Indole derivatives as alpha-1 antitrypsin modulators for the treatment of alpha-1 antitrypsin deficiency (AATD)

Abstract

This article discloses indole derivatives as modulators of α-1 antitrypsin deficiency (AATD) for the treatment of α-1 antitrypsin deficiency.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 004,717, 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)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe)) that can be used to treat 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:

[0009]

[0010] in:

[0011] For each of the two cases, it is either a single bond or a double bond, provided that one is a single bond and the other is a double bond;

[0012] V 1 and V 2 Each is independently N or -CR 2 ;

[0013] W 1 and W 2 Each is independently either N or C, provided that W is... 1 and W 2 One of them is N, and the other is C;

[0014] U can be hydrogen, -OH, -CH3, -NH2, or a halogen;

[0015] X does not exist or is a key, -(CR) a R b ) p -or -SO2-;

[0016] Y does not exist or is a key, -(CR) c R d ) q -, -C(=O)- or -SO2-;

[0017] R a and R bEach of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0018] R c and R d Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0019] Ring A is C3-C 12 Carbocyclic group, 3 to 12-membered heterocyclic group, C6 or C 10 aryl or 5 to 10-membered heteroaryl; condition is when W 1 For N and W 2 When it is C, ring A is not 1,5,6,7-tetrahydro-4H-indole-4-one or its tautomer;

[0020] Ring B is C4-C 12 cycloalkyl, C6 or C 10 aryl, 5- to 10-membered heteroaryl or benzyl;

[0021] Z is in

[0022] Ring C is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, C6 or C6 10 Aryl or 5 to 10-membered heteroaryl;

[0023] The condition is that when ring C is phenyl, the phenyl is reacted with R. 4 Substitution; the condition is that when ring C is phenyl, Y cannot be -SO2-; and

[0024] The condition is that when ring B is benzyl, ring C cannot be pyridyl or indole;

[0025] R E R F and R G Each is independently hydrogen, halogen, cyano, C1-C6 alkyl, C 2- C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)R s -C(=O)OR s -C(=O)NR p R q -CR p (=N)OR s -NR p C(=O)R s -NR pC(=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:

[0026] R E R F and R G The C1-C6 alkyl or the C2-C6 alkenyl group of either group is optionally substituted by one to three groups selected from the following: 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 ;in:

[0027] 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:

[0028] R p R q and R r The C1-C4 alkyl group of any one thereof 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

[0029] Rp R q and R r The C3-C6 cycloalkyl group or the 3- to 6-membered heterocyclic group of any one thereof is optionally substituted by 1 to 3 groups selected from the following groups: 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;

[0030] 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:

[0031] R s The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0032] R s The C3-C6 cycloalkyl, the phenyl, or the 5- or 6-membered heteroaryl group is optionally substituted by 1 to 3 groups selected from the following: 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;

[0033] R 1 It can be halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or -O- (C3-C6 cycloalkyl);

[0034] 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, phenyl, or 5 or 6-membered heteroaryl; wherein:

[0035] R 2The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl may optionally be substituted with one to three groups selected from the following: 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 i ;in:

[0036] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0037] R h R i and R j The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0038] R h R i and R jThe C3-C6 cycloalkyl group of any one thereof is optionally substituted with 1 to 3 groups selected from the following: 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;

[0039] 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:

[0040] -OR k It cannot be -OH; R k The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0041] R k The C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from the following: 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;

[0042] 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 vS(=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:

[0043] R 3 and R 4 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl of any of them is optionally substituted by one to three groups selected from the following: 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 Rw -S (=O) t R y and -S (=O) t NR v R w ;in:

[0044] 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:

[0045] R v R w and R x The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0046] R v R w and R x The C3-C6 cycloalkyl group, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group of any of them is optionally substituted by 1 to 3 groups selected from the following: 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;

[0047] 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

[0048] R yThe C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0049] R y The C3-C6 cycloalkyl, the phenyl, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group are optionally substituted by 1 to 3 groups selected from the following: 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;

[0050] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0051] k is an integer selected from 1, 2, and 3;

[0052] m and n are each an independent integer selected from 0, 1, 2 and 3;

[0053] p, r, s, and t are each an independent integer selected from 1 and 2; and

[0054] q is an integer selected from 1, 2, and 3.

[0055] In some embodiments, U is -OH, -CH3, -NH2, or a halogen in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, and all other variables are as defined with respect to formula (I).

[0056] In some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently integers selected from 1 and 2, and all other variables are as defined for formula (I).

[0057] In some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, U is -OH, -CH3, -NH2 or a halogen, p, q, r, s and t are each independently an integer selected from 1 and 2, and all other variables are as defined for formula (I).

[0058] Compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe)) are modulators of AAT activity. In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 2.0 μM or less. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 .

[0059] In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 the Z-AAT elastase activity assay, have an IC50 of 5.0 μM or less. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 the Z-AAT elastase activity assay, have an IC50 of less than 2.0 μM. 50 .

[0060] In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 2.0 μM or less. 50Furthermore, it exhibits an IC50 of 5.0 μM or less when tested in the Z-AAT elastase activity assay. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 5.0 μM or less when tested in the Z-AAT elastase activity assay. 50 In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 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. 50In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 .

[0061] In some embodiments, compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe)) 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 for the treatment of AATD. In some embodiments, the compound is selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, such as compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., tautomers of compounds 1-457), deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, and is used to treat AATD. In one aspect, the compound of formula (I) is selected from compounds 1-142, 144-177, 179-399, 401-422, 425-433 and 435-457, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, and is used to treat AATD.

[0062] In some embodiments, this disclosure provides pharmaceutical compositions comprising at least one compound selected from formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), 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. These compositions may further comprise at least one additional active pharmaceutical ingredient. These compositions may further comprise at least one carrier. These compositions may further comprise at least one additional active pharmaceutical ingredient and at least one carrier. These compositions may further comprise at least one additional active pharmaceutical ingredient or at least one carrier.

[0063] In some embodiments, this disclosure provides pharmaceutical compositions comprising at least one compound selected from formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), (Xa)-(Xf), (XIa)-(Xe), and (XIIa)-(XIIe) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W32 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may also comprise at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0064] Another aspect of this disclosure provides a method for treating AATD, comprising administering to a subject in need at least one compound selected from formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formula (I), (IIa)-(IIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe))), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method includes administering a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, such as compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the subject requiring treatment carries a ZZ mutation. In some embodiments, the subject requiring treatment carries an SZ mutation.

[0065] In some embodiments, the treatment method comprises administering at least one additional active agent to a subject in need of a compound selected from formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in the form of the same pharmaceutical composition or as a separate composition. In some embodiments, the method includes administering, either as the same pharmaceutical composition or as a single composition, a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, such as compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, along with at least one additional active agent. In some embodiments, the subject requiring treatment carries a ZZ mutation. In some embodiments, the subject requiring treatment carries an SZ mutation.

[0066] In some embodiments, the treatment method comprises administering at least one additional active agent to a subject in need of a compound selected from formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in the form of the same pharmaceutical composition or as a separate composition, wherein the additional active agent is α-1 antitrypsin protein (AAT) derived from plasma of a healthy human donor. In some embodiments, the method includes administering, either as the same pharmaceutical composition or as a single composition, a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, such as compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, with at least one additional active agent, wherein the additional active agent is α-1 antitrypsin protein (AAT) derived from healthy human donor plasma.

[0067] In some embodiments, the treatment method comprises administering at least one additional active agent to a subject in need of a compound selected from formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in the form of the same pharmaceutical composition or as a separate composition, wherein the additional active agent is recombinant AAT. In some embodiments, the method includes administering, either as the same pharmaceutical composition or as a single composition, a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, with at least one additional active agent, wherein the additional active agent is recombinant AAT.

[0068] A method for modulating AAT is also provided, comprising administering to a subject in need at least one compound selected from formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formula (I), (IIa)-(IIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe))), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method of regulating AAT includes administering at least one compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts.

[0069] One aspect of this disclosure provides compounds B1-B25 and compounds W1-W32 that can be used to treat 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.

[0070] In some embodiments, this disclosure provides pharmaceutical compositions comprising at least one compound selected from formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and W1-W32), 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.

[0071] 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 (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and compounds W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0072] In some embodiments, the treatment method comprises administering, to a subject in need, either as a pharmaceutical composition or as a single composition, at least one additional active agent and at least one compound selected from formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and compounds W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the subject in need of treatment carries a ZZ mutation. In some embodiments, the subject in need of treatment carries an SZ mutation.

[0073] In some embodiments, the treatment method includes administering at least one additional active agent to a subject in need, either as a pharmaceutical composition or as a separate composition, to at least one compound selected from (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein the additional active agent is α-1 antitrypsin protein (AAT) derived from plasma from a healthy human donor.

[0074] In some embodiments, the treatment method includes administering at least one additional active agent to a subject in need, either as a pharmaceutical composition or as a separate composition, to at least one compound selected from (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein the additional active agent is recombinant AAT.

[0075] Methods for modulating AAT are also provided, comprising administering to a subject in need at least one compound selected from (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and compounds W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or a pharmaceutical composition comprising at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0076] Also provided are at least one compound selected from formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe)) for therapeutic purposes, 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 1-457, compounds 458-531, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided for use in a therapeutic manner.

[0077] Also provided are pharmaceutical compositions for therapeutic purposes, said pharmaceutical compositions comprising at least one compound selected from formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 therapy is provided comprising a compound selected from compounds 1-457, compounds 458-531, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0078] Compounds of formulas (XIa)-(XIe) and (XIIa)-(XIIe) for therapeutic use (e.g., compounds B1-B25 and compounds W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are also provided. In some embodiments, compounds selected from compounds B1-B25 and compounds W1-W32, 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.

[0079] A pharmaceutical composition for therapeutic use is also provided, the pharmaceutical composition comprising compounds of formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and compounds W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition for therapeutic use is provided comprising compounds selected from compounds B1-B25 and compounds W1-W32, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0080] I. Definition

[0081] As used herein, the term “AAT” refers to α-1 antitrypsin or a mutation thereof, including but not limited to mutations in the AAT gene, such as the Z mutation. As used herein, “Z-AAT” refers to an AAT mutant with a Z mutation.

