, 1.04 mmol) in CH3CN (6 mL); 2-methylpropane-2-sulfonate (0.06 g, 0.10 mmol). The suspension was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the crude product was dissolved in EtOAc (10 mL) and washed with water. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-40% EtOAc / heptane gradient to give 300 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole-3-yl]cyclohexanone (83%). 1 HNMR (400MHz, DMSO-d6) δ8.74(s,1H),7.43-7.30(m,2H),7.26-7.05(m,2H),6.62(d,J=8Hz,1H),6.56(dd,J=8.8,2.1Hz,1H),3.85(d,J=11.0Hz ,2H),3.42(d,J=12.9Hz,1H),3.22-3.05(m,3H),2.80-2.63(m,2H),2.4 2-2.24(m,1H),2.21-2.11(m,1H),1.92-1.75(m,3H),1.65-1.62(m,2H). ESI-MS calculated m / z value: 511.25; measured value: 512.6 (M+1) +To a mixture of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanone (0.07 g), moistened Degussa Pd / C (0.05 g, 0.05 mmol) was added to the mixture of MeOH (5 mL) and EtOAc (2 mL). The suspension was purged with nitrogen. The system was evacuated and purged with hydrogen, and the mixture was then stirred under a hydrogen atmosphere for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / heptane gradient to give 60 mg of product: 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanone (20%). 1 H NMR (400MHz, DMSO-d6) δ8.74 (s, 1H), 7.43-7.30 (m, 2H), 7.26-7.05 (m, 2H), 6.62 (d, J = 8Hz, 1H), 6.56 (dd, J = 8.8, 2.1Hz, 1H), 3.85 (d, J = 11.0Hz, 2H),3.42(d,J=12.9Hz,1H),3.22-3.05(m,3H),2.80-2.63(m,2H),2.42 -2.24(m,1H),2.21-2.11(m,1H),1.92-1.75(m,3H),1.65-1.62(m,2H). ESI-MS calculated m / z value: 421.21; measured value: 422.59 (M+1) + .

[0760] Step 2. Synthesis of (E)-2-(3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexyl)ethyl acetate (C30)

[0761] KOtBu (0.13 g, 1.16 mmol) was added to a solution of ethyl 2-diethoxyphosphoryl ester (0.26 g, 1.15 mmol) in THF (5 mL). The reaction mixture was stirred at room temperature for 30 min. A solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanone C29 (0.30 g, 0.57 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was dissolved in water (10 mL). The aqueous phase was extracted twice with EtOAc and the combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-40% EtOAc / heptane gradient to give 240 mg of product. 2-[3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole-3-yl]cyclohexylene]ethyl acetate (69%). ESI-MS m / z calculated value 581.29, found value 582.57 (M+1). + .

[0762] Step 3. cis-2-(3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexyl)acetic acid (105)

[0763] LiOH was added to a solution of (2E)-2-[3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexyl]acetic acid C30 (0.18 g, 0.30 mmol) in MeOH (5 mL), THF (1 mL), and water (1 mL). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The crude product was dissolved in water (5 mL) and acidified with 6N HCl. The aqueous phase was acidified with 6M HCl. The aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum to give 160 mg of product. 2-[3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexyl]acetic acid (96%). ESI-MS calculated m / z value: 553.26; measured value: 554.49 (M+1) +The product (155 mg) was dissolved in methanol (5 mL) and moistened Degussa Pd / C (0.10 g, 0.09 mmol) was added. The system was evacuated and purged with hydrogen, and the mixture was stirred under hydrogen atmosphere for 3 hours. The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-80% EtOAc / heptane gradient to give 112 mg of product. Racemic cis-2-[3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexyl]acetic acid (78%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.25–7.00 (m, 4H), 6.61 (d, J = 8.7 Hz, 1H), 6.54 (dd, J = 8.8, 2.2 Hz, 1H), 3.96 (d, J = 11.5 Hz, 2H), 3.29–3.27 (m, 2H), 3.16–3.05 (m, 1H), 2.81–2.75 (m, 1H), 2.73–2.47 (m, 1H), 2.34 (s, 3H), 2.27 (q, J = 6.7, 5.8 Hz, 1H), 2.17–1.45 (m, 12H), 1.24–1.08 (m, 1H). ESI-MS m / z calculated value 465.2, measured value 466.6 (M+1). + .

[0764] Compounds 106 and 107

[0765] Synthesis of trans-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (106) and cis-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (107)

[0766]

[0767] Step 1. Synthesis of isopropyl 1-(hydroxymethyl)-3,3-dimethoxycyclobutane-1-carboxylate (C31)

[0768] To a cold (-78°C) solution of 10.00 g (34.68 mmol) of 3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diisopropyl ester in THF (40 mL), lithium tri-tert-butoxyaluminum hydride (80.0 mL 1 M solution, 80.0 mmol) was added. The mixture was stirred overnight at room temperature and then heated to 50°C for 2 hours. The mixture was cooled to room temperature and quenched with a saturated aqueous NH4Cl solution. The mixture was extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–40% EtOAc / heptane gradient to give 4.5 g of product: 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylic acid diisopropyl ester (56%). 1 ¹H NMR (400MHz, chloroform-d) δ 5.08 (p, J = 6.3 Hz, 1H), 3.83 (d, J = 6.6 Hz, 2H), 3.25–3.11 (m, 6H), 2.61–2.48 (m, 2H), 2.42 (td, J = 6.5, 1.1 Hz, 1H), 2.26–2.14 (m, 2H), 1.35–1.22 (m, 6H).

[0769] Step 2. Synthesis of isopropyl 3,3-dimethoxy-1-(methoxymethyl)cyclobutane-1-carboxylic acid (C32)

[0770] To a solution of 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylic acid isopropyl ester C31 (1.00 g, 4.31 mmol), NaH (0.27 g 60% w / w, 6.67 mmol) in DMF (10 mL) was added. The reaction mixture was stirred for 10 min. Methyl iodine (4.00 mL 2 M solution, 8.00 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–20% EtOAc / heptane gradient to give 180 mg of product: 3,3-dimethoxy-1-(methoxymethyl)cyclobutanecarboxylic acid isopropyl ester (17%). 1 ¹H NMR (400MHz, chloroform-d) δ 5.07 (septet, J = 6.2Hz, 1H), 3.63 (s, 2H), 3.36 (s, 3H), 3.16 (d, J = 2.2Hz, 6H), 2.62–2.51 (m, 2H), 2.25–2.10 (m, 2H), 1.26 (d, J = 6.3Hz, 6H).

[0771] Step 3. Synthesis of isopropyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (C33)

[0772] Dioxane (0.5 mL) was added to a vial containing bis(trifluoromethanesulfonyl)cyanate; indium(3+) (0.045 g, 0.047 mmol) and the mixture was stirred for 5 min. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole S5 (0.200 g, 0.481 mmol), 3,3-dimethoxy-1-(methoxymethyl)cyclobutanecarboxylic acid isopropyl ester C32 (0.130 g, 0.528 mmol), and methyl(diphenyl)silane (0.120 g, 0.605 mmol) were added to the mixture. The reaction mixture was heated at 47 °C for 90 min and then concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–30% CH2Cl2 / heptane gradient to give 170 mg of product. ESI-MS calculated m / z value: 599.3; measured value: 600.0 (M+1) + .

[0773] Step 4. Synthesis of trans-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (106) and cis-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(methoxymethyl)cyclobutane-1-carboxylic acid (107)

[0774] Pd / C (0.050 g 10% w / w, 0.047 mmol) was added to a solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-(methoxymethyl)cyclobutanecarboxylate C33 (0.169 g, 0.283 mmol) in MeOH (10 mL). The mixture was stirred under a hydrogen atmosphere for 1 hour. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated under vacuum to give 100 mg of 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]-1-(methoxymethyl)cyclobutanecarboxylate (69%). ESI-MS m / z calculated value 509.26, found value 510.0 (M+1). + .

[0775] Add NaOH (0.50 mL 3M solution, 1.50 mmol) to a solution of MeOH (10 mL). Stir the mixture at 50 °C for 1 hour. Neutralize the reactants with 1 N HCl and extract with CH2Cl2. Purify the residue by reversed-phase HPLC to give 10.4 mg of product. trans-3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]-1-(methoxymethyl)cyclobutanecarboxylic acid (7%). 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.44 (dd, J = 2.1, 0.8Hz, 1H), 7.28–7.15 (m, 2H), 7.13–7.03 (m, 1H), 6.68–6.48 (m, 2H), 4.11 (p, J = 9.8Hz, 1H), 4.01–3.87 (m, 2H), 3.80 (s, 2H), 2.84 (q, J = 13.8, 12.5Hz, 3H), 2.71–2.58 (m, 2H), 2.34 (d, J = 2.0Hz, 3H), 2.03 (q, J = 12.7Hz, 2H), 1.63 (d, J = 13.4Hz, 2H). ESI-MS m / z calculated value 467.2, measured value 468.5 (M+1). + Cis-3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]-1-(methoxymethyl)cyclobutanecarboxylic acid (10.9 mg, 7%). 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.28–7.18 (m, 3H), 7.18–7.08 (m, 1H), 4.13 (tt, J = 10.2, 9.0 Hz, 1H), 3.92 (dt, J = 11.2, 3.1 Hz, 3H), 3.71 (s, 2H), 3.40 (s, 4H), 3.36 (dd, J = 11.0, 3.7 Hz, 1H), 2.94–2.77 (m, 4H), 2.75–2.62 (m, 3H), 2.34 (d, J = 2.3 Hz, 3H), 1.77 (td, J = 9.9, 8.9, 3.8 Hz, 4H). ESI-MS m / z calculated value 467.21, measured value 468.58 (M+1). + .

[0776] Preparation of C34

[0777] 1-(fluoromethyl)-3,3-dimethoxycyclobutane-1-carboxylic acid isopropyl ester (C34)

[0778]

[0779] To a cold (-78°C) solution of 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylic acid isopropyl ester C31 (1.37 g, 5.89 mmol) in CH2Cl2 (10 mL), 2,6-dimethylpyridine (1.00 mL, 8.63 mmol) and trifluoromethanesulfonic anhydride (1.20 mL, 7.13 mmol) were added. The reaction mixture was stirred at -78°C and gradually heated to room temperature. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 solution, saturated NH4Cl solution, and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to give 1.8 g of product.

[0780] Trifluoromethylsulfonyloxymethyl)cyclobutane carboxylic acid ester. 1 ¹H NMR (400 MHz, chloroform-d) δ 5.10 (p, J = 6.3 Hz, 1H), 4.81 (s, 2H), 3.18 (d, J = 1.8 Hz, 6H), 2.65–2.55 (m, 2H), 2.29–2.20 (m, 2H), 1.28 (s, 6H). The product was dissolved in THF (10 mL) and cooled to -78 °C. Tetrabutylammonium fluoride (9.8 mL 1 M solution in THF, 9.8 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour, quenched with water, and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–30% EtOAc / heptane gradient to give 0.8 g of product. 1-(fluoromethyl)-3,3-dimethoxy-cyclobutanecarboxylic acid isopropyl ester (58%). 1 ¹H NMR (400MHz, chloroform-d) δ 5.08 (p, J = 6.3Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H), 3.17 (d, J = 0.6Hz, 6H), 2.62–2.53 (m, 2H), 2.28–2.18 (m, 2H), 1.28 (d, J = 6.3Hz, 6H).

[0781] Preparation of C35

[0782] 3,3-Dimethoxy-1-(methoxymethyl)cyclobutane-1-carboxylic acid isopropyl ester (C35)

[0783]

[0784] To a solution of 1-(hydroxymethyl)-3,3-dimethoxy-cyclobutanecarboxylic acid isopropyl ester C31 (1.00 g, 4.31 mmol), NaH (0.27 g 60% w / w, 6.67 mmol) was added and the mixture was stirred for 10 min. MeI (4.00 mL 2 M, 8.00 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–20% EtOAc / heptane gradient to give 180 mg of product: 3,3-dimethoxy-1-(methoxymethyl)cyclobutanecarboxylic acid isopropyl ester (17%). 1 ¹H NMR (400MHz, chloroform-d) δ 5.07 (septet, J = 6.2Hz, 1H), 3.63 (s, 2H), 3.36 (s, 3H), 3.16 (d, J = 2.2Hz, 6H), 2.62–2.51 (m, 2H), 2.25–2.10 (m, 2H), 1.26 (d, J = 6.3Hz, 6H).

[0785] Compounds 108-122

[0786] Compounds 108-122 were prepared using the method described for the preparation of compounds 106 and 107, employing a suitable aldehyde or ketone and a relevant indole intermediate. Any modifications to the method are documented in the table footnotes.