[0082] 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.

[0083] As used in this article, patients with a specific gene mutation who are "homozygous" have the same mutation on each allele.

[0084] As used in this article, patients with the PiZZ genotype are those who are homozygous for the Z mutation in the AAT protein.

[0085] As used in this article, the term “AATD” refers to α-1 antitrypsin deficiency, a genetic condition characterized by low circulating levels of AAT.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] "Stereoisomers" refers to both enantiomers and diastereomers.

[0092] 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.

[0093] 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.

[0094] As used herein, the term "alkyl" means a straight-chain (i.e., straight-chain or unbranched) or branched hydrocarbon chain that is fully saturated. 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.

[0095] As used herein, the term "alkenyl" refers to a straight-chain (i.e., straight-chain or unbranched) or branched hydrocarbon chain containing one or more carbon-carbon double bonds.

[0096] The terms "cycloalkyl", "cyclic alkyl", "carbocyclic", and "carbocyclic" refer to fused, spirocyclic, or bridged monocyclic C-rings. 3-9 Hydrocarbons or fused, spirocyclic or bridged bicyclic or tricyclic C 8-14Hydrocarbons that are fully saturated or contain one or more unsaturated units, but are not fully aromatic, wherein any single ring in the bicyclic system has 3-9 members. Typically, cycloalkyl groups are fully saturated, while carbocyclic groups may contain one or more unsaturated units, but are not aromatic. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 12 carbon atoms. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 8 carbon atoms. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 6 carbon atoms.

[0097] As used herein, the terms "heterocycle," "heterocyclic group," or "heterocyclic" refer to a non-aromatic monocyclic system or a fused, spirocyclic, or bridged non-aromatic bicyclic or tricyclic system, wherein 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, or 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.

[0098] 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).

[0099] 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.

[0100] 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.

[0101] As used in this article, “=O” refers to an oxo group.

[0102] As used in this article, the "cyano" or "nitrile" group refers to -C≡N.

[0103] As used in this article, "hydroxyl group" refers to -OH.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] Examples of useful protecting groups containing nitrogen-containing groups such as amines include, for example, tert-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylamine, and p-toluenesulfonamide. Methods for adding (commonly referred to as “protection”) and removing (commonly referred to as “deprotection”) such amine protecting groups are well known in the art and can be found, for example, in PJ Kocienski, Protecting Groups, Thieme, 1994, which is incorporated herein by reference in its entirety, and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition (John Wiley & Sons, New York, 1999).

[0108] Examples of suitable solvents that can be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or “dichloromethane” (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).

[0109] 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).

[0110] This disclosure includes pharmaceutically acceptable salts of the compounds disclosed herein. The 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.

[0111] 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.

[0112] 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.

[0113] Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1-4 Alkyl)4 salts. This disclosure also contemplates quaternization of any basic nitrogen-containing group in the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Other non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0114] The terms “patient” and “subject” are used interchangeably and refer to animals including humans.

[0115] 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., improvement of AATD or AATD symptoms, reduction of the severity of AATD or AATD symptoms, and / or reduction of 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).

[0116] 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.

[0117] 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.

[0118] Compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered once daily, twice daily, or three times daily for the treatment of AATD. In some embodiments, any one or more compounds are selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, such as compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), 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)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), 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)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily. In some embodiments, a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), 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)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily. In some embodiments, a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), 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.

[0119] Compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and 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 AATTD. In some embodiments, any one or more compounds are selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30 and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433 and 435-457), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0120] Compounds B1-B25 and W1-W32, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered once daily, twice daily, or three times daily for the treatment of AATD. In some embodiments, at least one compound selected from formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, at least one compound selected from formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily. In some embodiments, at least one compound selected from formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and compounds W1-W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily.

[0121] Compounds B1-B25 and W1-W32, 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 AATTD.

[0122] 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.

[0123] In some embodiments, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, 400 mg to 2,500 mg, or 400 mg to 600 mg of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 2000 mg, or 400 mg to 600 mg of a compound selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) are administered once daily, twice daily, or three times daily.

[0124] 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 selected from formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and compounds W1-W32), 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 compounds selected from formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and compounds W1-W32) are administered once, twice, or three times daily.

[0125] 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).

[0126] As used in this article, the term "environmental conditions" refers to room temperature, outdoor conditions, and uncontrolled humidity conditions.

[0127] It should be understood that the use of one or more compounds (e.g., compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) mentioned herein, or compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(I) are also referred to herein. The treatment methods (e.g., methods for treating AATD) of one or more compounds (e.g., compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe) and (Xa)-(Xf) (e.g., compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe) and (Xa)-(Xf)) (e.g., compounds of formula (I), (IIa)-(IIg), (IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe) and (Xa)-(Xf)) (IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe) and (IXa)-(IXe), and tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, in methods of treating, for example, AATD; and / or one or more compounds (e.g., of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (IIf), (IIIa)-(IIg), (IVa)-(IVb), (Va)-(Vc), (IIf), (IIIa)-(IIg), (IVa)-(IVb), (Va)-(Vc), (IIf), (IIIa)-(IIg), (IVa)-(IVb), (Va)-(Vc), (IIf), (IIIa)-(IIg), (IVa)-(IVb), (Va)-(Vc), (IIf), (IIIa)-(IIg), (IVa)-(IVb), (Va)-(Vc), (IIf), (IIIa)-(IIg), (IVa)-(IVb), (Va)-(Vc), (IIf), (II ... Use of compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) in the manufacture of a medicament for treating, for example, AATD.

[0128] Example implementation plan 1:

[0129] The non-restrictive embodiments disclosed herein include:

[0130] 1. A compound represented by the following structural formula:

[0131]

[0132] Its tautomer, the deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein:

[0133] For each of the two cases, it is either a single bond or a double bond, provided that one is a single bond and the other is a double bond;

[0134] V 1 and V 2 Each is independently N or -CR 2 ;

[0135] W 1 and W 2 Each is independently either N or C, provided that W is... 1 and W 2 One of them is N, and the other is C;

[0136] U is -OH, -CH3, -NH2 or a halogen;

[0137] X does not exist or is a key, -(CR) a R b ) p -or -SO2-;

[0138] Y does not exist or is a key, -(CR) c R d ) q -, -C(=O)- or -SO2-;

[0139] R a and R b Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0140] R c and R d Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0141] Ring A is C3-C 12 Carbocyclic group, 3 to 12-membered heterocyclic group, C6 or C 10 aryl or 5 to 10-membered heteroaryl; condition is when W 1 For N and W 2When it is C, ring A is not 1,5,6,7-tetrahydro-4H-indole-4-one or its tautomer;

[0142] Ring B is C4-C 12 cycloalkyl, C6 or C 10 aryl, 5- to 10-membered heteroaryl or benzyl;

[0143] Z is in

[0144] Ring C is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, C6 is C 10 Aryl or 5 to 10-membered heteroaryl;

[0145] The condition is that when ring C is phenyl, the phenyl is reacted with R. 4 Substitution; the condition is that when ring C is phenyl, Y cannot be -SO2-; and

[0146] The condition is that when ring B is benzyl, ring C cannot be pyridyl or indole;

[0147] 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 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:

[0148] R E R F and R G The C1-C6 alkyl or the C2-C6 alkenyl group of either group is optionally substituted by one to three groups selected from the following: cyano, -C(=O)R s -C(=O)OR s -C(=O)NRp 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 ;in:

[0149] 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:

[0150] R p R q and R r The C1-C4 alkyl group of any one thereof 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

[0151] R p R q and R r The C3-C6 cycloalkyl group or the 3- to 6-membered heterocyclic group of any one thereof is optionally substituted by 1 to 3 groups selected from the following groups: 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;

[0152] 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:

[0153] R sThe C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0154] R s The C3-C6 cycloalkyl, the phenyl, or the 5 or 6 heteroaryl group is optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, -OH, -OCH3, -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 1 It can be halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or -O- (C3-C6 cycloalkyl);

[0156] 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:

[0157] R 2 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl may optionally be substituted with one to three groups selected from the following: 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 i ;in:

[0158] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0159] R h R i and R j The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0160] R h R i and R j The C3-C6 cycloalkyl group of any one thereof is optionally substituted with 1 to 3 groups selected from the following: 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;

[0161] 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:

[0162] -OR k It cannot be -OH;

[0163] R kThe C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0164] R k The C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from the following: 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;

[0165] 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:

[0166] R 3 and R 4 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl of any of them is optionally substituted by one to three groups selected from the following: 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 ;in

[0167] 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:

[0168] R v R w and R xThe C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0169] R v R w and R x The C3-C6 cycloalkyl group, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group of any of them is optionally substituted by 1 to 3 groups selected from the following: 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;

[0170] 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

[0171] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0172] R yThe C3-C6 cycloalkyl, the phenyl, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group are optionally substituted by 1 to 3 groups selected from the following: 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;

[0173] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0174] k is an integer selected from 1, 2, and 3;

[0175] m and n are each independently an integer selected from 0, 1, 2, and 3; and

[0176] p, q, r, s, and t are each an integer selected from 1 and 2.

[0177] 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1, is represented by one of the following structural formulas:

[0178]

[0179] in:

[0180] U is -OH, -CH3, -NH2, F, or Cl;

[0181] Furthermore, all other variables not specifically defined herein are defined as in Implementation Scheme 1.

[0182] 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1, represented by one of the following structural formulas:

[0183]

[0184] in:

[0185] U is -OH, -CH3, -NH2, F, or Cl;

[0186] Furthermore, all other variables not specifically defined herein are defined as in Implementation Scheme 1.