[0787] Table 8. Preparation methods, structures, and physicochemical data of compounds 108-122

[0788]

[0789]

[0790]

[0791]

[0792] 1. Reduction alkylation of In[CF3SO2)2N]3,Ph2MeSiH, dioxane, 50℃

[0793] 2. Reduction alkylation of Et3SiH, TFA, CH2Cl2, 50℃

[0794] 3. Hydrogenation: H2, Pd(OH)2

[0795] 4. Hydrolysis conditions: NaOH, MeOH

[0796] 5. Hydrogenation: H2, Pd / C, MeOH

[0797] 6. SFC chiral chromatography

[0798] 7. Hydrolysis conditions: LiOH, MeOH, THF, H2O

[0799] Compound 123

[0800] Synthesis of cis-1-(difluoromethyl)-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclobutane-1-carboxylic acid (123)

[0801]

[0802] Step 1. Synthesis of dimethyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclobutane-1,1-dicarboxylic acid ester (C35)

[0803] Triethylsilane (0.600 mL, 3.757 mmol) was added to a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole S5 (0.500 g, 1.203 mmol) and dimethyl 3-oxocyclobutane-1,1-dicarboxylic acid (0.500 g, 2.686 mmol) in CH2Cl2 (7.0 mL), followed by the addition of 2,2,2-trifluoroacetic acid (0.250 mL, 3.245 mmol). The mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with 15 mL of CH2Cl2 and washed with saturated NaHCO3 aqueous solution and brine. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–60% EtOAc / heptane gradient to give 210 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclobutane-1,1-dicarboxylic acid dimethyl ester (30%). 1¹H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 2.3 Hz, 1H), 7.58–7.51 (m, 2H), 7.45–7.32 (m, 2H), 7.20–7.03 (m, 4H), 6.86 (dd, J = 8.8, 2.3 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 5.22 (s, 2H) ), 4.14-4.04 (m, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.48-3.26 (m, 2H), 3.03-2.94 (m, 1H), 2.36 (d, J = 2.0 Hz, 3H), 2.02 (dtd, J = 17.4, 12.4, 4.8 Hz, 2H), 1.68-1.50 (m, 2H). ESI-MS m / z calculated value: 585.25, measured value: 586.02 (M+1). + .

[0804] Step 2. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-formylcyclobutane-1-carboxylate (C36)

[0805] Dimethyl diisobutylaluminum hydride (0.340 mL 1M solution, 0.340 mmol) of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclobutane-1,1-dicarboxylic acid dimethyl ester C35 (0.100 g, 0.171 mmol) in CH2Cl2 (3.0 mL) was added to a cold (-78 °C) solution. The mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted three times with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-70% EtOAc / heptane gradient to give 33 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole-3-yl]-1-formyl-cyclobutane carboxylate (35%). ESI-MS m / z calculated value 555.24, measured value 556.32 (M+1). + .

[0806] Step 3. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(difluoromethyl)cyclobutane-1-carboxylate (C37)

[0807] Deoxofluor (0.023 mL, 0.125 mmol) was added to a cold (0°C) solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-formyl-cyclobutanecarboxylate C36 (0.032 g, 0.058 mmol) in CH2Cl2 (2 mL), and the mixture was heated to room temperature and stirred at that temperature for 2 hours. The reaction mixture was quenched with ice and extracted with CH2Cl2. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (4 g ISCO column) using a 0–50% EtOAc / heptane gradient to give 8 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole-3-yl]-1-(difluoromethyl)-cyclobutane carboxylate (24%). ESI-MS m / z calculated value 577.244, measured value 578.38 (M+1). + .

[0808] Step 4. Synthesis of 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1-(difluoromethyl)cyclobutane-1-carboxylic acid (C38)

[0809] Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-(difluoromethyl)cyclobutanecarboxylate C37 (0.023 g, 0.039 mmol) was stirred at 25 °C for 18 h in a solution of MeOH (0.6 mL), THF (0.25 mL), and H₂O (0.12 mL). The solvent was evaporated under reduced pressure, and the white solid was dissolved in water (10 mL) and slowly acidified with HCl (0.43 mL 2 M solution, 0.86 mmol). The aqueous layer was extracted three times with EtOAc, dried (MgSO₄), filtered, and concentrated under vacuum to give 21 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole-3-yl]-1-(difluoro-methyl)cyclobutanecarboxylic acid (86%). ESI-MS m / z calculated value 563.23, found value 564.42 (M+1). + .

[0810] Step 5. Synthesis of cis-1-(difluoromethyl)-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclobutane-1-carboxylic acid (123)

[0811] Pd / charcoal (0.010 g, 10% w / w, 0.004 mmol) was added to a solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]-1-(difluoromethyl)cyclobutanecarboxylic acid C38 (0.021 g, 0.037 mmol) purged with nitrogen in 1.0 mL of EtOAc. The reaction mixture was evacuated and purged with hydrogen and stirred under hydrogen atmosphere for 2 h. The crude mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (12 g ISCO column) using a 0–20% EtOAc / CH2Cl2 gradient to give 9.3 mg of product. 1-(difluoromethyl)-3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indole-3-yl]cyclobutanecarboxylic acid (48%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.70 (s, 1H), 7.17–6.94 (m, 4H), 6.72 (s, 2H), 6.40 (t, J = 56.4 Hz, 1H), 4.19–4.03 (m, 1H), 4.00 (dd, J = 11.6, 4.2 Hz, 2H), 3.30 (t, J = 11.3 Hz, 4H), 2.75 (dt, J = 22.1, 12.2 Hz, 3H), 2.33 (d, J = 1.9 Hz, 3H), 2.02 (d, J = 23.2 Hz, 3H), 1.60 (d, J = 13.2 Hz, 2H), 1.35–1.11 (m, 2H). ESI-MS m / z calculated value 473.18, measured value 474.31 (M+1). + .

[0812] Compound 124

[0813] Synthesis of trans-2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carboxylic acid (124)

[0814]

[0815] Step 1. Synthesis of 1-(4-fluoro-3-methylphenyl)-5-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)-3-vinyl-1H-indole (C39)

[0816] A solution of 1-(4-fluoro-3-methyl-phenyl)-3-iodo-5-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole S28 (0.23 g, 0.464 mmol), tetraethylammonium chloride (0.14 g, 0.85 mmol), palladium, and triphenylphosphine (0.028 g, 0.024 mmol) in DMF (5 mL) was added to tributyl(vinyl)stanane (0.180 mL, 0.616 mmol). The mixture was stirred under nitrogen atmosphere for 5 minutes, and then stirred overnight at 80 °C. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (12 g ISCO column) using a 0-20% EtOAc / heptane gradient to give 170 mg of product. 1-(4-fluoro-3-methyl-phenyl)-5-(methoxymethoxy)-2-tetrahydropyran-4-yl-3-vinyl-indole (93%). 1 H NMR (400MHz, chloroform-d) δ7.36(dd,J=2.4,0.5Hz,1H),6.98-6.82(m,4H),6.65(dd,J=8.8,2.3Hz,1H),6.55(dd,J=8.8,0.6Hz,1H),5.46(dd,J=17.7,1.7Hz ,1H),5.11(dd,J=11.5,1.6Hz,1H),4.98(s,2H),3.84-3.70(m,2H),3.29(s ,3H), 3.08(d,J=2.1Hz,1H), 2.13(d,J=2.0Hz,3H), 1.40(d,J=13.6Hz,2H).

[0817] Step 2. Synthesis of trans-2-(1-(4-fluoro-3-methylphenyl)-5-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carboxylic acid ethyl ester (124)

[0818] A solution of ethyl 2-diazonylacetate (0.35 mL, 3.33 mmol) in toluene (3 mL) was added to a suspension of 1-(4-fluoro-3-methyl-phenyl)-5-(methoxymethoxy)-2-tetrahydropyran-4-yl-3-vinyl-indole C39 (0.170 g, 0.430 mmol), (R,R)-PyBox (0.013 g, 0.043 mmol), and acridine-3,6-diamine; 10-methylacridin-10-on-3,6-diamine; chloride (0.010 g, 0.021 mmol) in THF (10 mL). The reaction mixture was heated at 50 °C overnight. The mixture was concentrated, diluted with EtOAc, washed with water, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (12g ISCO column) using a 0-40% EtOAc / heptane gradient to give 120 mg of trans-cyclopropyl as the major isomer. Trans-2-[1-(4-fluoro-3-methyl-phenyl)-5-(methoxymethoxy)-2-tetrahydropyran-4-yl-indol-3-yl]cyclopropane-ethyl formate (58%). ESI-MS m / z calculated value 481.2, found value 482.0 (M+1). + .

[0819] Step 3. Synthesis of trans-2-(1-(4-fluoro-3-methylphenyl)-5-(methoxymethoxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclopropane-1-carboxylic acid ethyl ester (124)

[0820] Ethyl trans-2-[1-(4-fluoro-3-methyl-phenyl)-5-(methoxymethoxy)-2-tetrahydro-pyran-4-yl-indol-3-yl]cyclopropanecarboxylic acid C40 (0.120 g, 0.249 mmol) was added to a solution of MeOH (1 mL) with NaOH (1.00 mL 1 M solution, 1.00 mmol). The mixture was heated at 50 °C for 1 hour. The mixture was concentrated under vacuum and acidified with 4 M HCl in dioxane and stirred for 1 hour. HCl and dioxane were removed. The crude residue was purified by reversed-phase HPLC to give 2.8 mg of trans-2-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclopropanecarboxylic acid. 1H NMR (400MHz, chloroform-d) δ7.01-6.78(m,4H),6.44(t,J=1.4Hz,2H),3.87-3.70(m,2H),3.11(t,J=11.9Hz,2H),2.76(dt,J=12.3,6.3Hz,1H),2.48- 2.36(m,1H),2.24-2.06(m,4H),2.05-1.90(m,1H),1.89-1.75(m,2H), 1.58(dt,J=9.0,4.6Hz,1H), 1.42(d,J=11.7Hz,2H), 1.36-1.21(m,1H). ESI-MS calculated m / z value: 409.2; measured value: 408.6 (M+1) + .

[0821] Compounds 125-139

[0822] Compounds (125-139) in Table 9 were prepared by a method similar to that described for compound 124. A suitable vinylindole intermediate was used in each example.

[0823] Table 9. Preparation methods, structures, and physicochemical data of compounds 125-135

[0824]

[0825]

[0826] 1. Cyclopropanization: 2-diazoylethyl acetate, (R,R)-PyBox, THF, toluene 50℃

[0827] 2. Hydrolysis conditions: NaOH, MeOH

[0828] 3. Hydrolysis conditions: LiOH, MeOH, THF, H2O

[0829] 4. Hydrogenation: H2, Pd / C, MeOH

[0830] 5. Cyclopropanization: Ethyl 2-diazopropionate, (R,R)-PyBox, THF, toluene 50℃

[0831] 6. Cyclopropanization was carried out using ethyl 2-diazopropionate and Rh(OAc)2 in dichloromethane. The compound is a mixture of stereoisomers.

[0832] Compound 136

[0833] Synthesis of cis-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexane-1-carboxylic acid (136)

[0834]

[0835] Step 1. Synthesis of 3-(5-(benzyloxy)-1-(3,4-difluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohex-2-en-1-carboxylic acid (C42)

[0836] A solution of 5-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole S4 (0.50 g, 1.14 mmol), ethyl 3-oxocyclohexanecarboxylate (0.39 g, 2.29 mmol), phosphoric acid (0.20 mL, 3.44 mmol), and acetic anhydride (0.20 mL, 2.12 mmol) in acetic acid (2.00 mL, 35.17 mmol) was heated at 110 °C in a sealable tube reactor for several days. The solvent was removed under reduced pressure, and the sample was diluted with water (10 mL). The aqueous phase was extracted three times with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–80% EtOAc / heptane gradient to give 213 mg of product. 3-[5-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indol-3-yl]cyclohex-2-en-1-carboxylic acid (33%). ESI-MS m / z calculated value 543.2, measured value 544.5 (M+1). + .

[0837] Step 2. Synthesis of cis-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)cyclohexane-1-carboxylic acid (136)

[0838] Pd(OH)₂ (0.08 g, 0.11 mmol) was added to a solution of 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexane-2-en-1-carboxylic acid C42 (0.213 g, 0.469 mmol) in MeOH (8 mL) and EtOAc (2 mL). The system was evacuated and purged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere for 18 hours. The crude mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum. 200 mg of the product was given as a racemic mixture of cis-isomers. 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]cyclohexanecarboxylic acid (91%). ESI-MS m / z calculated value 455.19, found value 456.57 (M+1). + .

[0839] Compounds 137 and 138

[0840] Compounds 137-138 were prepared by S4 using the same method as described for the preparation of compound 136.

[0841] Table 10. Preparation methods, structures, and physicochemical data of compounds 137-138

[0842]

[0843] 1. Reduction alkylation: H3PO4, Ac2O, AcOH, 110℃

[0844] 2. Hydrogenation: H2, Pd(OH)2

[0845] 3. Hydrolysis conditions: LiOH, THF, MeOH, H2O

[0846] Compound 139

[0847] Synthesis of trans-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(trifluoromethyl)-1H-indol-3-yl)-1-methylcyclobutane-1-carboxylic acid (139)

[0848]

[0849] Step 1. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)-1-methylcyclobutane-1-carboxylate (C43)

[0850] To a solution of methyl 1-methyl-3-oxo-cyclobutane carboxylate (0.48 g, 3.34 mmol), 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indole S16 (0.75 g, 2.21 mmol) in CH2Cl2 (10 mL), trifluoroacetic acid (0.35 mL, 4.54 mmol) and triethylsilane (1.10 mL, 6.89 mmol) were added. The reaction mixture was stirred at 50 °C for 48 hours. The mixture was diluted in water and dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-50% EtOAc / heptane gradient to give 0.68 g of product methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indole-3-yl]-1-methyl-cyclobutane carboxylate (65%). ESI-MS calculated m / z value: 457.2; measured value: 458.5 (M+1) + The mixture of cis and trans isomers proceeds to the next step without further purification.

[0851] Step 2. Synthesis of 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(trifluoromethyl)-1H-indol-3-yl)-1-methylcyclobutane-1-carboxylic acid (C44)

[0852] To a solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-1-methyl-cyclobutanecarboxylate C43 (0.68 g, 1.43 mmol) in CH3CN (10 mL), 1-(trifluoromethyl)-1-3,2-benzyl-3-one (1.2 g, 2.278 mmol) (Togni reagent) was added. The reaction mixture was heated to 80 °C for 2 days. The solvent was removed under reduced pressure. The crude product was dissolved in EtOAc (10 mL) and washed with water. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified by reversed-phase rapid chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 35 mg of product. Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-(trifluoromethyl)indol-3-yl]-1-methyl-cyclobutane carboxylic acid (5%). The product was dissolved in MeOH (4.0 mL), THF (1.0 mL), and water (1.0 mL) with the addition of lithium hydroxide (0.05 g, 2.09 mmol). The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The crude residue was diluted in water (5 mL) and acidified with 6N HCl. The aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum to give 25 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-(trifluoromethyl)indol-3-yl]-1-methyl-cyclobutane carboxylic acid. The crude product was used in the following steps without further purification.

[0853] Step 3. Synthesis of trans-3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(trifluoromethyl)-1H-indol-3-yl)-1-methylcyclobutane-1-carboxylic acid (139)

[0854] A solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-(trifluoromethyl)indol-3-yl]-1-methyl-cyclobutanecarboxylic acid C44 (0.025 g, 0.049 mmol) in MeOH (3 mL) was purged with nitrogen. Pd / C (0.010 g, 0.009 mmol) was added, followed by EtOAc (2 mL). The system was evacuated and purged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere for 18 hours. The crude mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum. The crude residue was purified by reversed-phase rapid chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 12 mg of product. 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-(trifluoromethyl)indol-3-yl]-1-methyl-cyclobutanecarboxylic acid (53%). 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.33 (d, J = 2.2Hz, 1H), 7.24–7.04 (m, 4H), 6.84–6.76 (m, 2H), 4.13–3.98 (m, 1H), 2.92 (td, J = 9.0, 2.7Hz, 2H), 2.58 (td, J = 10.0, 2.7Hz, 2H), 2.33 (s, 3H), 1.52 (s, 3H). ESI-MS m / z calculated value 421.13, measured value 422.23 (M+1). + .

[0855] Compound 140

[0856] 6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(trifluoromethyl)-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (140)

[0857]

[0858] Compound 140 was prepared from 6-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid, as described in C44 of the preparation of 139. Hydrogenation with Pd / C in EtOAc yielded the final product. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.26 (dd, J = 2.2, 0.7 Hz, 1H), 7.22–7.09 (m, 3H), 6.86–6.72 (m, 2H), 3.94–3.78 (m, 1H), 3.07–3.07 (m, 1H), 2.69–2.41 (m, 6H), 2.35–2.28 (m, 5H). LCMS m / z 448.5 [M+H] + .

[0859] Compounds 141 and 142

[0860] Synthesis of trans-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylic acid (141) and cis-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylic acid (142)

[0861]

[0862] Step 1. Synthesis of methyl 3-(5-(benzyloxy)-1-(3,4-difluorophenyl)-2-isopropyl-1H-indol-3-yl)cyclobut-2-ene-1-carboxylate (C46)

[0863] Add iPrMgCl-LiCl (0.58 mL 1.3 M solution, 0.75 mmol) to a cold (0 °C) solution of 5-benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-isopropyl-indole S29 (0.37 g, 0.73 mmol) in 2 mL THF. Stir the reaction mixture for 1 hour, then slowly heat to room temperature over 30 minutes. Add a solution of methyl 3-oxocyclobutanecarboxylate (0.10 g, 0.78 mmol) in 0.5 mL THF to the reaction mixture, and stir for 2 hours at room temperature. Quench the reaction mixture with H2O and extract with CH2Cl2. Concentrate the organic phase under vacuum and use it in the next step without further purification.

[0864] Triethylamine (0.16 mL, 2.08 mmol) and triethylsilane (0.45 mL, 2.82 mmol) were added to a solution of the crude product dissolved in CH₂Cl₂ (5 mL). The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel chromatography using a 0–10% MeOH / CH₂Cl₂ gradient to give 120 mg of product. Methyl 3-[5-benzyloxy-1-(3,4-difluorophenyl)-2-isopropyl-indole-3-yl]cyclobutanecarboxylate (34%) ESI-MS m / z calculated value 489.2, found value 490.3 (M+1). + .

[0865] Step 2. Synthesis of trans-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylic acid (141) and cis-3-(1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylic acid (142)

[0866] Pd(OH)₂ (0.03 g, 0.21 mmol) was added to a solution of methyl 3-[5-benzyloxy-1-(3,4-difluorophenyl)-2-isopropyl-indol-3-yl]cyclobutanecarboxylate C46 (0.12 g, 0.25 mmol) in EtOAc (10 mL). The reaction mixture was evacuated and purged with hydrogen, and stirred under hydrogen atmosphere for 2 hours. The crude mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum to give 80 mg of crude product, which was used in the next step without further purification. Methyl 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-indol-3-yl]cyclobutanecarboxylate (82%). ESI-MS m / z calculated value 399.2, found value 400.5 (M+1). + .

[0867] Methyl 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-indole-3-yl]cyclobutanecarboxylic acid (80 mg) was added to a solution of MeOH (10 mL) with NaOH (0.50 mL 3M solution, 1.50 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The crude residue was purified by reversed-phase rapid chromatography with CH3CN / water (0-100%, 0.1% TFA) to give 18.6 mg of 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-indole-3-yl]cyclobutanecarboxylic acid (37%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.39–7.30 (m, 2H), 7.22–7.12 (m, 1H), 7.07 (ddd, J = 8.8, 4.0, 1.8Hz, 1H), 6.80–6.75 (m, 1H), 6.68 (dd, J = 8.7, 2.4Hz, 1H), 4.29 (t, J = 9.4Hz, 1H), 3.45 (t, J = 9.8Hz, 1H), 3.18–3.02 (m, 2H), 2.99–2.87 (m, 1H), 2.81–2.70 (m, 2H), 1.28 (d, J = 7.2Hz, 6H). ESI-MS m / z calculated value 385.1, measured value 386.0 (M+1). + And 18 mg of 3-[1-(3,4-difluorophenyl)-5-hydroxy-2-isopropyl-indol-3-yl]cyclobutanecarboxylic acid (18.5 mg, 37%). 1¹H NMR (400MHz, chloroform-d) δ 7.74 (dd, J = 2.0, 0.9Hz, 1H), 7.38–7.32 (m, 1H), 7.15 (ddd, J = 10.5, 7.1, 2.5Hz, 1H), 7.07 (ddd, J = 8.8, 3.9, 1.9Hz, 1H), 6.82–6.75 (m, 2H), 3.94 (d, J = 9.4Hz, 1H), 3.16 (d, J = 10.7Hz, 2H), 3.02–2.88 (m, 1H), 2.68–2.56 (m, 2H), 1.30 (d, J = 7.2Hz, 6H). ESI-MS m / z calculated value 385.1, measured value 386.0 (M+1). + .

[0868] Compounds 143-146

[0869] Compounds 143-146 (Table 11) were prepared from a suitable ketone and an indole iodine intermediate using the method described for the preparation of compounds 141 and 142.

[0870] Table 11. Preparation methods, structures, and physicochemical data of compounds 143-146

[0871]

[0872]

[0873] 1. iPrMgCl-LiCl,THF,0℃

[0874] 2. Et3SiH,TFA,CH2Cl2

[0875] 3. Hydrolysis conditions: NaOH, MeOH

[0876] 4. The intermediate amine 3-(azacyclobutane-3-yl)-5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole was alkylated with 2-chloroacetic acid benzyl ester, and then the benzyl group was removed by hydrolysis to give the product.

[0877] Compounds 148 and 149

[0878] Synthesis of 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (148) and 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (149)

[0879]

[0880] Step 1. Synthesis of methyl 6-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylate (C47)

[0881] To a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole S8 (0.80 g, 2.14 mmol), methyl 2-oxospiro[3.3]heptane-6-carboxylate (0.56 g, 3.33 mmol) in CH2Cl2 (12.0 mL), trifluoroacetic acid (0.34 mL, 4.41 mmol) and triethylsilane (1.05 mL, 6.57 mmol) were added. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–50% EtOAc / heptane gradient to give 0.94 g of product. Methyl 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]spiro[3.3]heptane-2-carboxylate (82%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.49–7.44 (m, 2H), 7.43–7.35 (m, 2H), 7.36–7.29 (m, 2H), 7.11–7.01 (m, 3H), 6.81–6.62 (m, 2H), 5.13 (s, 2H), 3.86–3.74 (m, 1H), 3.71 (s, 3H), 3.11 (p, J = 8 0.5Hz, 1H), 2.94(h, J = 7.2Hz, 1H), 2.70(dt, J = 25.0, 10.7Hz, 2H), 2.48(dd, J = 8.5, 1.3Hz, 2H), 2.40(dd, J = 11.5, 8.5Hz, 1H), 2.35(d, J = 5.3Hz, 5H), 1.23(dt, J = 7.3, 1.6Hz, 6H). ESI-MS m / z calculated value: 525.27, measured value: 525.21 (M+1). + .

[0882] Step 2. Synthesis of methyl 6-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-fluorospiro[3.3]heptane-2-carboxylate (C48)

[0883] Methyl 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]spiro[3.3]heptane-2-carboxylate C47 (0.85 g, 1.59 mmol) in tetrahydrofuran (20 mL) at a cold (-78 °C) temperature was added to (1.05 mL, 2 M, 2.10 mmol). The mixture was heated to -10 °C and stirred for 30 min. The mixture was cooled to -78 °C and N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (0.65 g, 2.06 mmol) in THF (2.0 mL) was added, and the mixture was slowly heated to room temperature. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 0.5 g of product. Methyl 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-yl]-2-fluoro-spiro[3.3]heptane-2-carboxylate (58%). 1 H NMR (400MHz, chloroform-d) δ7.47(dd,J=8.1,1.5Hz,2H),7.44-7.35(m,2H),7.35-7.30(m,2H),7.19-6.99(m,3H),6.92-6.65(m,2H),5.13(s,2H),3. 84-379(m,4H),2.96(ddd,J=14.7,9.4,5.5Hz,2H),2.85-2.58(m,5H),2.59-2.41(m,2H),2.33(d,J=2.0Hz,3H),1.23(dd,J=7.2,1.4Hz,6H).