[0187] 4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1 or Embodiment 2, represented by one of the following structural formulas:

[0188]

[0189] in:

[0190] U is -OH or -NH2;

[0191] Ring A can be arbitrarily assigned to R 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group, a phenyl group, or a 5- to 9-membered heteroaryl group;

[0192] Ring B was R 1 Substitution and ring B is C4-C6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or benzyl; and

[0193] When Z is arbitrarily assigned to R 4 When the ring C is substituted, the ring C is a C4-C8 cycloalkyl, a 4- to 8-membered heterocyclic group, a phenyl, or a 5- or 6-membered heteroaryl group;

[0194] Furthermore, all other variables not specifically defined herein are defined as in Implementation Scheme 1 or Implementation Scheme 2.

[0195] 5. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1, 2, and 4, represented by one of the following structural formulas:

[0196]

[0197] in:

[0198] Ring B was R 1 The substitution is performed, and ring B is cyclohexyl, phenyl, pyridyl, or benzyl; and all other variables not specifically defined herein are defined as in any of embodiments 1, 2, and 4.

[0199] 6. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1, 2, 4, and 5, represented by the following structural formula:

[0200]

[0201] in:

[0202] R 1 It is a halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy group; and

[0203] k is an integer selected from 1 and 2;

[0204] Furthermore, all other variables not specifically defined herein are defined as in any of the implementation schemes 1, 2, 4, and 5.

[0205] 7. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 6, wherein R 1 It is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3 or -OCH(CH3)2; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0206] 8. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 7, wherein at least one R 1 Let F be the variable; and all other variables not specifically defined herein shall be defined as in any of the foregoing implementation schemes.

[0207] 9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 8, wherein:

[0208] X does not exist or is a key, -(CR) a R b - or -SO2-;

[0209] R a and R b Each of these variables, when it appears, is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0210] 10. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 9, wherein X is absent or is a bond, -CH2-, or -SO2-; and wherein all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0211] 11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 10, wherein:

[0212] Y does not exist or is a key, -(CR) c R d ) q -, -C(=O)- or -SO2-;

[0213] R c and R d Each of these variables, when it appears, is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0214] 12. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 11, wherein Y is absent or is a bond, -CH2-, -CHCH3-, -C(CH3)2-, -C(=O)-, or -SO2-; and wherein all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0215] 13. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 12, wherein ring A is optionally converted by R 3 The ring A is substituted with a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group containing 1 to 3 oxygen atoms, a phenyl group, or a 5- to 9-membered heteroaryl group containing 1 to 3 heteroatoms selected from O and N; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0216] 14. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 13, wherein ring A is optionally converted by R. 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group containing one or two oxygen atoms, a phenyl group, or a 5- to 9-membered heteroaryl group containing one or two nitrogen atoms or one or two oxygen atoms; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0217] 15. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 14, wherein ring A is optionally converted by R. 3 Replacement, and ring A is selected from

[0218] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0219] 16. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 15, wherein ring A is optionally converted by R 3 Replacement, and ring A is selected from

[0220] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0221] 17. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 16, wherein Z is a ring C, and the ring C is optionally replaced by R. 4Substituted and having a C4-C8 cycloalkyl ring; a 4- to 8-membered heterocyclic group containing one or two heteroatoms selected from O, N, and S; phenyl; or a 5-membered heteroaryl group containing one or two heteroatoms selected from O and N;

[0222] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0223] 18. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 17, wherein Z is a ring C, and the ring C is optionally replaced by R. 4 Replacement, and ring C is selected from

[0224] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0225] 19. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 18, wherein Z is a ring C, and the ring C is optionally (R 4 ) o Replacement, and ring C is selected from

[0226] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0227] 20. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 19, wherein R E R F and R G Each can be independently hydrogen, halogen, cyano (-C≡N), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -C(=O)OR. s -C(=O)NR p R q -CR p (=N)OR s or -OR s ;in:

[0228] R E R F and R G The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: cyano, -C(=O)R s -C(=O)OR s -C(=O)NR p R q -ORs -OC(=O)R s -OC(=O)OR s -OC(=O)NR p R q and -S(=O)2R s ;in:

[0229] R p and R q Each of these groups is independently hydrogen, C1-C2 alkyl, C3-C5 cycloalkyl, or a 5- or 6-membered heterocyclic group; wherein:

[0230] R p and R q The C1-C2 alkyl group of any one of them is optionally substituted by one to three groups selected from the following: halogen, cyano and -OH;

[0231] R p and R q The C3-C5 cycloalkyl group or the 5- or 6-membered heteroaryl group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano and -OH;

[0232] R s Each time it appears, it is independently hydrogen, C1-C2 alkyl, or 5 or 6-membered heteroaryl; wherein R s The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH and -NH2; wherein:

[0233] R s The 5 or 6 heteroaryl group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano, -OH and -NH2;

[0234] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0235] 21. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 20, wherein R E R F and R G Each of these can be independently hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, or -C(=O)NR. p R q -CR p (=N)OR s or -OR s ;in:

[0236] R E R F and R GThe C1-C2 alkyl group of any one thereof is optionally substituted by one to three groups selected from the following: cyano, -C(=O)NR p R q -OR s -OC(=O)NR p R q and -S(=O)2R s ;in:

[0237] R p and R q Each of these components, when appearing independently, is hydrogen, C1-C2 alkyl, cyclopentyl, or tetrahydrofuranyl; wherein:

[0238] R p and R q The C1-C2 alkyl group of any one of them is optionally substituted with 1 to 3 halogen groups selected from F and Cl;

[0239] R s Each occurrence is independently hydrogen, C1-C2 alkyl, pyridyl, or pyrimidinyl; wherein:

[0240] R s The C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups selected from F and Cl;

[0241] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0242] 22. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 21, wherein R E R F and R GEach of these can be independently represented as hydrogen, F, -OH, -CH(OH)CH3, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CF3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -C2H5, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -(CH2)2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(C H2)2S(=O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH (cyclopentyl), -CH2(O)C(=O)NH (tetrahydrofuranyl), -CH2(O) (pyridin-2-yl) or -CH2(O) (pyrimidin-2-yl); and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0243] 23. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 22, wherein R E R F and R G Each is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, or -CH2OCH3; and

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

[0245] 24. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 23, represented by one of the following structural formulas:

[0246]

[0247]

[0248] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0249] 25. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 24, represented by one of the following structural formulas:

[0250]

[0251]

[0252] 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.

[0253] 26. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 25, represented by one of the following structural formulas:

[0254]

[0255]

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

[0257] 27. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 26, represented by one of the following structural formulas:

[0258]

[0259]

[0260] 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.

[0261] 28. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 27, wherein R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), C1-C6 alkoxy, C1-C6 haloalkyl, -NR h R i Or C3-C6 cycloalkyl; wherein R h and R i Each of these variables is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0262] 29. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 28, wherein R 2Each time it appears, it is independently hydrogen, halogen, cyano, C1-C4 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), C1-C4 alkoxy, C1-C4 haloalkyl, -NR h R i Or C3-C5 cycloalkyl; wherein R h and R i Each of these variables is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0263] 30. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 29, wherein R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), C1-C2 haloalkyl, -NR h R i Or C3-C4 cycloalkyl; wherein R h and R i Each time it appears, it is independently either hydrogen or -CH3;

[0264] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0265] 31. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 30, wherein R 2 Each occurrence is independently hydrogen, F, Cl, cyano, -CH3, -CHF2, -CF3, -NH2, or cyclopropyl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0266] 32. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 31, wherein R 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or -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)2R y -NR v Rw -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y or -P(=O)R z R z ;in:

[0267] R 3 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)OR y and -NR v R w ;in:

[0268] R v R w and R x Each of these components is independently hydrogen or a C1-C2 alkyl group; wherein R v R w and R x The C1-C2 alkyl group of any one thereof is optionally substituted with one to three groups selected from the group consisting of halogen, cyano, -OH, and -NH2; and

[0269] R y Each occurrence is independently hydrogen, C1-C4 alkyl, or a 5- or 6-membered heterocyclic group; wherein:

[0270] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -NH2 and -C(=O)OH; and

[0271] R y The 5- or 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -NH2 and -C(=O)OH;

[0272] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0273] 33. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 32, wherein R 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -C(=O)R. y -C(=O)OR y -C(=O)NRv R w -C(=O)NR v OR y -C(=O)NR v S(=O)2R y -NR v R w -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y or -P(=O)R z R z ;in:

[0274] R 3 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y and -C(=O)OR y ;in:

[0275] R v R w and R x Each of these components is independently hydrogen or a C1-C4 alkyl group; wherein R v R w and R x The C1-C4 alkyl group in any of them is optionally substituted with -OH; and

[0276] R y Each occurrence is independently hydrogen, C1-C2 alkyl, or a 6-membered heterocyclic group; wherein:

[0277] R y The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: -OH and -C(=O)OH; and

[0278] R y The 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OH and -C(=O)OH;

[0279] R z Each time it appears, it is independently -CH3, -OH, or -OCH3;

[0280] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0281] 34. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, wherein R3 Each time it appears, it is independently a halogen, cyano, =O, C1-C2 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, or -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)2R y -NR v R w -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y or -P(=O)R z R z ;in:

[0282] R 3 The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following: -OH and -C(=O)OR y ;in:

[0283] R v R w and R x Each of these components is independently hydrogen or a C1-C2 alkyl group; wherein R v R w and R x The C1-C2 alkyl group in any of them is optionally substituted with -OH; and

[0284] R y Each time it appears, it is independently hydrogen, C1-C2 alkyl, or tetrahydro-2H-pyranyl; wherein:

[0285] R y The C1-C2 alkyl group is optionally substituted with -C(=O)OH; and

[0286] R y The tetrahydro-2H-pyranyl group is optionally substituted by one to three groups selected from the following: -OH and -C(=O)OH;

[0287] R z Each time it appears, it is independently -CH3 or -OH;