[0884] Step 3. Synthesis of 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (C49)

[0885] Lithium hydroxide (0.65 g, 15.49 mmol) was added to a solution of methyl 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-fluoro-spiro[3.3]heptane-2-carboxylate C48 (0.50 g, 0.92 mmol) in MeOH (10.0 mL), THF (3.0 mL), and H2O (1.5 mL). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the white solid was dissolved in water (10 mL) and slowly acidified with HCl (12.0 mL 2 M, 24.0 mmol). The aqueous phase was extracted three times with EtOAc, dried (MgSO4), filtered, and concentrated under vacuum to give 480 mg of product. 6-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-fluoro-spiro[3.3]heptane-2-carboxylic acid (95%). ESI-MS m / z calculated value 529.24, measured value 530.51 (M+1). + The product (480.0 mg, 0.9063 mmol) in a solution of EtOAc (20.0 mL) was purged with nitrogen. Pd / charcoal (0.24 g 10% w / w, 0.09 mmol) was added to the mixture and the mixture was evacuated and purged with hydrogen. The crude mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (4 g ISCO column) using a 0-10% MeOH / heptane gradient to give 0.38 g of product (89%). The crude product was submitted for SFC purification to give 67.5 mg of 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (148). 1 ¹H NMR (400MHz, chloroform-d) δ 7.20 (d, J = 2.3Hz, 1H), 7.15–6.99 (m, 3H), 6.70 (d, J = 8.7Hz, 1H), 6.61 (dd, J = 8.7, 2.4Hz, 1H), 3.86–3.74 (m, 1H), 3.10–2.41 (m, 9H), 2.32 (d, J = 2.1Hz, 3H), 1.26–1.15 (m, 6H); ESI-MS m / z calculated value 439.19, measured value 440.55 (M+1). +, and 61 mg 2-fluoro-6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (149). 1H NMR (400MHz, chloroform-d) δ 7.20 (d, J = 2.3Hz, 1H), 7.15-7.00 (m, 3H), 6.70 (d, J = 8.7Hz, 1H), 6.60 (dd, J = 8.7, 2.4Hz, 1H), 3.81 (tt, J = 10.1, 8.4Hz, 1H), 3.09-2.41 (m, 9H), 2.32 (d, J = 1.9Hz, 3H), 1.23 (dt, J = 7.2, 1.2Hz, 6H).

[0886] Compound 150

[0887] 6-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(trifluoromethyl)-1H-indol-3-yl)spiro[3.3]heptane-2-carboxylic acid (150)

[0888]

[0889] Compound 150 was prepared from methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)cyclobutane-1-carboxylate, as described in C48 of the preparation of 148. Ester hydrolysis was performed with sodium hydroxide in methanol, followed by hydrogenation with Pd / C in EtOAc to give the final product. Compound 150 was isolated as a single stereoisomer with an unknown absolute configuration. 1 H NMR (400MHz, chloroform-d) δ7.71-7.60(m,1H),7.17-7.03(m,3H),6.80-6.68(m,2H),4.41(p,J=9.6Hz,1H),3.54(dt,J=28.6,11.6H z, 2H), 2.95 (p, J = 7.2Hz, 1H), 2.76 (dddd, J = 20.2, 11.5, 8.8, 3.3Hz, 2H), 2.33 (d, J = 2.0Hz, 3H), 1.29 (dd, J = 7.2, 1.7Hz, 6H). LCMS m / z 400.3[M+H] + .

[0890] Compound 151

[0891] Synthesis of 3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-methoxy-2-methylpropionic acid (151)

[0892]

[0893] Step 1. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-hydroxy-2-methylpropionate (C50)

[0894] To a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole S8 (0.50 g, 1.34 mmol) in 1,2-dichloroethane (7.0 mL), methyl 2-methylethylene oxide-2-carboxylate (0.43 mL, 4.02 mmol) and tris(trifluoromethanesulfonyloxy)ytterbium (0.40 g, 0.65 mmol) were added. The reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined organic phases were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using 0–40% EtOAc / heptane to give 275 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-yl]-2-hydroxy-2-methyl-propionate methyl ester (42%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.54–7.48 (m, 2H), 7.47–7.38 (m, 2H), 7.38–7.30 (m, 1H), 7.23–7.06 (m, 4H), 6.87–6.76 (m, 1H), 6.64 (d, J = 8.8 Hz, 1H), 5.13 (s, 2H), 3.74 (d, J = 2.8 Hz, 3H), 3.43–3.10 (m, 3H), 2.35 (dd, J = 4.0, 2.0 Hz, 3H), 1.60 (s, 3H), 1.15 (ddd, J = 11.3, 7.2, 1.2 Hz, 6H).

[0895] Step 2. Synthesis of methyl 3-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-methoxy-2-methylpropionate (C51)

[0896] Sodium hydride (0.020 g 60% w / w, 0.500 mmol) was added to a cold (0 °C) solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-hydroxy-2-methyl-propionate C50 (0.11 g, 0.22 mmol) in DMF (2 mL). The reaction mixture was stirred for 30 min. Iodomethane (0.030 mL, 0.482 mmol) was added to the mixture and the mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–40% EtOAc / heptane gradient to give 95 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-yl]-2-methoxy-2-methyl-propionate (84%). 1 H NMR (400MHz, chloroform-d) δ7.56-7.45(m,2H),7.45-7.39(m,2H),7.38-7.29(m ,1H),7.22(d,J=2.4Hz,1H),7.19-7.08(m,3H),6.87-6.72(m,1H),6.63( d,J=8.7Hz,1H),5.12(s,2H),3.76(d,J=0.5Hz,3H),3.43-3.34(m,1H),3 .29(s,3H),3.24-3.13(m,2H),2.34(d,J=1.9Hz,3H),1.19-1.02(m,6H).

[0897] Step 3. Synthesis of 3-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-methoxy-2-methylpropionic acid (151)

[0898] Lithium hydroxide (0.128 g, 3.050 mmol) was added to a solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methoxy-2-methyl-propionate C51 (0.090 mg, 0.178 mmol) in MeOH (2.0 mL), THF (0.6 mL), and H₂O (0.40 mL). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and the white solid was dissolved in water (10 mL) and slowly acidified with HCl (1.8 mL 2 M, 3.6 mmol). The aqueous phase was extracted three times with EtOAc. The organic phase was dried (MgSO₄), filtered, and concentrated under vacuum to give 80 mg of product. 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-yl]-2-methoxy-2-methyl-propionic acid (91%). 1 H NMR (400MHz, chloroform-d) δ7.53-7.45(m,2H),7.45-7.35(m,2H),7.35-7.27(m,1H),7.21-7.07(m,4H),6.79(dd,J= 8.8, 2.5Hz, 1H), 6.62 (d, J = 8.8Hz, 1H), 5.12 (s, 2H), 3.38-3.22 (m, 4H), 2.40-2.26 (m, 2H), 1.16-1.03 (m, 6H). Pd / C (0.039 g 10% w / w, 0.015 mmol) was added to a nitrogen-purged solution of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methoxy-2-methyl-propionic acid (0.070 g, 0.143 mmol) in EtOAc (2.0 mL), and the mixture was evacuated and filled with hydrogen. The mixture was stirred under a hydrogen atmosphere for 2 h. The crude mixture was filtered through a diatomaceous earth pad, filtered, and concentrated under vacuum. The residue was purified using ISCO (4 g gold) by silica gel chromatography (4 g ISCO column) with 0–10% MeOH / CH2Cl2 to obtain 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]-2-methoxy-2-methyl-propionic acid (33%). 1¹H NMR (400MHz, chloroform-d) δ 7.17–7.07 (m, 3H), 7.05 (d, J = 2.3 Hz, 1H), 6.67–6.51 (m, 2H), 3.35 (s, 3H), 3.29 (q, J = 7.2 Hz, 1H), 3.22–3.17 (m, 2H), 2.33–2.27 (m, 3H), 1.54 (s, 3H), 1.15–1.07 (m, 6H). ESI-MS m / z calculated value 399.18, measured value 400.31 (M+1). + .

[0899] Compound 152

[0900] 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indole-3-yl]-2-hydroxy-2-methyl-propionic acid (152)

[0901]

[0902] Compound 152 was prepared from 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole S8 as described in the preparation of C51 for 151. Ester hydrolysis was performed using methanol, THF, and lithium hydroxide in water, followed by hydrogenation with Pd / C (charcoal) in EtOAc to give the final product. 1 H NMR (400MHz, chloroform-d) δ7.23-7.08(m,3H),7.04(d,J=2.2Hz,1H),6.75-6.52(m,2H),3.48(d,J=14.9Hz,1H), 3.31 (p, J = 7.3Hz, 1H), 3.17 (d, J = 14.9Hz, 1H), 2.34 (d, J = 2.1Hz, 3H), 1.64 (s, 3H), 1.16 (t, J = 6.5Hz, 6H). LCMS m / z 386.3[M+H] + .

[0903] Preparation 153

[0904] Synthesis of 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indole-3-yl)acetic acid (153)

[0905]

[0906] Step 1. Synthesis of 5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole-3-carboxaldehyde (C52)

[0907] DMF (13.0 mL, 167.9 mmol) was added to a solution of oxaloyl chloride (13.0 mL, 2 M solution, 26.0 mmol) in CH2Cl2 at 0 °C. The suspension was stirred at 0 °C for 10 min. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole S8 (5.0 g, 13.4 mmol) was added dropwise to CH2Cl2 (50 mL). The reaction mixture was stirred overnight at room temperature. The solution was alkalized with saturated NaHCO3 aqueous solution and extracted three times with CH2Cl2. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (80 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 4.67 g of product: 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-carboxaldehyde (81%). 1 ¹H NMR (300MHz, chloroform-d) δ 10.42 (s, 1H), 7.95 (d, J = 2.5Hz, 1H), 7.47–7.37 (m, 2H), 7.40–7.21 (m, 3H), 7.18–6.99 (m, 3H), 6.83 (dd, J = 8.9, 2.5Hz, 1H), 6.69 (dd, J = 8.9, 0.5Hz, 1H), 5.09 (s, 2H), 3.09 (p, J = 7.2Hz, 1H), 2.30 (d, J = 2.0Hz, 3H), 1.38 (dd, J = 7.2, 2.1Hz, 6H). ESI-MS m / z calculated value 401.18, measured value 402.27 (M+1). + .

[0908] Step 2. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)acetonitrile (C53)

[0909] Potassium tert-butoxide (1.21 g, 10.46 mmol) was added fractionally to a cold (0 °C) solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-carboxaldehyde C52 (1.75 g, 4.36 mmol) and TOSMIC (1.13 g, 5.67 mmol) in DME (16.5 mL) and EtOH (0.5 mL). The reaction mixture was stirred at 0 °C for 1 hour. MeOH (16.5 mL) was added, and the reaction mixture was heated to 90 °C and stirred for 30 minutes. The mixture was concentrated under vacuum. The residue was dissolved in excess saturated aqueous NH4Cl and CH2Cl2 to pH 4. The phases were separated, and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40g ISCO column) using a 0-50% EtOAc / heptane gradient to give 1.12g of product: 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetonitrile (62%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.53–7.45 (m, 2H), 7.44–7.35 (m, 2H), 7.35–7.28 (m, 1H), 7.20–7.04 (m, 4H), 6.86 (dd, J = 8.8, 2.3Hz, 1H), 6.79 (dd, J = 8.9, 0.5Hz, 1H), 5.14 (s, 2H), 3.90 (s, 2H), 3.00 (septet, J = 7.3Hz, 1H), 2.34 (d, J = 2.0Hz, 3H), 1.33 (d, J = 4.1Hz, 3H), 1.31 (d, J = 4.1Hz, 3H). ESI-MS m / z calculated value 412.2, measured value 411.9 (M+1). + .

[0910] Step 3. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indole-3-yl)acetic acid (C54)

[0911] To a solution of 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetonitrile C53 (0.10 g, 0.24 mmol) in EtOH (1.7 mL), KOH (0.79 g, 50% w / w, 7.005 mmol) in water (1.7 mL) was added. The mixture was irradiated with microwave at 145 °C for 45 min. After cooling to room temperature, the reaction mixture was poured into a solution of water (20 mL) containing HCl (0.72 mL, 37% w / v, 7.276 mmol) and CH2Cl2 (20 mL). The aqueous phase was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 104 mg of product. 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetic acid (97%). ESI-MS calculated m / z value: 431.19; measured value: 432.45 (M+1) + The crude product is used in the next step without further purification.

[0912] Step 4: Synthesis of 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indole-3-yl)acetic acid (153)

[0913] Add 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-yl]acetic acid C54 (0.104 g, 0.241 mmol) to a vial containing Pd / C (moistened, Degussa, 0.027 g, 0.025 mmol). Seal the vial and purge with a vacuum and a single cycle of nitrogen. Add EtOAc (4.8 mL), evacuate the reaction mixture, purge with hydrogen, and stir under hydrogen atmosphere for 5 hours. Filter the crude mixture through a diatomaceous earth pad and concentrate the filtrate under vacuum. Purify the residue by silica gel chromatography (40 g ISCO column) using a 0–30% MeOH / CH2Cl2 gradient to give 33 mg of product: 2-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indole-3-yl]acetic acid (39%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.17–7.07 (m, 3H), 6.91–6.87 (m, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 3.83 (s, 2H), 3.06–2.92 (m, 1H), 2.34 (s, 3H), 1.30–1.21 (m, 6H). ESI-MS m / z calculated value 341.14, measured value 342.07 (M+1). + .

[0914] Compounds 154 and 155

[0915] Synthesis of 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-methylpropionic acid (154) and 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)propionic acid (155)

[0916]

[0917] Step 1. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)propionitrile (C55) and 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-methylpropionitrile (C56)

[0918] Sodium hydride (0.100 g, 2.425 mmol) was added to a cold (0 °C) solution of 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]acetonitrile C53 (0.200 g, 0.485 mmol) in DMF (2.4 mL). The mixture was stirred until gas escaping stopped, and then methyl iodine (0.151 mL, 2.426 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 60 min. The mixture was then stirred overnight at 50 °C. The reaction mixture was quenched by adding a saturated aqueous solution of NH4Cl. The aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography to give the following inseparable mixture: 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methyl-propionitrile (85 mg, 23%): ESI-MS m / z calculated value 440.2, measured value 439.9 (M+1). + And 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]propionitrile (56 mg, 27%): ESI-MS m / z calculated value 426.21, measured value 427.81 (M+1). + The mixture proceeds to the next step without further purification.

[0919] Step 2. Synthesis of 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)propionic acid (C57) and 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-isopropyl-1H-indol-3-yl)-2-methylpropionic acid (C58)

[0920] A solution of 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-2-methyl-propionitrile C55 (0.085 g, 0.190 mmol) and 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]propionitrile C56 (0.056 g, 0.131 mmol) in EtOH (3.2 mL) was added to a solution of KOH (0.625 g 50% w / w, 5.570 mmol) in water (3.2 mL). The reaction mixture was irradiated in a microwave reactor at 180 °C for 2.5 h. After cooling to room temperature, the reaction mixture was poured into a solution of water (20 mL) containing HCl (0.570 mL 37% w / v, 5.784 mmol) and CH2Cl2 (20 mL). The phases were separated, and the aqueous phase was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the following mixture: 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-yl]-2-methyl-propionamide (71 mg, 80%): ESI-MS m / z calculated value 458.24, measured value 459.41 (M+1). + And 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-yl]propionic acid (71 mg, 83%): ESI-MS m / z calculated value 445.21, measured value 446.40 (M+1). + The mixture is used in the next step without further purification.

[0921] Step 3: Synthesis of 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-methylpropionic acid (154) and 2-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)propionic acid (155)

[0922] Add 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-yl]acetic acid (0.104 g, 0.241 mmol) to a vial containing Pd / C (moistened, Degussa, 0.027 g, 0.025 mmol). Seal the vial and purge with a vacuum and a single cycle of nitrogen. Add EtOAc (3 mL) and evacuate the reaction mixture, purging with hydrogen and stirring under a hydrogen atmosphere for 16 hours. Filter the crude mixture through a diatomaceous earth pad and concentrate the filtrate under vacuum. Purify the crude residue by reversed-phase rapid chromatography (RF ISCO, C18 column, 30 g) with CH3CN / water (0-100%, 0.1% TFA) to give 2-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indole-3-yl]propionic acid (4.9 mg, 9%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.19–7.00 (m, 4H), 6.72 (d, J = 8.6 Hz, 1H), 6.68–6.60 (m, 1H), 4.27–4.14 (m, 1H), 3.07–2.92 (m, 1H), 2.33 (s, 3H), 1.63 (d, J = 7.1 Hz, 3H), 1.34 (d, J = 7.2 Hz, 3H), 1.29 (d, J = 7.0 Hz, 3H). ESI-MS m / z calculated value 355.1584, measured value 356.07 (M+1). + And 2-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indole-3-yl]-2-methyl-propionamide (20.3 mg, 35%): 1 ¹H NMR (400MHz, chloroform-d) δ 7.35–7.30 (m, 1H), 7.19–7.10 (m, 3H), 6.63 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 5.77 (s, 1H), 5.47 (s, 1H), 3.31 (s, 1H), 2.33 (s, 3H), 1.81 (s, 6H), 1.07 (d, J = 7.1 Hz, 6H). ESI-MS m / z calculated value 368.19, measured value 369.13 (M+1). + .

[0923] Preparation of 156

[0924] Synthesis of 2-(2-cyclopropyl-1-(4-fluoro-3-methylphenyl)-5-hydroxy-1H-indol-3-yl)-3-phenylpropionic acid (156)

[0925]

[0926] Step 1. Synthesis of methyl 2-(5-(benzyloxy)-1H-indol-3-yl)acetate (C59)

[0927] H₂SO₄ (2.0 mL, 37.5 mmol) was added to a solution of 2-(5-benzyloxy-1H-indol-3-yl)acetic acid (10.0 g, 35.6 mmol) in MeOH (50.0 mL, 1.2 mol). The reaction mixture was heated to reflux and stirred for 3 hours, then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO₃. The organic phase was dried (MgSO₄), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a 10–90% EtOAc / heptane gradient to give 10.1 g of product: methyl 2-(5-benzyloxy-1H-indol-3-yl)acetate (96%). 1 ¹H NMR (400 MHz, chloroform-d) δ 7.98 (s, 1H), 7.51 (ddd, J = 6.8, 1.5, 0.8 Hz, 2H), 7.46–7.39 (m, 2H), 7.35 (d, J = 7.3 Hz, 1H), 7.30–7.25 (m, 2H), 7.18 (dd, J = 3.9, 2.5 Hz, 2H), 6.98 (dd, J = 8.8, 2.4 Hz, 1H), 5.14 (s, 2H), 3.76 (s, 2H), 3.71 (s, 3H). ESI-MS m / z calculated value 295.12, measured value 296.09 (M+1). + .

[0928] Step 2. Synthesis of methyl 2-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)acetate (C60)

[0929] Copper iodide (I) (3.20 g, 16.80 mmol) was added to a solution of methyl 2-(5-benzyloxy-1H-indol-3-yl)acetate C59 (10.50 g, 34.12 mmol), 1-fluoro-4-iodo-2-methylbenzene (10.50 g, 44.49 mmol), KH₂PO₄ (9.30 g, 68.34 mmol), and N,N-dimethylethylenediamine (3.60 mL, 33.81 mmol) purged with nitrogen in toluene (80 mL) and DMSO (9 mL). The solution was heated at 120 °C for 20 h. The reaction mixture was cooled to room temperature and filtered. The solids were washed with EtOAc (200 mL). The filtrate was washed with a saturated aqueous solution of NaHCO₃. The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (120 g ISCO column) using a 0-60% EtOAc / heptane gradient to give 6.4 g of product: methyl 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate (45%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.59–7.48 (m, 2H), 7.44–7.33 (m, 4H), 7.32–7.24 (m, 4H), 7.20 (d, J = 2.4 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 6.99 (dd, J = 9.0, 2.5 Hz, 1H), 5.16 (s, 2H), 3.80 (d, J = 0.9 Hz, 2H), 3.73 (s, 3H), 2.37 (d, J = 2.0 Hz, 3H). ESI-MS m / z calculated value 403.16, measured value 404.1 (M+1). + .

[0930] Step 3. Synthesis of methyl 2-(5-(benzyloxy)-2-bromo-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)acetate (C61)

[0931] N-bromosuccinimide was added to a solution of methyl 2-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate C60 (0.81 g, 1.94 mmol) in CCl4 (15 mL). The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / heptane gradient to give 0.32 g of product: methyl 2-[5-benzyloxy-2-bromo-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate (30%). 1¹H NMR (400MHz, chloroform-d) δ 7.48–7.40 (m, 2H), 7.38–7.31 (m, 2H), 7.30–7.24 (m, 1H), 7.18–7.04 (m, 4H), 6.94 (d, J = 8.9 Hz, 1H), 6.85 (dd, J = 8.9, 2.4 Hz, 1H), 5.08 (s, 2H), 3.76 (s, 2H), 3.67 (s, 3H), 2.31 (d, J = 2.0 Hz, 3H). ESI-MS m / z calculated value 481.06888, measured value 482.0 (M+1). + .

[0932] Step 4. Synthesis of methyl 2-(5-(benzyloxy)-2-cyclopropyl-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)acetate (C62)

[0933] Palladium(II) acetate (0.114 g, 0.508 mmol) was added to a solution of cyclopropyl(trifluoro)borohydride (potassium ion (1)) (1.90 g, 12.84 mmol), methyl 2-[5-benzyloxy-2-bromo-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate C61 (1.40 g, 2.55 mmol), X-Phos (1.89 g, 2.546 mmol), and Pd(OAc)2 (0.114 g, 0.507 mmol) in toluene (70 mL) and water (10 mL) purged with nitrogen. The reactants were capped in a resealable tube and the reaction mixture was heated at 120 °C for 18 hours. Cyclopropyl(trifluoro)-borohydride (potassium ion (1)) (1.90 g, 12.84 mmol), X-Phos (1.89 g, 2.55 mmol), and Pd(OAc)2 (0.114 g, 0.507 mmol) were added, and the reaction mixture was heated at 120 °C for 18 hours. The mixture was cooled to room temperature and the solid was filtered. The solid was washed with EtOAc (100 mL). The combined filtrates were washed with water (50 mL), and the organic phase was separated. The organic layer was dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-60% EtOAc / heptane gradient to give 0.72 g of product. The crude residue was purified by reversed-phase rapid chromatography (RF ISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA). The crude residue was purified again by reversed-phase rapid chromatography (RF ISCO, C18 column, 30 g) elution with CH3CN / water (0-100%, 0.1% TFA) to give 650 mg of product. Methyl 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate (57%). ¹H NMR (400MHz, chloroform-d) δ 7.52–7.49 (m, 2H), 7.44–7.38 (m, 2H), 7.36–7.24 (m, 1H), 7.24–7.13 (m, 4H), 7.01 (dd, J = 8.9, 0.5Hz, 1H), 6.88 (dd, J = 8.8, 2.4Hz, 1H), 5.14 (s, 2H), 3.71 (s, 3H), 2.36 (d, J = 2.0Hz, 3H), 1.79–1.76 (m, 1H), 0.85–0.69 (m, 2H), 0.63–0.40 (m, 2H). ESI-MS m / z calculated value 443.2, measured value 444.2 (M+1). + .

[0934] Step 5. Synthesis of methyl 2-(5-(benzyloxy)-2-cyclopropyl-1-(4-fluoro-3-methylphenyl)-1H-indol-3-yl)-3-phenylpropionate (C63)

[0935] LDA (450 μL 2M, 0.9000 mmol) was added to a cold (-78°C) solution of methyl 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]acetate (C62) (0.27 g, 0.60 mmol) in anhydrous THF (10 mL). The solution was stirred at -78°C for 45 min. A solution of benzyl bromide (1.10 mL, 9.29 mmol) in THF (1 mL) was added dropwise, and the reaction mixture was stirred at -78°C for 2 h and then slowly heated to room temperature. The reaction mixture was quenched with saturated NH4Cl aqueous solution (5 mL) and extracted twice with EtOAc (10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-5% EtOAc / heptane gradient to give 240 mg of product. Methyl 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-3-phenyl-propionate (74%). 1 H NMR (400MHz, chloroform-d) δ7.53-7.44(m,2H),7.35-7.30(m,3H),7.29-6.90(m,10H), 6.81(dd,J=8.8,2.4Hz,1H),5.11(s,2H),4.32(dd,J=9.1,6.5Hz,1H),3.58(s, 3H),3.48(dd,J=13.3,6.5Hz,1H),3.10(dd,J=13.3,9.1Hz,1H),2.26(s,3H),1 .11-0.90(m,1H),0.62-0.60(m,1H),0.51-0.47(m,1H),0.43-0.26(m,1H),0.04 -0.05 (m, 1H). ESI-MS m / z calculated value: 533.2; measured value: 534.2 (M+1). + .

[0936] Step 6. Synthesis of 2-(2-cyclopropyl-1-(4-fluoro-3-methylphenyl)-5-hydroxy-1H-indol-3-yl)-3-phenylpropionic acid (156)

[0937] LiOH (0.050 g, 2.088 mmol) was added to a stirred solution of methyl 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-3-phenyl-propionic acid C63 (0.075 g, 0.127 mmol) in THF (1 mL), MeOH (3 mL), and water (1 mL). The reaction mixture was stirred at room temperature for 18 hours and the solvent was removed under reduced pressure. The residue was dissolved in water (2 mL) and acidified with 6N HCl. The white ppt was extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried and concentrated under reduced pressure to give 65 mg of product. 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-3-phenyl-propionic acid (96%). ESI-MS calculated m / z value: 519.22; measured value: 520.25 (M+1). + .