[0288] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0289] 35. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, wherein R 3 Each time it appears, it is independently F, Cl, cyano, -OH, =O, -CH3, -OCH3, -CF3, -CH3CN, -C(CH3)2CH2OH, -CH2COOH, -CH2OCH3, -C(=O)CHCH3OH, -COOH, -C(=O)O(2-tetrahydro-2H-pyranyl), -C(=O)NH2, -C(=O)NH(CH2)2OH, -C(=O)NHOH, -C(=O)NHS(=O)2CH3, -NH2. -NHCH3, -OCH2COOH, NHS(=O)2CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHC(=O)CH3 or -P(=O)(CH3)2; wherein the 2-tetrahydro-2H-pyranyl group in -C(=O)O(2-tetrahydro-2H-pyranyl) is substituted by 1 to 3 groups selected from -OH and -C(=O)OH; and wherein all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0290] 36. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 35, wherein R 4 Each time it appears, it is independently a halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or -C(=O)R. y -C(=O)OR y -OR y or -S(=O)2R y ;in:

[0291] R 4 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)OR y and -NR v R w ;in:

[0292] R v and R w Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0293] R y Each occurrence is independently of hydrogen and C1-C4 alkyl; wherein:

[0294] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -OCH3 and -NH2;

[0295] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0296] 37. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 36, wherein R 4 Each time it appears, it is independently a halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -C(=O)R. y -C(=O)OR y -OR y or -S(=O)2R y ;in:

[0297] R 4 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)OR y and -NR v R w ;in:

[0298] R v and R w Each of them is independently hydrogen or C1-C4 alkyl;

[0299] R y Each occurrence is independently hydrogen or C1-C2 alkyl; wherein:

[0300] R y The C1-C2 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following groups: halogen, cyano, -OH, -OCH3, and -NH2; and

[0301] Where o is an integer selected from 0, 1, and 2; and

[0302] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0303] 38. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 37, wherein R 4 Each time it appears, it is independently cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, or -C(=O)R. y -C(=O)OR y-OR y or -S(=O)2R y ;in:

[0304] R 4 The C1-C2 alkyl group is optionally substituted with a cyano group, -OH or -OCH3;

[0305] R y Each occurrence is independently hydrogen or C1-C2 alkyl; wherein:

[0306] R y The C1-C2 alkyl group is optionally substituted with -OCH3;

[0307] Where o is an integer selected from 0 and 1;

[0308] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0309] 39. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 38, wherein R 4 Each time it appears, it is independently a cyano group, -OH, -OCH3, -CH3, -C2H5, -CF3, -CH2CN, -CH2OH, -CH2OCH3, -COOH, -C(=O)CH3, -C(=O)OCH3, -C(=O)CH2OCH3, -S(=O)2CH3, S(=O)2C2H5, or S(=O)2CF3; and

[0310] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0311] 40. A compound selected from compounds 1-457, its tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives.

[0312] 41. A pharmaceutical composition comprising at least one compound according to any one of embodiments 1 to 40, a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0313] 42. 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 40, or a therapeutically effective amount of a pharmaceutical composition according to embodiment 41.

[0314] 43. 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 40, or a therapeutically effective amount of a pharmaceutical composition according to embodiment 41.

[0315] 44. The method according to embodiment 42 or embodiment 43, wherein said 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.

[0316] To avoid confusion, the features described by the inductive formula (I') can also be combined with the features described by the inductive formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe).

[0317] Example implementation plan 2:

[0318] The non-restrictive implementation schemes / terms of this disclosure include:

[0319] 1. A compound represented by the following structural formula:

[0320]

[0321] Its tautomer, the deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein:

[0322] For each of the two cases, it is either a single bond or a double bond, provided that one is a single bond and the other is a double bond;

[0323] V 1 and V 2 Each is independently N or -CR 2 ;

[0324] W 1 and W 2 Each is independently either N or C, provided that W is... 1 and W 2 One of them is N, and the other is C;

[0325] U can be hydrogen, -OH, -CH3, -NH2, or a halogen;

[0326] X does not exist or is a key, -(CR) a R b ) p-or -SO2-;

[0327] Y does not exist or is a key, -(CR) c R d ) q -, -C(=O)- or -SO2-;

[0328] R a and R b Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0329] R c and R d Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0330] Ring A is C3-C 12 Carbocyclic group, 3 to 12-membered heterocyclic group, C6 or C 10 aryl or 5 to 10-membered heteroaryl; condition is when W 1 For N and W 2 When it is C, ring A is not 1,5,6,7-tetrahydro-4H-indole-4-one or its tautomer;

[0331] Ring B is C4-C 12 cycloalkyl, C6 or C 10 aryl, 5- to 10-membered heteroaryl or benzyl;

[0332] Z is in

[0333] Ring C is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, C6 is C 10 Aryl or 5 to 10-membered heteroaryl;

[0334] The condition is that when ring C is phenyl, the phenyl is reacted with R. 4 Substitution; the condition is that when ring C is phenyl, Y cannot be -SO2-; and

[0335] The condition is that when ring B is benzyl, ring C cannot be pyridyl or indole;

[0336] 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 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:

[0337] R E R F and R G The C1-C6 alkyl or the C2-C6 alkenyl group of either group is optionally substituted by one to three groups selected from the following: 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 ;in:

[0338] 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:

[0339] R pR q and R r The C1-C4 alkyl group of any one thereof 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

[0340] R p R q and R r The C3-C6 cycloalkyl group or the 3- to 6-membered heterocyclic group of any one thereof is optionally substituted by 1 to 3 groups selected from the following groups: 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;

[0341] 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:

[0342] R s The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0343] R s The C3-C6 cycloalkyl, the phenyl, or the 5 or 6 heteroaryl group is optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, -OH, -OCH3, -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;

[0344] R 1 It can be halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or -O- (C3-C6 cycloalkyl);

[0345] R 2Each 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:

[0346] R 2 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl may optionally be substituted with one to three groups selected from the following: 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 i ;in:

[0347] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0348] R h R i and R jThe C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0349] R h R i and R j The C3-C6 cycloalkyl group of any one thereof is optionally substituted with 1 to 3 groups selected from the following: 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;

[0350] 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:

[0351] -OR k It cannot be -OH;

[0352] R k The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0353] R kThe C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from the following: 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;

[0354] 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:

[0355] R3 and R 4 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl of any of them is optionally substituted by one to three groups selected from the following: 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 ;in

[0356] 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:

[0357] R v R w and R x The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0358] R v R w and R xThe C3-C6 cycloalkyl group, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group of any of them is optionally substituted by 1 to 3 groups selected from the following: 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;

[0359] 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

[0360] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0361] R y The C3-C6 cycloalkyl, the phenyl, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group are optionally substituted by 1 to 3 groups selected from the following: 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;

[0362] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0363] k is an integer selected from 1, 2, and 3;

[0364] m and n are each an independent integer selected from 0, 1, 2 and 3;

[0365] p, r, s, and t are each an independent integer selected from 1 and 2; and

[0366] q is an integer selected from 1, 2, and 3.

[0367] 2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in Clause 1, represented by one of the following structural formulas:

[0368]

[0369] in:

[0370] U is -OH, -CH3, -NH2, F, or Cl;

[0371] Furthermore, all other variables not specifically defined herein are defined as in Implementation Scheme 1.

[0372] 3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in Clause 1, represented by one of the following structural formulas:

[0373]

[0374] in:

[0375] U is -OH, -CH3, -NH2, F, or Cl;

[0376] Furthermore, all other variables not specifically defined herein are defined as in Implementation Scheme 1.

[0377] 4. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, as defined in Clause 1 or Clause 2, represented by one of the following structural formulas:

[0378]

[0379] in:

[0380] U is -OH or -NH2;

[0381] Ring A can be arbitrarily assigned to R 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group, a phenyl group, or a 5- to 9-membered heteroaryl group;

[0382] Ring B was R 1 Substitution and ring B is C4-C6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or benzyl; and

[0383] When Z is arbitrarily assigned to R 4 When the ring C is substituted, the ring C is a C4-C8 cycloalkyl, a 4- to 8-membered heterocyclic group, a phenyl, or a 5- or 6-membered heteroaryl group;

[0384] Furthermore, all other variables not specifically defined herein are defined as in Clause 1 or Clause 2.

[0385] 5. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1, 2, and 4, represented by one of the following structural formulas:

[0386]

[0387] in:

[0388] Ring B was R 1 Substitution, and ring B is cyclohexyl, phenyl, pyridyl or benzyl; and all other variables not specifically defined herein are defined as in any of clauses 1, 2 and 4.

[0389] 6. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1, 2, 4, and 5, represented by the following structural formula:

[0390]

[0391] in:

[0392] R 1 It is a halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy group; and

[0393] k is an integer selected from 1 and 2;

[0394] Furthermore, all other variables not specifically defined herein are defined as any of the items in Clauses 1, 2, 4, and 5.

[0395] 7. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 6, wherein R 1 It is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3 or -OCH(CH3)2; and all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0396] 8. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 7, wherein at least one R 1 Let F be the variable; and all other variables not specifically defined herein shall be defined as in any of the preceding clauses.

[0397] 9. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 8, wherein:

[0398] X does not exist or is a key, -(CR) a R b - or -SO2-;

[0399] Ra and R b Each of these variables, when it appears, is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0400] 10. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 9, wherein X is absent or is a bond, -CH2-, or -SO2-; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0401] 11. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 10, wherein:

[0402] Y does not exist or is a key, -(CR) c R d ) q -, -C(=O)- or -SO2-;

[0403] R c and R d Each of these variables, when it appears, is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0404] 12. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 11, wherein q is an integer selected from 1 and 2; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0405] 13. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 12, wherein Y is absent or is a bond, -CH2-, -CHCH3-, -C(CH3)2-, -C(=O)- or -SO2-; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0406] 14. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 13, wherein ring A is optionally converted by R 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group containing 1 to 3 oxygen atoms, a phenyl group, or a 5- to 9-membered heteroaryl group containing 1 to 3 heteroatoms selected from O and N; and all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0407] 15. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 14, wherein ring A is optionally converted by R 3 The substituted ring A is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group containing one or two oxygen atoms, a phenyl group, or a 5- to 9-membered heteroaryl group containing one or two nitrogen atoms or one or two oxygen atoms; and all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0408] 16. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 15, wherein ring A is optionally converted by R 3 Replacement, and ring A is selected from

[0409] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0410] 17. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 16, wherein ring A is optionally converted by R 3 Replacement, and ring A is selected from

[0411] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0412] 18. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein Z is a ring C, and the ring C is optionally replaced by R. 4 Substituted and having a C4-C8 cycloalkyl ring; a 4- to 8-membered heterocyclic group containing one or two heteroatoms selected from O, N, and S; phenyl; or a 5-membered heteroaryl group containing one or two heteroatoms selected from O and N;

[0413] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0414] 19. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 18, wherein Z is a ring C, and the ring C is optionally replaced by R. 4 Replacement, and ring C is selected from

[0415] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0416] 20. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 19, wherein Z is a ring C, and the ring C is optionally (R 4 ) o Replacement, and ring C is selected from

[0417] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0418] 21. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 20, wherein R E R F and R G Each can be independently hydrogen, halogen, cyano (-C≡N), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -C(=O)OR. s -C(=O)NR p R q -CR p (=N)OR s or -OR s ;in:

[0419] R E R F and R G The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: cyano, -C(=O)R s -C(=O)OR s -C(=O)NR p R q -OR s -OC(=O)R s -OC(=O)OR s -OC(=O)NR p R q and -S(=O)2R s ;in:

[0420] R p and R q Each of these groups is independently hydrogen, C1-C2 alkyl, C3-C5 cycloalkyl, or a 5- or 6-membered heterocyclic group; wherein:

[0421] R p and R q The C1-C2 alkyl group of any one of them is optionally substituted by one to three groups selected from the following: halogen, cyano and -OH;

[0422] R p and Rq The C3-C5 cycloalkyl group or the 5- or 6-membered heteroaryl group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano and -OH;

[0423] R s Each time it appears, it is independently hydrogen, C1-C2 alkyl, or 5 or 6-membered heteroaryl; wherein R s The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH and -NH2; wherein:

[0424] R s The 5 or 6 heteroaryl group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano, -OH and -NH2;

[0425] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0426] 22. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 21, wherein R E R F and R G Each of these can be independently hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, or -C(=O)NR. p R q -CR p (=N)OR s or -OR s ;in:

[0427] R E R F and R G The C1-C2 alkyl group of any one thereof is optionally substituted by one to three groups selected from the following: cyano, -C(=O)NR p R q -OR s -OC(=O)NR p R q and -S(=O)2R s ;in:

[0428] R p and R q Each of these components, when appearing independently, is hydrogen, C1-C2 alkyl, cyclopentyl, or tetrahydrofuranyl; wherein:

[0429] R p and R q The C1-C2 alkyl group of any one of them is optionally substituted with 1 to 3 halogen groups selected from F and Cl;

[0430] Rs Each occurrence is independently hydrogen, C1-C2 alkyl, pyridyl, or pyrimidinyl; wherein:

[0431] R s The C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups selected from F and Cl;

[0432] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0433] 23. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 22, wherein R E R F and R G Each of these can be independently represented as hydrogen, F, -OH, -CH(OH)CH3, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CF3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -C2H5, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -(CH2)2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -( CH2)2S(=O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH (cyclopentyl), -CH2(O)C(=O)NH (tetrahydrofuranyl), -CH2(O) (pyridin-2-yl) or -CH2(O) (pyrimidin-2-yl); and all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0434] 24. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 23, wherein R E R F and R G Each is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, or -CH2OCH3; and

[0435] All other variables not specifically defined herein are defined as in any of the preceding clauses.

[0436] 25. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 24, represented by one of the following structural formulas:

[0437]

[0438]

[0439] All other variables not specifically defined herein are defined as in any of the preceding clauses.

[0440] 26. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 25, represented by one of the following structural formulas:

[0441]

[0442]

[0443] 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 preceding clauses.

[0444] 27. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 26, represented by one of the following structural formulas:

[0445]

[0446]

[0447] All other variables not specifically defined herein are defined as in any of the preceding clauses.

[0448] 28. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 27, represented by one of the following structural formulas:

[0449]

[0450]

[0451] 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 preceding clauses.

[0452] 29. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 28, wherein R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), C1-C6 alkoxy, C1-C6 haloalkyl, -NR h Ri Or C3-C6 cycloalkyl; wherein R h and R i Each of these variables is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0453] 30. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 29, wherein R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C4 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), C1-C4 alkoxy, C1-C4 haloalkyl, -NR h R i Or C3-C5 cycloalkyl; wherein R h and R i Each of these variables is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0454] 31. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 30, wherein R 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), C1-C2 haloalkyl, -NR h R i Or C3-C4 cycloalkyl; wherein R h and R i Each time it appears, it is independently either hydrogen or -CH3;

[0455] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0456] 32. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 31, wherein R 2 Each time it appears, it is independently hydrogen, F, Cl, cyano, -CH3, -CHF2, -CF3, -NH2, or cyclopropyl; and all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0457] 33. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R 3Each time it appears, it is independently a halogen, cyano, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or -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)2R y -NR v R w -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y or -P(=O)R z R z ;in:

[0458] R 3 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)OR y and -NR v R w ;in:

[0459] R v R w and R x Each of these components is independently hydrogen or a C1-C2 alkyl group; wherein R v R w and R x The C1-C2 alkyl group of any one thereof is optionally substituted with one to three groups selected from the group consisting of halogen, cyano, -OH, and -NH2; and

[0460] R y Each occurrence is independently hydrogen, C1-C4 alkyl, or a 5- or 6-membered heterocyclic group; wherein:

[0461] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -NH2 and -C(=O)OH; and

[0462] R y The 5- or 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -NH2 and -C(=O)OH;

[0463] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0464] 34. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 33, wherein R 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -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)2R y -NR v R w -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y or -P(=O)R z R z ;in:

[0465] R 3 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y and -C(=O)OR y ;in:

[0466] R v R w and R x Each of these components is independently hydrogen or a C1-C4 alkyl group; wherein R v R w and R x The C1-C4 alkyl group in any of them is optionally substituted with -OH; and

[0467] R y Each occurrence is independently hydrogen, C1-C2 alkyl, or a 6-membered heterocyclic group; wherein:

[0468] R y The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: -OH and -C(=O)OH; and

[0469] R yThe 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OH and -C(=O)OH;

[0470] R z Each time it appears, it is independently -CH3, -OH, or -OCH3;

[0471] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0472] 35. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 34, wherein R 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C2 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, or -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)2R y -NR v R w -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y or -P(=O)R z R z ;in:

[0473] R 3 The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following: -OH and -C(=O)OR y ;in:

[0474] R v R w and R x Each of these components is independently hydrogen or a C1-C2 alkyl group; wherein R v R w and R x The C1-C2 alkyl group in any of them is optionally substituted with -OH; and

[0475] R y Each time it appears, it is independently hydrogen, C1-C2 alkyl, or tetrahydro-2H-pyranyl; wherein:

[0476] Ry The C1-C2 alkyl group is optionally substituted with -C(=O)OH; and

[0477] R y The tetrahydro-2H-pyranyl group is optionally substituted by one to three groups selected from the following: -OH and -C(=O)OH;

[0478] R z Each time it appears, it is independently -CH3 or -OH;

[0479] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0480] 36. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 35, wherein R 3 Each time it appears, it is independently F, Cl, cyano, -OH, =O, -CH3, -OCH3, -CF3, -CH3CN, -C(CH3)2CH2OH, -CH2COOH, -CH2OCH3, -C(=O)CHCH3OH, -COOH, -C(=O)O(2-tetrahydro-2H-pyranyl), -C(=O)NH2, -C(=O)NH(CH2)2OH, -C(=O)NHOH, -C(=O)NHS(=O)2CH3, -NH2 -NHCH3, -OCH2COOH, NHS(=O)2CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHC(=O)CH3 or -P(=O)(CH3)2; wherein the 2-tetrahydro-2H-pyranyl group in -C(=O)O(2-tetrahydro-2H-pyranyl) is substituted by 1 to 3 groups selected from -OH and -C(=O)OH; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0481] 37. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 36, wherein R 4 Each time it appears, it is independently a halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or -C(=O)R. y -C(=O)OR y -OR y or -S(=O)2R y ;in:

[0482] R 4 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)ORy and -NR v R w ;in:

[0483] R v and R w Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0484] R y Each occurrence is independently of hydrogen and C1-C4 alkyl; wherein:

[0485] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -OCH3 and -NH2;

[0486] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0487] 38. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 37, wherein R 4 Each time it appears, it is independently a halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -C(=O)R. y -C(=O)OR y -OR y or -S(=O)2R y ;in:

[0488] R 4 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)OR y and -NR v R w ;in:

[0489] R v and R w Each of them is independently hydrogen or C1-C4 alkyl;

[0490] R y Each occurrence is independently hydrogen or C1-C2 alkyl; wherein:

[0491] R y The C1-C2 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following groups: halogen, cyano, -OH, -OCH3, and -NH2; and

[0492] Where o is an integer selected from 0, 1, and 2; and

[0493] All other variables not specifically defined herein are defined as in any of the preceding clauses.

[0494] 39. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 38, wherein R 4 Each time it appears, it is independently cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, or -C(=O)R. y -C(=O)OR y -OR y or -S(=O)2R y ;in:

[0495] R 4 The C1-C2 alkyl group is optionally substituted with a cyano group, -OH or -OCH3;

[0496] R y Each occurrence is independently hydrogen or C1-C2 alkyl; wherein:

[0497] R y The C1-C2 alkyl group is optionally substituted with -OCH3;

[0498] Where o is an integer selected from 0 and 1;

[0499] Furthermore, all other variables not specifically defined herein are defined as in any of the preceding clauses.

[0500] 40. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 39, wherein R 4 Each time it appears, it is independently cyano, -OH, -OCH3, -CH3, -C2H5, -CF3, -CH2CN, -CH2OH, -CH2OCH3, -COOH, -C(=O)CH3, -C(=O)OCH3, -C(=O)CH2OCH3, -S(=O)2CH3, S(=O)2C2H5, or S(=O)2CF3; and all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0501] 41. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 40, wherein U is -OH, -CH3, -NH2 or a halogen; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0502] 42. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt according to any one of clauses 1 to 40, wherein U is -OH; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0503] 43. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt pursuant to any one of clauses 1 to 40, wherein U is a halogen; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0504] 44. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt pursuant to any one of clauses 1 to 40, wherein U is fluorine; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0505] 45. A compound, tautomer, deuterated derivative or pharmaceutically acceptable salt pursuant to any one of clauses 1 to 40, wherein U is hydrogen; and wherein all other variables not specifically defined herein are as defined in any of the preceding clauses.