[0938] Pd / C (0.100 g, 0.094 mmol) was added to a solution of 2-[5-benzyloxy-2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)indol-3-yl]-3-phenyl-propionic acid (0.060 mg, 0.112 mmol) in MeOH (5 mL) and EtOAc (2 mL). The mixture was purged with nitrogen. The reaction mixture was evacuated and purged with hydrogen and stirred under hydrogen atmosphere for 1 hour. The crude mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum. The crude residue was purified by reversed-phase rapid chromatography (RFISCO, C18 column, 30 g) eluting with CH3CN / water (0-100%, 0.1% TFA) to give 35 mg of product: 2-[2-cyclopropyl-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-indol-3-yl]-3-phenyl-propionic acid (70%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.27–7.25 (m, 2H), 7.21–7.12 (m, 3H), 7.07 (t, J = 8.8 Hz, 1H), 6.95–6.93 (m, 4H), 6.75 (dd, J = 8.8, 2.3 Hz, 1H), 4.38 (dd, J = 9.5, 5.8 Hz, 1H), 3.49–3.44 (m, 1H), 3.15–2.90 (m, 1H), 2.30 (s, 3H), 1.11–1.08 (m, 1H), 0.64–0.62 (m, 1H), 0.55–0.23 (m, 2H). ESI-MS m / z calculated value 429.2, measured value 430.2 (M+1). + .

[0939] Table 12. Preparation methods, structures, and physicochemical data of compounds 157-162

[0940]

[0941]

[0942] 1. Methyl 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetate was used as a substitute for C62. The hydrogenation step was omitted. BBr3 was used in the final step to remove the OMe group.

[0943] Compound 163

[0944] Synthesis of 3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)propionic acid (163)

[0945]

[0946] Step 1. Synthesis of 6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indole-3-carboxaldehyde (C64)

[0947] Oxaloyl chloride (3.3 mL 2M, 6.600 mmol) was added to a cold (0 °C) solution of DMF (3.00 mL, 38.74 mmol) in CH₂Cl₂ (5 mL). The solution was stirred at room temperature for 30 min. A solution of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole S19 (1.20 g, 3.67 mmol) in CH₂Cl₂ (15 mL) was added. The resulting solution was stirred at room temperature for 2 h. A saturated aqueous solution of NaHCO₃ was slowly added to quench the reaction. The organic phase was dried (MgSO₄), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a 0–60% EtOAc / heptane gradient to give 1.12 g of product: 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole-3-carboxaldehyde (89%). 1 ¹H NMR (400MHz, chloroform-d) δ 10.51 (s, 1H), 8.01 (d, J = 8.4Hz, 1H), 7.30–7.20 (m, 2H), 7.20–7.04 (m, 2H), 6.62 (d, J = 11.0Hz, 1H), 4.01 (s, 3H), 3.19 (p, J = 7.2Hz, 1H), 2.40 (d, J = 2.0Hz, 3H), 1.47 (dd, J = 7.2, 2.6Hz, 6H). ESI-MS m / z calculated value 343.1384, measured value 344.19 (M+1). + .

[0948] Step 2. Synthesis of (E)-3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indol-3-yl)ethyl acrylate (C65)

[0949] Add 2-(triphenyl-) to a solution of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indole-3-carboxaldehyde C64 (0.36 g, 1.05 mmol) in toluene (10 mL) Ethyl (5-phosphine)ethyl acetate (0.73 g, 2.10 mmol). The reaction mixture was heated at 120 °C for 48 hours. The mixture was cooled to room temperature and diluted with water. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-60% EtOAc / heptane gradient to give 0.24 g of product. Ethyl (E)-3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propyl-2-enoate (55%). ¹H NMR (400MHz, chloroform-d): δ 8.22 (d, J = 15.8Hz, ¹H), 7.43 (d, J = 8.0Hz, ¹H), 7.26–7.06 (m, ³H), 6.63 (d, J = 11.2Hz, ¹H), 6.38 (d, J = 15.9Hz, ¹H), 4.33 (q, J = 7.1Hz, 2H), 4.00 (s, ³H), 3.16 (p, J = 7.2Hz, 1H), 2.39 (d, J = 2.0Hz, ³H), 1.48–1.32 (m, 9H). ESI-MS m / z calculated value 413.18, measured value 414.28 (M+1). + .

[0950] Step 3. Synthesis of ethyl 3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indol-3-yl)propionate (C66)

[0951] Palladium hydroxide (0.05 g, 0.07 mmol) was added to a nitrogen-purged solution of ethyl (E)-3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]prop-2-enoate C65 (0.24 g, 0.57 mmol) in MeOH (10 mL). The reaction mixture was evacuated and purged with hydrogen, and stirred under a hydrogen atmosphere for 2 hours. The crude mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum to give 220 mg of product: ethyl 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propionate (92%). 1¹H NMR (400MHz, chloroform-d) δ 7.23–7.04 (m, 4H), 6.62 (d, J = 11.5 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.26–3.15 (m, 2H), 3.08–2.97 (m, 1H), 2.74–2.61 (m, 2H), 2.36 (d, J = 2.0 Hz, 3H), 1.38–1.22 (m, 9H). ESI-MS m / z calculated value 415.19, measured value 416.35 (M+1). + .

[0952] Step 4. Synthesis of 3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-2-isopropyl-5-methoxy-1H-indole-3-yl)propionic acid (C67)

[0953] Lithium hydroxide (0.14 g, 3.36 mmol) was added to a solution of ethyl 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propionate C66 (0.14 g, 0.34 mmol) in MeOH (6.0 mL), THF (3.0 mL), and water (1.0 mL). After 2 hours, the solvent was concentrated under vacuum, and the crude residue was dissolved in water (10 mL) and acidified with 10% HCl. The aqueous phase was extracted three times with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum to give 130 mg of product 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propionate (99%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.21–6.98 (m, 4H), 6.63 (d, J = 11.5 Hz, 1H), 3.97 (s, 3H), 3.30–3.18 (m, 2H), 3.11–2.89 (m, 1H), 2.82–2.62 (m, 2H), 2.37 (d, J = 2.0 Hz, 1H), 1.30 (d, J = 2.4 Hz, 3H), 1.28 (d, J = 2.5 Hz, 3H). ESI-MS m / z calculated value 387.16, measured value 388.26 (M+1). + .

[0954] Step 5. Synthesis of 3-(6-fluoro-1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-isopropyl-1H-indol-3-yl)propionic acid (163)

[0955] Tribromoborane (1.0 mL 1M, 1.000 mmol) was added to a cold (0 °C) solution of 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-5-methoxy-indol-3-yl]propionic acid C67 (0.130 g, 0.334 mmol) in CH2Cl2 (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted to water and extracted with CH2Cl2. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The crude residue was purified by reversed-phase rapid chromatography (RF ISCO, C18 column, 30 g) elution with CH3CN / water (0-100%, 0.1% TFA) to give 112 mg of product: 3-[6-fluoro-1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]propionic acid (86%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.19 (s, 1H), 9.09 (s, 1H), 7.32–7.28 (m, 2H), 7.19 (d, J = 4.2Hz, 1H), 7.00 (d, J = 8.5Hz, 1H), 6.49 (d, J = 11.5Hz, 1H), 5.75 (s, 1H), 3.00–2.96 (m, 4H), 2.30 (s, 3H), 1.21 (d, J = 7.2Hz, 6H). MS m / z calculated value 373.14896, measured value 374.29 (M+1). + .

[0956] Compound 164

[0957] Synthesis of 4-(1-(4-fluorophenyl)-5-hydroxy-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indol-3-yl)benzoic acid (164)

[0958]

[0959] Step 1. Synthesis of 4-methoxy-3,3-dimethylbut-1-yne (C68)

[0960] NaH (8.2 g 60% w / w, 204.0 mmol) was added dropwise to a cold (0 °C) solution of 2,2-dimethylbut-3-yn-1-ol (20.0 g, 203.8 mmol) in 140 mL of DMF over 10 minutes. The mixture was stirred for 30 minutes. Dimethyl sulfate (23.5 mL, 248.4 mmol) was added dropwise to the mixture. After 10 minutes at 0 °C, the reaction mixture was stirred at room temperature for 90 minutes. The mixture was diluted to 280 mL of cold water and stirred for 15 minutes. The organic phase was filtered to give 16 g of crude product, which was used without further purification. 4-Methoxy-3,3-dimethylbut-1-yn-yne (73%). 1 ¹H NMR (300MHz, chloroform-d) δ 3.43 (s, 3H), 3.27 (s, 2H), 2.15 (s, 1H), 1.25 (s, 6H).

[0961] Step 2. Synthesis of benzyl 4-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)benzoate (C69)

[0962] A solution of benzyl 4-iodobenzoate (15.00 g, 44.40 mmol), Pd(PPh3)2Cl2 (0.94 g, 1.33 mmol), and copper iodide (0.51 g, 2.66 mmol) in triethylamine (100 mL) and THF (100 mL) was purged with nitrogen for 5 min. 4-Methoxy-3,3-dimethyl-but-1-yne C68 (7.22 g, 64.37 mmol) was added to the mixture. The mixture was purged with nitrogen for 1 min. The flask was stirred at room temperature for 5 min and then heated to 50 °C for 2 h. The mixture was filtered, and the resulting solid was washed twice with EtOAc. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (330 g ISCO column) using a 0–50% EtOAc / heptane gradient to give 13 g of product. 4-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzyl benzoate (79%). 1 ¹H NMR (300MHz, chloroform-d) δ 8.04–7.94 (m, 2H), 7.51–7.32 (m, 7H), 5.37 (s, 2H), 3.46 (q, 3H), 3.36 (q, 2H), 1.33 (s, 6H). ESI-MS m / z calculated 322.2, measured 323.1 (M+1). + .

[0963] Step 3. Synthesis of 4-(benzyloxy)-2-bromo-N-(4-fluorophenyl)aniline (C70)

[0964] A 50 mL round-bottom flask containing 0.50 g (1.78 mmol) of 4-benzyloxy-2-bromo-aniline, 0.50 g (3.55 mmol) of (4-fluorophenyl)boric acid, 0.65 g (3.55 mmol) of copper(II) acetate, and 0.50 g of 4A sieve was stirred in open air for 15 minutes. Triethylamine (0.62 mL, 4.45 mmol) was added dropwise at ambient temperature, and the resulting deep blue / purple mixture was stirred in open air for 16 hours. The crude reaction mixture was diluted with ethyl acetate and then washed with water and brine. The combined organic phases were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0–20% EtOAc / heptane gradient to give 380 mg of product: 4-benzyloxy-2-bromo-N-(4-fluorophenyl)aniline (56%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 7.47–7.37 (m, 5H), 7.37–7.34 (m, 1H), 7.32 (d, J = 2.9 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.00 (ddd, J = 8.8, 5.9, 3.1 Hz, 3H), 6.81–6.74 (m, 2H), 5.09 (s, 2H). ESI-MS m / z calculated value 371.03, measured value 372.19 (M+1). + .

[0965] Step 4. Synthesis of benzyl benzoate (C71) 4-(5-(benzyloxy)-1-(4-fluorophenyl)-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indol-3-yl)benzoate

[0966] A solution of 4-benzyloxy-2-bromo-N-(4-fluorophenyl)aniline C70 (0.25 g, 0.66 mmol), benzyl 4-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzoate C69 (0.38 g, 1.05 mmol), and Pd[P(tBu)3]2 (0.017 g, 0.033 mmol) was evacuated and purged twice with nitrogen. A solution of 1,4-dioxane (4 mL) and N-cyclohexyl-N-methyl-cyclohexylamine (0.35 mL, 1.61 mmol) was bubbled with nitrogen for 2 min and then added to the reaction vial. The reaction vial was sealed and heated to 100 °C. After 1 hour, LC-MS showed complete consumption of the limited starting material. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40g ISCO column) using a 10-35% EtOAc / heptane gradient to give 355 mg of product: 4-[5-benzyloxy-1-(4-fluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoate (79%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.21–8.14 (m, 2H), 7.59–7.49 (m, 4H), 7.50–7.29 (m, 10H), 7.28–7.18 (m, 2H), 6.82 (dd, J = 8.8, 2.4Hz, 1H), 6.63–6.53 (m, 2H), 5.45 (s, 2H), 4.93 (s, 2H), 3.08 (s, 3H), 3.07 (s, 2H), 1.12 (s, 6H). ESI-MS m / z calculated value 613.26, measured value 614.37 (M+1). + .