[0506] 46. ​​A compound selected from compounds 1-457, compounds 458-532, compounds B1-B25, compounds W1-W32 and compounds P1-P225, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of said compounds, tautomers and deuterated derivatives.

[0507] 47. A compound selected from compounds 1-457, its tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives.

[0508] 48. A compound selected from compounds 458-532, its tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds, tautomers, and deuterated derivatives.

[0509] 49. A compound selected from compounds B1-B25 and compounds W1-W32, its tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of said compounds, tautomers, and deuterated derivatives.

[0510] 50. A compound selected from compounds P1 to P225, its tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of said compounds, tautomers, and deuterated derivatives.

[0511] 51. A pharmaceutical composition comprising at least one compound as described in any one of clauses 1 to 50, a tautomer thereof, a deuterated derivative of said compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0512] 52. 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 clauses 1 to 50, or a therapeutically effective amount of a pharmaceutical composition according to clause 51.

[0513] 53. 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 clauses 1 to 50, or a therapeutically effective amount of a pharmaceutical composition according to clause 51.

[0514] 54. The method according to Clause 52 or Clause 53, wherein said 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.

[0515] II. Compounds and Compositions

[0516] In some embodiments, the compounds disclosed herein are compounds of formula (I):

[0517]

[0518] Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0519] For each of the two cases, it is either a single bond or a double bond, provided that one is a single bond and the other is a double bond;

[0520] V 1 and V 2 Each is independently N or -CR 2 ;

[0521] W 1 and W 2 Each is independently either N or C, provided that W is... 1 and W 2 One of them is N, and the other is C;

[0522] U can be hydrogen, -OH, -CH3, -NH2, or a halogen;

[0523] X does not exist or is a key, -(CR) a R b ) p -or -SO2-;

[0524] Y does not exist or is a key, -(CR) c R d ) q -, -C(=O)- or -SO2-;

[0525] R a and R b Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0526] R c and R d Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0527] Ring A is C3-C 12 Carbocyclic group, 3 to 12-membered heterocyclic group, C6 or C 10 aryl or 5 to 10-membered heteroaryl; condition is when W 1 For N and W 2 When it is C, ring A is not 1,5,6,7-tetrahydro-4H-indole-4-one or its tautomer;

[0528] Ring B is C4-C 12 cycloalkyl, C6 or C 10 aryl, 5- to 10-membered heteroaryl or benzyl;

[0529] Z is in

[0530] Ring C is C3-C 12 Cycloalkyl, 3 to 12-membered heterocyclic, C6 is C 10 Aryl or 5 to 10-membered heteroaryl;

[0531] The condition is that when ring C is phenyl, the phenyl is reacted with R. 4 Substitution; the condition is that when ring C is phenyl, Y cannot be -SO2-; and

[0532] The condition is that when ring B is benzyl, ring C cannot be pyridyl or indole;

[0533] R E R F and R GEach 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 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:

[0534] R E R F and R G The C1-C6 alkyl or the C2-C6 alkenyl group of either group is optionally substituted by one to three groups selected from the following: 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 ;in:

[0535] R p R q and R rEach 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:

[0536] R p R q and R r The C1-C4 alkyl group of any one thereof 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

[0537] R p R q and R r The C3-C6 cycloalkyl group or the 3- to 6-membered heterocyclic group of any one thereof is optionally substituted by 1 to 3 groups selected from the following groups: 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;

[0538] 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:

[0539] R s The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0540] R s The C3-C6 cycloalkyl, the phenyl, or the 5 or 6-membered group is optionally substituted by 1 to 3 groups selected from the following: 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;

[0541] R 1It can be halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or -O-(C3-C6 cycloalkyl) such as -O-(cyclopropyl) or -O-(cyclobutyl);

[0542] 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, phenyl, or 5 or 6-membered heteroaryl; wherein:

[0543] R 2 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl may optionally be substituted with one to three groups selected from the following: 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 i ;in:

[0544] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0545] R h R i and R jThe C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0546] R h R i and R j The C3-C6 cycloalkyl group of any one thereof is optionally substituted with 1 to 3 groups selected from the following: 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;

[0547] 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:

[0548] -OR k It cannot be -OH;

[0549] R k The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0550] R kThe C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from the following: 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;

[0551] 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:

[0552] R3 and R 4 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl of any of them is optionally substituted by one to three groups selected from the following: 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 ;in:

[0553] 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:

[0554] R v R w and R x The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0555] R v R w and R xThe C3-C6 cycloalkyl group, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group of any of them is optionally substituted by 1 to 3 groups selected from the following: 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;

[0556] 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

[0557] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: halogen, cyano, -OH, -OCH3, -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

[0558] R y The C3-C6 cycloalkyl, the phenyl, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group are optionally substituted by 1 to 3 groups selected from the following: halogen, cyano, -OH, -OCH3, -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;

[0559] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0560] k is an integer selected from 1, 2, and 3;

[0561] m and n are each an independent integer selected from 0, 1, 2 and 3;

[0562] p, r, s, and t are each an independent integer selected from 1 and 2; and

[0563] q is an integer selected from 1, 2, and 3.

[0564] In some embodiments, U is -OH, -CH3, -NH2, or a halogen in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein, and all other variables are as defined with respect to formula (I).

[0565] In some embodiments, U is hydrogen in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, and all other variables are as defined in formula (I).

[0566] In some embodiments, U is -OH in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, and all other variables are as defined with respect to formula (I).

[0567] In some embodiments, U is a halogen in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, and all other variables are as defined in formula (I).

[0568] In some embodiments, U is fluorine in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, and all other variables are as defined in formula (I).

[0569] In some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently integers selected from 1 and 2, and all other variables are as defined for formula (I).

[0570] In some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, U is -OH, -CH3, -NH2 or a halogen, p, q, r, s and t are each independently an integer selected from 1 and 2, and all other variables are as defined for formula (I).

[0571] In some embodiments, V is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2 For -CR 2 , where R 2 For halogen, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0572] In some embodiments, V is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2 For -CR 2 , where R 2The variable is fluorine, and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0573] In some embodiments, V is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 For -CR 2 , where R 2 For halogen, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0574] In some embodiments, V is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 For -CR 2 , where R 2 The variable is fluorine, and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0575] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIa) or formula (IIb):

[0576]

[0577] in:

[0578] U is -OH, -CH3, -NH2, F, or Cl; and

[0579] All other variables not specifically defined in this paper are defined in equation (I).

[0580] In some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently an integer selected from 1 and 2, wherein all other variables not specifically defined herein are as defined in the foregoing embodiments.

[0581] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIc), (IId), (IIe), or (IIIf):

[0582]

[0583] in:

[0584] U is -OH, -CH3, -NH2, F, or Cl; and

[0585] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0586] In some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently an integer selected from 1 and 2, wherein all other variables not specifically defined herein are as defined in the foregoing embodiments.

[0587] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIg):

[0588]

[0589] All other variables not specifically defined in this paper are defined in equation (I).

[0590] For example, in some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently an integer selected from 1 and 2, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0591] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIIa) or formula (IIIb):

[0592]

[0593] in:

[0594] U is -OH or -NH2;

[0595] Ring A can be arbitrarily assigned to R 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group, a phenyl group, or a 5- to 9-membered heteroaryl group;

[0596] Ring B was R 1 Substitution and ring B is C4-C6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or benzyl; and

[0597] When Z is arbitrarily assigned to R 4 When the ring C is substituted, the ring C is a C4-C8 cycloalkyl, a 4- to 8-membered heterocyclic group, a phenyl group, or a 5- or 6-membered heteroaryl group; and

[0598] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0599] For example, in some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently an integer selected from 1 and 2, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0600] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IIIc):

[0601]

[0602] in:

[0603] Ring A can be arbitrarily assigned to R 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group, a phenyl group, or a 5- to 9-membered heteroaryl group;

[0604] Ring B was R 1 Substitution and ring B is C4-C6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, or benzyl; and

[0605] When Z is arbitrarily assigned to R 4 When the ring C is substituted, the ring C is a C4-C8 cycloalkyl, a 4- to 8-membered heterocyclic group, a phenyl group, or a 5- or 6-membered heteroaryl group; and

[0606] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0607] For example, in some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently an integer selected from 1 and 2, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0608] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The substitution is performed, and ring A is a C3 carbocyclic group, a C4 carbocyclic group, or a C7 carbocyclic group, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0609] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 When substituted, and ring A is phenyl, all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0610] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The substitution is performed, and ring A is pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0611] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring B is R 1 When substituted, and ring B is phenyl, all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0612] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IVa) or formula (IVb):

[0613]

[0614] in:

[0615] Ring B was R 1 Substitution, and ring B is cyclohexyl, phenyl, pyridyl, or benzyl; or

[0616] Ring B was R 1 Substitution, and ring B is cyclohexyl, phenyl, or benzyl;

[0617] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0618] For example, in some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently an integer selected from 1 and 2, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0619] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (Va) or formula (Vb):

[0620]

[0621] in:

[0622] R 1 It is a halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy group; and

[0623] k is an integer selected from 1 and 2;

[0624] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0625] In some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently an integer selected from 1 and 2, wherein all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0626] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by the formula (Vc):

[0627]

[0628] in:

[0629] R 1 It is a halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy group; and

[0630] k is an integer selected from 1 and 2;

[0631] Furthermore, all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0632] In some embodiments, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts disclosed herein, p, q, r, s and t are each independently an integer selected from 1 and 2, wherein all other variables not specifically defined herein are as defined in the foregoing embodiments.

[0633] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 The variable is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0634] In some embodiments, at least one R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 F; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0635] In some embodiments, in the compounds, deuterated derivatives, pharmaceutically acceptable salts, or tautomers disclosed herein, X is absent or is a bond, -(CR) a R b - or -SO2-; R a and R bEach of these variables, when it appears, is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0636] In some embodiments, X is absent or is a bond, -CH2- or -SO2- 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.

[0637] In some embodiments, Y is absent or is a bond, -(CR) in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. c R d ) q -、-C(=O)- or -SO2-; R c and R d Each of these variables, when it appears, is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0638] In some embodiments, Y is absent or is a bond, -CH2-, -CHCH3-, -C(CH3)2-, -C(=O)-, or -SO2- 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.

[0639] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The ring A is substituted with a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group containing 1 to 3 oxygen atoms, a phenyl group, or a 5- to 9-membered heteroaryl group containing 1 to 3 heteroatoms selected from O and N; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0640] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The ring A is substituted with a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group containing one or two oxygen atoms, a phenyl group, or a 5- to 9-membered heteroaryl group containing one or two nitrogen atoms or one or two oxygen atoms; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0641] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 Replacement, and ring A is selected from

[0642] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0643] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 Replacement, and ring A is selected from

[0644] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0645] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, wherein Z is a ring C, and the ring C is optionally replaced by R 4 Replacement, and ring C is selected from

[0646] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0647] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, Z is a ring C, and the ring C is optionally replaced by R. 4 Replacement, and ring C is selected from

[0648] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0649] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. E R F and R G Each can be independently hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)OR s -C(=O)NR p R q -CR p (=N)OR s or -OR s ;in:

[0650] R E R F and RG The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: cyano, -C(=O)R s -C(=O)OR s -C(=O)NR p R q -OR s -OC(=O)R s -OC(=O)OR s -OC(=O)NR p R q and -S(=O)2R s ;in:

[0651] R p and R q Each time it appears, it is independently hydrogen, C1-C2 alkyl, C3-C5 cycloalkyl, or a 5- or 6-membered heterocyclic group; where R p and R q The C1-C2 alkyl group of any one thereof is optionally substituted with 1 to 3 groups selected from the following: halogen, cyano, and -OH; wherein:

[0652] R p and R q The C3-C5 cycloalkyl group or the 5- or 6-membered heteroaryl group of any of them is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano and -OH;

[0653] R s Each time it appears, it is independently hydrogen, C1-C2 alkyl, or 5- or 6-membered heteroaryl; wherein:

[0654] R s The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH and -NH2;

[0655] R s The 5 or 6 heteroaryl group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano, -OH and -NH2;

[0656] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0657] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. E R F and R G Each of these can be independently hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, or -C(=O)NR. p R q-CR p (=N)OR s or -OR s ;in:

[0658] R E R F and R G The C1-C2 alkyl group of any one thereof is optionally substituted by one to three groups selected from the following: cyano, -C(=O)NR p R q -OR s -OC(=O)NR p R q and -S(=O)2R s ;in:

[0659] R p and R q Each of these components, when appearing independently, is hydrogen, C1-C2 alkyl, cyclopentyl, or tetrahydrofuranyl; wherein:

[0660] R p and R q The C1-C2 alkyl group of any one of them is optionally substituted with 1 to 3 halogen groups selected from F and Cl;

[0661] R s Each occurrence is independently hydrogen, C1-C2 alkyl, pyridyl, or pyrimidinyl; wherein:

[0662] R s The C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups selected from F and Cl;

[0663] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0664] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. E R F and R GEach of these can be independently represented as hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(= -CH2(O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridin-2-yl), -CH2(O)(pyrimidin-2-yl); and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0665] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. E R F and R G Each of these variables is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0666] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (VIa), (VIb), (VIc), (VId), or (VIe):

[0667]

[0668]

[0669] (VIe);

[0670] All other variables not specifically defined herein are defined as described in any of the foregoing implementation schemes. In some implementation schemes, o is an integer selected from 0, 1, and 2.

[0671] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (VIf) or formula (VIg):

[0672]

[0673] All other variables not specifically defined herein are defined as described in any of the foregoing implementation schemes. In some implementation schemes, o is an integer selected from 0, 1, and 2.

[0674] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these can be independently represented as hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(= -CH2(O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridin-2-yl), -CH2(O)(pyrimidin-2-yl); and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0675] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these variables is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0676] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these variables is independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0677] 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):

[0678]

[0679] 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 embodiments. In some embodiments, o is an integer selected from 0, 1, and 2.

[0680] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (VIIf) or formula (VIIg):

[0681]

[0682] 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 embodiments. In some embodiments, o is an integer selected from 0, 1, and 2.

[0683] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group, a phenyl group, or a 5- to 9-membered heteroaryl group, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0684] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The substitution is performed, and ring A is a C3 carbocyclic group, a C4 carbocyclic group, or a C7 carbocyclic group, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0685] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 When substituted, and ring A is phenyl, all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0686] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3The substitution is performed, and ring A is pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0687] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these can be independently represented as hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(= -CH2(O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridin-2-yl), -CH2(O)(pyrimidin-2-yl); and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0688] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these variables is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0689] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these variables is independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0690] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (VIIIa), (VIIIb), (VIIIc), (VIIId), or (VIIIe):

[0691]

[0692] All other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0693] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (IXa), (IXb), (IXc), (IXd), or (IXe):

[0694]

[0695] 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.

[0696] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C6 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), C1-C6 alkoxy, C1-C6 haloalkyl, -NR h R i Or C3-C6 cycloalkyl; wherein R h and R i Each of these variables is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0697] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2 Each time it appears, it is independently hydrogen, halogen, cyano, C1-C4 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), C1-C4 haloalkyl, -NR h R i Or C3-C5 cycloalkyl; wherein R h and R i Each of these variables is independently hydrogen or C1-C2 alkyl, and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0698] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2Each time it appears, it is independently hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted by 1 to 3 groups selected from: cyano, -OH, -OCH3 and -NH2), -NR. h R i Or C3-C4 cycloalkyl; wherein R h and R i Each of these variables is independently hydrogen or -CH3 each time it appears; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0699] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2 Each occurrence is independently hydrogen, F, Cl, cyano, -CH3, -CF3, -NH2, or cyclopropyl; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0700] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or -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)2R y -NR v R w -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y or -P(=O)R z R z ;in:

[0701] R 3 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)OR y and -NR v R w ;in:

[0702] R v Rw and R x Each of these components is independently hydrogen or a C1-C2 alkyl group; wherein R v R w and R x The C1-C2 alkyl group of any one thereof is optionally substituted with one to three groups selected from the group consisting of halogen, cyano, -OH, and -NH2; and

[0703] R y Each occurrence is independently hydrogen, C1-C4 alkyl, or a 5- or 6-membered heterocyclic group; wherein:

[0704] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -NH2 and -C(=O)OH; and

[0705] R y The 5- or 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -NH2 and -C(=O)OH;

[0706] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0707] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -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)2R y -NR v R w -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y or -P(=O)R z R z ;in:

[0708] R 3The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y and -C(=O)OR y ;in:

[0709] R v R w and R x Each of these components is independently hydrogen or a C1-C4 alkyl group; wherein R v R w and R x The C1-C4 alkyl group in any of them is optionally substituted with -OH; and

[0710] R y Each occurrence is independently hydrogen, C1-C2 alkyl, or a 6-membered heterocyclic group; wherein:

[0711] R y The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: -OH and -C(=O)OH; and

[0712] R y The 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from the following: -OH and -C(=O)OH;

[0713] R z Each time it appears, it is independently -CH3, -OH, or -OCH3;

[0714] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0715] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 3 Each time it appears, it is independently a halogen, cyano, =O, C1-C2 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, or -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)2R y -NR v R w -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NRv C(=O)R y or -P(=O)R z R z ;in:

[0716] R 3 The C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from the following: -OH and -C(=O)OR y ;in:

[0717] R v R w and R x Each of these components is independently hydrogen or a C1-C2 alkyl group; wherein R v R w and R x The C1-C2 alkyl group in any of them is optionally substituted with -OH; and

[0718] R y Each time it appears, it is independently hydrogen, C1-C2 alkyl, or tetrahydro-2H-pyranyl; wherein:

[0719] R y The C1-C2 alkyl group is optionally substituted with -C(=O)OH; and R y The tetrahydro-2H-pyranyl group is optionally substituted by one to three groups selected from the following: -OH and -C(=O)OH;

[0720] R z Each time it appears, it is independently -CH3 or -OH;

[0721] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0722] 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 F, Cl, cyano, -OH, =O, -CH3, -OCH3, -CF3, -CH3CN, -C(CH3)2CH2OH, -CH2COOH, -CH2OCH3, -C(=O)CHCH3OH, -COOH, -C(=O)O(2-tetrahydro-2H-pyranyl), -C(=O)NH2, -C(=O)NH(CH2)2OH, -C(=O)NHOH, -C(=O)NHS(=O)2CH3, -NH2. -NHCH3, NHS(=O)2CH3, -OCH2COOH, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHC(=O)CH3 or -P(=O)(CH3)2; wherein the 2-tetrahydro-2H-pyranyl group in -C(=O)O(2-tetrahydro-2H-pyranyl) is substituted by 1 to 3 groups selected from -OH and -C(=O)OH; and wherein all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0723] 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 a halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or -C(=O)R. y -C(=O)OR y -OR y or -S(=O)2R y ;in:

[0724] R 4 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)OR y and -NR v R w ;in:

[0725] R v and R w Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0726] R y Each occurrence is independently of hydrogen and C1-C4 alkyl; wherein:

[0727] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following groups: halogen, cyano, -OH, -OCH3 and -NH2;

[0728] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0729] 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 a halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or -C(=O)R. y -C(=O)OR y -OR y or -S(=O)2R y ;in:

[0730] R 4 The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -OR y -C(=O)OR y and -NR v R w ;in:

[0731] R v and R w Each of them is independently hydrogen or C1-C4 alkyl;

[0732] R y Each occurrence is independently hydrogen or C1-C2 alkyl; wherein:

[0733] R y The C1-C2 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following groups: halogen, cyano, -OH, -OCH3, and -NH2; and

[0734] Where m is an integer selected from 0, 1, and 2;

[0735] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0736] 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 cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, or -C(=O)R. y -C(=O)OR y -OR y or -S(=O)2R y ;in:

[0737] R 4 The C1-C2 alkyl group is optionally substituted with a cyano group, -OH or -OCH3;

[0738] R y Each time it appears, it is independently hydrogen or C1-C2 alkyl; wherein R y The C1-C2 alkyl group is optionally substituted with -OCH3;

[0739] Where m is an integer selected from 0 and 1;

[0740] Furthermore, all other variables not specifically defined herein are defined as in any of the aforementioned implementation schemes.