[0967] Step 5. Synthesis of benzyl benzoate (164) of 4-(5-(benzyloxy)-1-(4-fluorophenyl)-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indol-3-yl)benzoate

[0968] A solution of 4-[5-benzyloxy-1-(4-fluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoate C71 (0.14 g, 0.21 mmol) in EtOAc (10 mL) was added to a slurry of Pd / C (0.06 g, 0.06 mmol) in EtOH (10 mL). The reaction vial was evacuated and backfilled with hydrogen three times, and then stirred at room temperature under hydrogen at 1 atm for 30 min. The reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated to dryness. The resulting material was ground with a 9:1 heptane:EtOAc mixture, filtered, and concentrated under vacuum to give 89 mg of product. 4-[1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid (85%). 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.96 (s, 1H), 8.67 (s, 1H), 8.02 (d, J = 8.2Hz, 3H), 7.61–7.36 (m, 7H), 6.53 (dd, J = 8.7, 2.3Hz, 1H), 6.37 (d, J = 8.7Hz, 1H), 6.26 (d, J = 2.3Hz, 1H), 3.01 (s, 3H), 2.99 (s, 4H), 1.05 (s, 7H). ESI-MS m / z calculated value 433.17, measured value 434.32 (M+1). + .

[0969] Compound 165

[0970] Synthesis of 4-(2-(1-cyano-2-methylprop-2-yl)-1-(4-fluorophenyl)-5-hydroxy-1H-indol-3-yl)benzoic acid (165)

[0971]

[0972] Step 1. Synthesis of methyl 4-(4-cyano-3,3-dimethylbut-1-yn-1-yl)benzoate (C72)

[0973] A solution of benzyl 4-iodobenzoate (15.00 g, 44.36 mmol), Pd(PPh3)2Cl2 (0.94 g, 1.33 mmol), and CuI (0.51 g, 2.66 mmol) in triethylamine (100 mL) and THF (100 mL) was purged with nitrogen for 5 min. 4-Methoxy-3,3-dimethyl-but-1-yne (7.22 g, 64.37 mmol) was added to the mixture. The reaction mixture was purged with nitrogen for 2 min. The flask was sealed and heated to 50 °C for 2 h. The mixture was filtered, and the solid was washed twice with EtOAc. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (330 g ISCO column) using a 0–50% EtOAc / heptane gradient to give 13 g of product: benzyl 4-(4-methoxy-3,3-dimethyl-but-1-yne)benzoate (79%). 1 ¹H NMR (300MHz, chloroform-d) δ 8.04–7.94 (m, 2H), 7.51–7.32 (m, 7H), 5.37 (s, 2H), 3.46 (q, 3H), 3.36 (q, 2H), 1.33 (s, 6H). ESI-MS m / z calculated 322.2, measured 323.1 (M+1). + .

[0974] Step 2. Synthesis of 2-bromo-N-(4-fluorophenyl)-4-methoxyaniline (C73)

[0975] At ambient temperature, 2-bromo-4-methoxyaniline (0.52 g, 2.57 mmol), (4-fluorophenyl)boronic acid (0.73 g, 5.18 mmol), copper(II) acetate (0.94 g, 5.15 mmol), and 4A sieve (0.47 g) were charged into a 50 mL round-bottom flask. Dichloromethane (15 mL) was added to the mixture, and the slurry was stirred in open air for 15 minutes. Triethylamine (0.89 mL, 6.39 mmol) was added dropwise at ambient temperature, and the resulting deep purple mixture was stirred in open air overnight. The mixture was filtered through a diatomaceous earth mat and washed with CH2Cl2. The filtrate was washed with water and brine. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (80 g ISCO column) using a 0–20% EtOAc / heptane gradient to give 543 mg of product. 2-Bromo-N-(4-fluorophenyl)-4-methoxyaniline (67%). 1¹H NMR (400 MHz, chloroform-d) δ 7.15 (d, J = 2.8 Hz, 1H), 7.13 (s, 1H), 7.03–6.96 (m, 4H), 6.82 (dd, J = 8.9, 2.8 Hz, 1H), 5.65 (s, 1H), 3.80 (s, 3H). ESI-MS m / z calculated value 295.01, measured value 296.12 (M+1). + .

[0976] Step 3. Synthesis of methyl 4-(2-(1-cyano-2-methylprop-2-yl)-1-(4-fluorophenyl)-5-methoxy-1H-indol-3-yl)benzoate (C74)

[0977] A vial containing methyl 4-(4-cyano-3,3-dimethyl-but-1-ynyl)benzoate C72 (0.31 g, 1.29 mmol), 2-bromo-N-(4-fluorophenyl)-4-methoxy-aniline C73 (0.25 g, 0.84 mmol), and Pd[P(tBu)3]2 (0.02 g, 0.05 mmol) was evacuated and purged with nitrogen (2x). A solution of 1,4-dioxane (5 mL) and N-cyclohexyl-N-methylcyclohexylamine (0.45 mL, 2.10 mmol) was added, and the reaction mixture was stirred at 90 °C for 17 h. LC-MS showed incomplete conversion to the product. The mixture was cooled to room temperature and purged with nitrogen. An additional 0.05 equivalent of Pd[P(tBu)3]2 (0.02 g, 0.04 mmol) and the mixture were heated to 90 °C for 21 h. The reactants were diluted with water and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (40 g ISCO column) using a 0-50% EtOAc / heptane gradient to give 155 mg of product: methyl 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-methoxy-indol-3-yl]benzoate (38%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.18 (d, J = 8.2Hz, 2H), 7.60 (d, J = 8.2Hz, 2H), 7.54–7.47 (m, 1H), 6.80 (dd, J = 8.9, 2.5Hz, 1H), 6.59 (d, J = 8.9Hz, 1H), 6.48 (d, J = 2.4Hz, 1H), 4.00 (s, 3H), 3.72 (s, 3H), 2.44 (s, 2H), 1.31 (s, 6H). ESI-MS m / z calculated value 456.18, measured value 457.36 (M+1). + .

[0978] Step 4. Methyl 4-(2-(1-cyano-2-methylprop-2-yl)-1-(4-fluorophenyl)-5-hydroxy-1H-indol-3-yl)benzoate (C75)

[0979] To a cold (0°C) solution of methyl 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-methoxy-indol-3-yl]benzoate C74 (0.093 g, 0.204 mmol) in dichloromethane (5.5 mL), tribromoborane (0.300 mL 1 M solution, 0.300 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The product (minor) and starting material (major) were then visualized by LC-MS. Additional tribromoborane (0.200 mL 1 M solution, 0.200 mmol) was added, and the reaction mixture was stirred again at room temperature for 1 hour. The reaction flask was cooled to 0°C and quenched with a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered through a phase separator, and concentrated under vacuum. The residue was purified by silica gel chromatography (40g ISCO column) using a 0-20% EtOAc / heptane gradient to give 42 mg of product: methyl 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-hydroxy-indol-3-yl]benzoate (35%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.19–8.13 (m, 2H), 7.61–7.55 (m, 2H), 7.53–7.46 (m, 2H), 7.33–7.29 (m, 2H), 6.72 (dd, J = 8.7, 2.5Hz, 1H), 6.55 (dd, J = 8.7, 0.6Hz, 1H), 6.46 (dd, J = 2.5, 0.6Hz, 1H), 4.49 (s, 1H), 4.00 (s, 3H), 2.44 (s, 2H), 1.31 (s, 6H). ESI-MS m / z calculated value 442.16928, measured value 443.23 (M+1). + .

[0980] Step 5. Synthesis of 4-(2-(1-cyano-2-methylpropyl-2-yl)-1-(4-fluorophenyl)-5-hydroxy-1H-indol-3-yl)benzoic acid (165)

[0981] Methyl 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-hydroxy-indole-3-yl]benzoate C75 (0.040 g, 0.069 mmol) was added to a solution of water (0.5 mL), THF (0.5 mL), and MeOH (1 mL) with lithium hydroxide ions (0.015 g, 0.626 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated and diluted in water, acidified with 6N HCl, and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, and concentrated under vacuum. The product was then ground with 9:1 heptane:ethyl acetate to give 10 mg of product. 4-[2-(2-cyano-1,1-dimethyl-ethyl)-1-(4-fluorophenyl)-5-hydroxy-indole-3-yl]benzoic acid (32%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.25–8.17 (m, 2H), 7.63–7.56 (m, 2H), 7.52–7.44 (m, 2H), 7.31–7.26 (m, 2H), 6.71 (dd, J = 8.7, 2.5Hz, 1H), 6.53 (d, J = 8.8Hz, 1H), 6.45 (d, J = 2.4Hz, 1H), 2.43 (s, 2H), 1.30 (s, 6H). ESI-MS m / z calculated value 428.15, measured value 429.28 (M+1). + .

[0982] Compound 166

[0983] Synthesis of 4-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)benzoic acid (166)

[0984]

[0985] Step 1. Synthesis of methyl 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)benzoate (C76)

[0986] Pd(dppf)Cl₂-CH₂Cl₂ (0.009 mg, 0.011 mmol) was added to a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-3-iodo-2-tetrahydropyran-4-yl-indole S₂₅ (0.062 g, 0.109 mmol), (4-methoxycarbonylphenyl)boronic acid (0.022 g, 0.122 mmol), and sodium carbonate (0.110 mL 2M solution, 0.220 mmol) in DMF (1 mL). The reaction mixture was heated to 100 °C and stirred overnight at this temperature. The mixture was diluted in EtOAc and water and filtered through diatomaceous earth. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water (2x) and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using a 0–35% EtOAc / heptane gradient to give 45 mg of product. Methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole-3-yl]benzoate (71%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.15 (d, J = 8.2Hz, 2H), 7.52 (d, J = 8.2Hz, 2H), 7.42 (d, J = 7.2Hz, 2H), 7.36 (t, J = 7.5Hz, 2H), 7.31 (d, J = 7.0Hz, 1H), 7.20 (dd, J = 13.7, 7.0Hz, 3H), 6.92 (d, J = 2.4Hz, 1H), 6.87–6.8 3 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 5.00 (s, 2H), 3.98 (s, 3H), 3.83 (d, J = 11.5 Hz, 2H), 3.20 (t, J = 11.4 Hz, 2H), 3.00 (d, J = 12.4 Hz, 1H), 2.39-2.34 (m, 3H), 1.79 (d, J = 13.0 Hz, 2H), 1.60 (d, J = 12.3 Hz, 2H). ESI-MS m / z calculated value: 549.23, measured value: 550.49 (M+1). + .

[0987] Step 2. Synthesis of methyl 4-(5-(benzyloxy)-1-(4-fluoro-3-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)benzoate (C77)

[0988] Methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]benzoate C76 (0.045 g, 0.078 mmol) was added to a solution of THF (1.6 mL) / methanol (1.6 mL) with LiOH (0.800 mL 1 M solution, 0.800 mmol). The reaction mixture was heated to 50 °C and stirred overnight at this temperature. The mixture was concentrated under reduced pressure. 1 mL of water was added and the mixture was acidified to pH 5 with 1 N HCl. The mixture was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered, and concentrated under vacuum to give 40 mg of product: 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]benzoic acid (95%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.20–8.14 (m, 2H), 7.52–7.46 (m, 2H), 7.37–7.33 (m, 2H), 7.32–7.25 (m, 2H), 7.26–7.19 (m, 1H), 7.17–7.10 (m, 3H), 6.87 (d, J = 2.3 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz). Hz, 1H), 6.71 (d, J = 8.8Hz, 1H), 4.94 (s, 2H), 3.86-3.77 (m, 2H), 3.72-3.66 (m, 1H), 3.22-3.11 (m, 2H), 2.99-2.87 (m, 1H), 2.33-2.26 (m, 3H), 1.83-1.70 (m, 3H), 1.60-1.48 (m, 2H). ESI-MS m / z calculated value: 535.22, measured value: 536.49 (M+1). + .

[0989] Step 3. Synthesis of 4-(1-(4-fluoro-3-methylphenyl)-5-hydroxy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)benzoic acid (166)

[0990] Dihydroxypalladium (0.002 g, 0.014 mmol) was added to a solution of 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-3-yl]benzoic acid C77 (0.040 g, 0.074 mmol) in MeOH (1 mL). The mixture was placed under a hydrogen atmosphere of 1 atmosphere and stirred for 1 hour. The mixture was filtered through a diatomaceous earth pad and then through a Floris silica pad. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (4 g ISCO column) using a 0-10% MeOH / CH2Cl2 gradient to give 28 mg of product: 4-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-tetrahydropyran-4-yl-indol-3-yl]benzoic acid (83%). 1 ¹H NMR (400MHz, methanol-d⁴) δ 8.16–8.06 (m, 2H), 7.53–7.44 (m, 2H), 7.31–7.17 (m, 3H), 6.78 (dd, J = 2.0, 1.0 Hz, 1H), 6.72–6.64 (m, 2H), 3.83 (d, J = 11.2 Hz, 2H), 3.29–3.19 (m, 2H), 3.07–2.96 (m, 1H), 2.42–2.34 (m, 3H), 1.89–1.75 (m, 2H), 1.69–1.57 (m, 2H). ESI-MS m / z calculated value 445.17, measured value 446.49 (M+1). + .

[0991] Compounds 167-176

[0992] Compounds 167-176 (Table 13) were prepared as described for the preparation of compound 166 by coupling appropriate boric acid with the relevant iodoindole intermediate via Suzuki.

[0993] Table 13. Structural and physicochemical data of compounds 167-176

[0994]

[0995]

[0996]

[0997]

[0998] 1. Suzuki coupling: Pd(dppf)Cl2-CH2Cl2, Na2CO3, H2O, DMF at 100℃.

[0999] 2. Hydrolysis conditions: LiOH, THF, MeOH, H2O

[1000] 3. Hydrogenation: H2, Pd(OH)2, MeOH

[1001] 4. Suzuki coupling: Pd(Ph3P)4, K2CO3, dioxane at 110℃

[1002] 5. BBr3, CH2Cl2, 0℃

[1003] 6. Hydrolysis conditions: NaOH, MeOH

[1004] 7. Hydrogenation: H2, Pd / C (charcoal) or H2, Pd / C, EtOAc

[1005] 8. Suzuki coupling: Pd(Ph3P)2Cl2, Na2CO3, H2O, DME at 80℃.

[1006] Compound 177

[1007] Synthesis of 4-(6-chloro-1-(4-fluorophenyl)-5-hydroxy-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indol-3-yl)benzoic acid (177)

[1008]

[1009] To a solution of 4-[1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid 164 (0.025 g, 0.058 mmol) in MeCN (1.25 mL), 1-chloropyrrolidine-2,5-dione (0.015 g, 0.112 mmol) was added. The reaction mixture was stirred at room temperature for 20 min and then at 45 °C for 1 h. The crude mixture was purified by direct loading onto a reversed-phase HPLC to give 3.3 mg of the product: 4-[6-chloro-1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid (12%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.23–8.17 (m, 2H), 7.62–7.56 (m, 2H), 7.49–7.42 (m, 2H), 7.29 (s, 6H), 6.67 (s, 1H), 6.63 (s, 1H), 3.09 (s, 3H), 3.07 (s, 2H), 1.14 (s, 6H).

[1010] Compound 178

[1011] Synthesis of 4-(4-chloro-1-(4-fluorophenyl)-5-hydroxy-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indol-3-yl)benzoic acid (178)

[1012]

[1013] Sodium hypochlorite (0.130 mL 5% w / v solution, 0.087 mmol) was added to a solution of 4-[1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid 164 (0.029 g, 0.067 mmol) in NaOH (1.0 mL 1 M solution, 1.0 mmol). After 1 minute, the reaction mixture was diluted with water (1 mL) and HCl (1.5 mL 1 M solution, 1.5 mmol). The mixture was extracted three times with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated under vacuum. The crude material was ground with a 9:1 heptane:EtOAc mixture and filtered to give 9.8 mg of the product as a grayish-white solid. 4-[4-chloro-1-(4-fluorophenyl)-5-hydroxy-2-(2-methoxy-1,1-dimethyl-ethyl)indol-3-yl]benzoic acid (29%). 1 ¹H NMR (400MHz, chloroform-d) δ 8.17–8.09 (m, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.49–7.41 (m, 2H), 7.29–7.22 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 3.11 (s, 3H), 2.99 (s, 2H), 1.08 (s, 7H). ESI-MS m / z calculated value 467.13, measured value 468.29 (M+1). + .

[1014] Compound 179

[1015] Synthesis of 4-(1-(4-fluorophenyl)-5-hydroxy-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indol-3-yl)benzoic acid (179)

[1016]

[1017] Step 1. Synthesis of 4-methoxy-3,3-dimethylbut-1-yne (C78)

[1018] DMF (13 mL, 167.9 mmol) was added to a cold (0 °C) solution of oxaloyl chloride (13.00 mL, 2 M, 26.00 mmol) in CH₂Cl₂. The suspension was stirred at 0 °C for 10 minutes. 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole S8 (5.00 g, 13.39 mmol) was added dropwise to CH₂Cl₂ (50 mL), and the mixture was stirred overnight at room temperature. The solution was alkalized with a saturated aqueous solution of NaHCO₃ and extracted three times with CH₂Cl₂. The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (80 g ISCO column) using a 0–60% EtOAc / heptane gradient to give 4.67 g of product: 5-Benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-carboxaldehyde (81%). 1 ¹H NMR (300MHz, chloroform-d) δ 10.42 (s, 1H), 7.95 (d, J = 2.5Hz, 1H), 7.47–7.37 (m, 2H), 7.40–7.21 (m, 3H), 7.18–6.99 (m, 3H), 6.83 (dd, J = 8.9, 2.5Hz, 1H), 6.69 (dd, J = 8.9, 0.5Hz, 1H), 5.09 (s, 2H), 3.09 (p, J = 7.2Hz, 1H), 2.30 (d, J = 2.0Hz, 3H), 1.38 (dd, J = 7.2, 2.1Hz, 6H). ESI-MS m / z calculated value 401.18, measured value 402.27 (M+1). + .

[1019] Step 2. Synthesis of 4-(4-methoxy-3,3-dimethylbut-1-yn-1-yl)benzoate (C79)

[1020] To a cold (-78°C) solution of methyl propionate (0.105 mL, 1.180 mmol) in THF (1 mL), add n-butyllithium (0.470 mL, 2.5 M, 1.175 mmol). Stir the reaction mixture for 30 min and add dropwise a solution of 5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole-3-carboxaldehyde C78 (0.335 g, 0.782 mmol) in THF (4 mL). Stir the mixture for 1 h and convert the -78°C bath to 0°C and stir for 1 h. Quench the reaction mixture with the addition of a saturated aqueous NH4Cl solution and extract with EtOAc. Dry the organic phase (MgSO4), filter, and concentrate under vacuum. Purify the residue by silica gel chromatography using a 0–30% EtOAc / heptane gradient to give 154 mg of product. 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-4-hydroxy-but-2-acetylacetic acid methyl ester (40%). 1 H NMR (400MHz, chloroform-d) δ7.56 (d, J = 2.3Hz, 1H), 7.52-7.48 (m, 2H), 7.41-7.36 (m, 2H) ),7.34-7.30(m,1H),7.18-7.05(m,3H),6.85(dd,J=8.9,2.4Hz,1H),6.77(dd,J =8.8,0.5Hz,1H),6.08(d,J=4.1Hz,1H),5.15(s,2H),3.77(d,J=1.4Hz,3H),3.0 7-3.00(m,1H),2.34(d,J=2.0Hz,3H),2.21(d,J=4.5Hz,1H),1.36-1.28(m,6H). ESI-MS calculated m / z value: 485.20; measured value: 486.01 (M+1) + .

[1021] Step 3. Synthesis of 4-(benzyloxy)-2-bromo-N-(4-fluorophenyl)aniline (C80)

[1022] Methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-4-hydroxy-but-2-acetylanate C79 (0.154 g, 0.310 mmol) was added to a solution of CH2Cl2 (2 mL) with Dys-Martin periodide (0.160 g, 0.377 mmol). The reaction mixture was stirred for 2 hours and 2-methyl-2-propanol (0.100 mL, 1.046 mmol) was added to accelerate the reaction. The mixture was then stirred overnight at room temperature. The residue was purified by silica gel chromatography (4 g ISCO column) using a 0-20% EtOAc / heptane gradient to give 10 mg of product: Methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-4-oxo-but-2-acetylanate (6%). 1 H NMR (400MHz, chloroform-d) δ8.09(d,J=2.4Hz,1H),7.49(d,J=7.7Hz,2H),7.39(t,J=7.4Hz,2H),7.33(d,J=7.2Hz,1H),7.20(t,J=8.7Hz,1H),7.14(t,J= 6.5Hz,2H),6.90(dd,J=8.7,2.5Hz,1H),6.72(d,J=8.9Hz,1H),5.18(s, 2H), 3.88 (s, 3H), 3.68-3.58 (m, 1H), 2.37 (s, 3H), 1.29 (d, J = 2.3Hz, 6H). ESI-MS m / z calculated value: 483.18; measured value: 484.05 (M+1) + .

[1023] Step 4. Synthesis of benzyl benzoate (C81) 4-(5-(benzyloxy)-1-(4-fluorophenyl)-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indol-3-yl)benzoate

[1024] Methyl 4-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-4-oxo-but-2-acetylacetic acid C90 (0.010 g, 0.019 mmol) was added to a solution of ethanol (0.5 mL) with hydrazine hydrate (0.005 mL, 0.102 mmol). The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (4 g ISCO column) using a 0-10% EtOAc / CH2Cl2 gradient to give 8 mg of product. Methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylate (78%). 1¹H NMR (400MHz, chloroform-d) δ 10.34 (s, 1H), 7.47–7.42 (m, 2H), 7.41–7.35 (m, 2H), 7.34–7.30 (m, 1H), 7.21–7.12 (m, 3H), 6.98 (d, J = 10.0 Hz, 2H), 6.89–6.76 (m, 2H), 5.04 (s, 2H), 4.00 (s, 3H), 3.15–3.06 (m, 1H), 2.36 (d, J = 2.0 Hz, 3H), 1.16 (dd, J = 7.1, 1.3 Hz, 6H). ESI-MS m / z calculated value 497.21, measured value 498.03 (M+1). + .

[1025] Step 5. Synthesis of benzyl benzoate (179) of 4-(5-(benzyloxy)-1-(4-fluorophenyl)-2-(1-methoxy-2-methylpropyl-2-yl)-1H-indol-3-yl)benzoate

[1026] Lithium hydroxide (0.300 mL 1M, 0.300 mmol) was added to a solution of methyl 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylic acid C81 (0.008 g, 0.015 mmol) in THF (0.3 mL) / methanol (0.3 mL). The reaction mixture was heated to 50 °C and stirred overnight. The mixture was acidified with 1N HCl and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give 5 mg of product: 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylic acid (68%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.44 (d, J = 7.4Hz, 2H), 7.35 (t, J = 7.4Hz, 2H), 7.29 (d, J = 7.2Hz, 1H), 7.23–7.14 (m, 3H), 7.04–7.00 (m, 2H), 6.88 (dd, J = 8.9, 2.3Hz, 1H), 6.81 (d, J = 8.8Hz, 1H), 5.06 (s, 2H), 3.17–3.08 (m, 1H), 2.37 (d, J = 1.9Hz, 3H), 1.17 (d, J = 7.1Hz, 6H). ESI-MS m / z calculated value 483.2, measured value 484.2 (M+1). + .

[1027] A mixture of 3-[5-benzyloxy-1-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylic acid (0.005 g, 0.010 mmol) and dihydroxypalladium (0.001 g, 0.007 mmol) in methanol (0.5 mL) was stirred for 1 hour under a hydrogen atmosphere. The crude mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated under vacuum to give 3.9 mg of product. 3-[1-(4-fluoro-3-methyl-phenyl)-5-hydroxy-2-isopropyl-indol-3-yl]-1H-pyrazole-5-carboxylic acid (96%). 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.32–7.16 (m, 3H), 6.84 (s, 1H), 6.72 (d, J = 2.2 Hz, 1H), 6.70–6.58 (m, 2H), 4.12 (d, J = 12.2 Hz, 1H), 3.12–3.04 (m, 1H), 2.36 (d, J = 1.9 Hz, 3H), 1.15 (d, J = 7.1 Hz, 6H). ESI-MS m / z calculated value 393.15, measured value 394.07 (M+1). + .

[1028] Preparation of 180 [10...

Claims

1. A compound selected from: Its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

2. A pharmaceutical composition comprising at least one compound according to claim 1, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt.

3. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 in the preparation of a medicament for treating α-1 antitrypsin deficiency in patients in need.

4. Use of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 in the preparation of a medicament for modulating the activity of α-1 antitrypsin (AAT) in patients in need.

5. The use according to claim 3 or claim 4, wherein the at least one compound, tautomer, deuterated derivative or pharmaceutically acceptable salt is administered in combination with AAT intensification therapy and / or AAT replacement therapy.

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