[0741] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 4 Each occurrence is independently cyano, -OH, -OCH3, -CH3, -C2H5, -CH2CN, -CH2OH, -CH2OCH3, -COOH, -C(=O)CH3, -C(=O)OCH3, -C(=O)CH2OCH3, -S(=O)2CH3, S(=O)2C2H5, or S(=O)2CF3; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0742] In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure are represented by formula (Xa), (Xb), (Xc), (Xd), (Xe), or (Xf):

[0743]

[0744]

[0745] All other variables not specifically defined herein are defined as described in any of the foregoing implementation schemes. In some implementation schemes, o is an integer selected from 0, 1, and 2.

[0746] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group, a phenyl group, or a 5- to 9-membered heteroaryl group, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0747] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The substitution is performed, and ring A is a C3 carbocyclic group, a C4 carbocyclic group, or a C7 carbocyclic group, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0748] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 When substituted, and ring A is phenyl, all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0749] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The substitution is performed, and ring A is pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, wherein all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0750] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these can be independently represented as hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(= -CH2(O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridin-2-yl), -CH2(O)(pyrimidin-2-yl); and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0751] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these variables is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0752] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein.F and R G Each of these variables is independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0753] In some embodiments, the compounds disclosed herein are compounds of formula (XIa), (XIb), (XIc), (XId), (XIe), or (XIIf):

[0754]

[0755] Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0756] U is hydrogen or -OH;

[0757] X does not exist or is a key, -(CR) a R b ) p -or -SO2-;

[0758] R a and R b Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0759] 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 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:

[0760] R E R F and R G The C1-C6 alkyl or the C2-C6 alkenyl group of either group is optionally substituted by one to three groups selected from the following: 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 ;in:

[0761] 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:

[0762] R p R q and R r The C1-C4 alkyl group of any one thereof 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

[0763] R p R q and R rThe C3-C6 cycloalkyl group or the 3- to 6-membered heterocyclic group of any one thereof is optionally substituted by 1 to 3 groups selected from the following groups: 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;

[0764] 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:

[0765] R s The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0766] R s The C3-C6 cycloalkyl, the phenyl, or the 5- or 6-membered heteroaryl group is optionally substituted by 1 to 3 groups selected from the following: 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;

[0767] R 1 It can be halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or -O- (C3-C6 cycloalkyl);

[0768] 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, phenyl, or 5 or 6-membered heteroaryl; wherein:

[0769] R 2 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl may optionally be substituted with one to three groups selected from the following: cyano, -C(=O)R k -C(=O)ORk -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 i ;in:

[0770] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0771] R h R i and R j The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0772] R h R i and R jThe C3-C6 cycloalkyl group of any one thereof is optionally substituted with 1 to 3 groups selected from the following: 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;

[0773] 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:

[0774] -OR k It cannot be -OH; R k The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0775] R k The C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from the following: 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;

[0776] 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 vS(=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:

[0777] R 3 and R 4 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl of any of them is optionally substituted by one to three groups selected from the following: 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 Rw -S (=O) t R y and -S (=O) t NR v R w ;in:

[0778] 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:

[0779] R v R w and R x The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0780] R v R w and R x The C3-C6 cycloalkyl group, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group of any of them is optionally substituted by 1 to 3 groups selected from the following: 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;

[0781] 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

[0782] R yThe C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0783] R y The C3-C6 cycloalkyl, the phenyl, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group are optionally substituted by 1 to 3 groups selected from the following: 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;

[0784] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0785] k is an integer selected from 1, 2, and 3; and

[0786] o, p, r, s, and t are each an integer selected from 1 and 2.

[0787] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R GEach of these can be independently represented as hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C( =O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridin-2-yl), -CH2(O)(pyrimidin-2-yl); and all other variables not specifically defined herein as defined in formulas (XIa), (XIb), (XIc), (XId), (XIe) or (XIf).

[0788] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined in formulas (XIa), (XIb), (XIc), (XId), (XIe), or (XIf).

[0789] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 The variable is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0790] In some embodiments, at least one R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 F; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0791] In some embodiments, in the compounds, deuterated derivatives, pharmaceutically acceptable salts, or tautomers disclosed herein, X is absent or is a bond, -(CR) a Rb - or -SO2-; R a and R b Each of these variables, when it appears, is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0792] In some embodiments, X is absent or is a bond, -CH2- or -SO2- 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.

[0793] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2 Each occurrence is independently hydrogen, F, Cl, cyano, -CH3, -CF3, or -NH2; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0794] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 3 It is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)R y -C(=O)OR y -OR y -OC(=O)R y or -OC(=O)OR y ;

[0795] R 3 The C1-C6 alkyl or the C2-C6 alkenyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -C(=O)R y -C(=O)OR y -OR y -OC(=O)R y and -OC(=O)OR y ;where R y 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.

[0796] In some embodiments, the compounds disclosed herein are compounds of formula (XIIa), (XIIb), (XIIc), (XIId), (XIIe), or (XIIIf):

[0797]

[0798]

[0799] Its tautomer, the deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0800] U is hydrogen or -OH;

[0801] Y does not exist or is a key, -(CR) c R d ) q -, -C(=O)- or -SO2-;

[0802] R c and R d Each of these elements is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0803] Ring A is C3-C 12 Carbocyclic groups, 3 to 12-membered heterocyclic groups, C6 is C 10 Aryl or 5 to 10-membered heteroaryl;

[0804] 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 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:

[0805] R E R F and R GThe C1-C6 alkyl or the C2-C6 alkenyl group of either group is optionally substituted by one to three groups selected from the following: 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 ;in:

[0806] 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:

[0807] R p R q and R r The C1-C4 alkyl group of any one thereof 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

[0808] R p R q and R r The C3-C6 cycloalkyl group or the 3- to 6-membered heterocyclic group of any one thereof is optionally substituted by 1 to 3 groups selected from the following groups: 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;

[0809] Rs Each time it appears, it is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl; wherein:

[0810] R s The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0811] R s The C3-C6 cycloalkyl, the phenyl, or the 5- or 6-membered heteroaryl group is optionally substituted by 1 to 3 groups selected from the following: 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;

[0812] 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, phenyl, or 5 or 6-membered heteroaryl; wherein:

[0813] R 2 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl may optionally be substituted with one to three groups selected from the following: 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 i ;in:

[0814] R h R i and R j Each of these elements is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein:

[0815] R h R i and R j The C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0816] R h R i and R j The C3-C6 cycloalkyl group of any one thereof is optionally substituted with 1 to 3 groups selected from the following: 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;

[0817] 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:

[0818] -OR k It cannot be -OH; R kThe C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0819] R k The C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from the following: 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;

[0820] 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:

[0821] R 3 and R 4 The C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl of any of them is optionally substituted by one to three groups selected from the following: 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 ;in:

[0822] 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:

[0823] R v R w and R xThe C1-C4 alkyl group of any one thereof is optionally substituted with one to three groups selected from the following: 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

[0824] R v R w and R x The C3-C6 cycloalkyl group, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group of any of them is optionally substituted by 1 to 3 groups selected from the following: 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;

[0825] 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

[0826] R y The C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from the following: 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

[0827] R yThe C3-C6 cycloalkyl, the phenyl, the 5- or 6-membered heterocyclic group, or the 5- or 6-membered heteroaryl group are optionally substituted by 1 to 3 groups selected from the following: 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;

[0828] R z Each time it appears, it is independently C1-C2 alkyl, -OH, or -O (C1-C2 alkyl);

[0829] n is an integer selected from 0, 1, 2, and 3; and

[0830] o, q, r, s, and t are each an integer selected from 1 and 2.

[0831] In some implementations, U is -OH.

[0832] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The ring A is substituted and is a C3-C7 carbocyclic group, a 6- to 9-membered heterocyclic group, a phenyl group, or a 5- to 9-membered heteroaryl group, wherein all other variables not specifically defined herein are as defined in formula (XIIa), formula (XIIb), formula (XIIc), formula (XIId), or formula (XIIe).

[0833] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The substitution is performed, and ring A is a C3 carbocyclic group, a C4 carbocyclic group, or a C7 carbocyclic group, wherein all other variables not specifically defined herein are defined as in equations (XIIa), (XIIb), (XIIc), (XIId), or (XIIe).

[0834] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 When substituted, and ring A is phenyl, all other variables not specifically defined herein are defined as in formula (XIIa), (XIIb), (XIIc), (XIId), or (XIIe).

[0835] In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, ring A is optionally replaced by R. 3 The substitution is performed, and ring A is pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, wherein all other variables not specifically defined herein are as defined in formulas (XIIa), (XIIb), (XIIc), (XIId), or (XIIe).

[0836] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these can be independently represented as hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O) -CH2(O)C(=O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridin-2-yl), -CH2(O)(pyrimidin-2-yl); and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0837] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. F and R G Each of these variables is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0838] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 The variable is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0839] In some embodiments, at least one R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 1 F; and all other variables not specifically defined herein are defined as in any of the foregoing implementation schemes.

[0840] In some embodiments, in the compounds, deuterated derivatives, pharmaceutically acceptable salts, or tautomers disclosed herein, X is absent or is a bond, -(CR) a R b - or -SO2-; R a and R b Each of these variables, when it appears, is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0841] In some embodiments, X is absent or is a bond, -CH2- or -SO2- 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.

[0842] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 2 Each occurrence is independently hydrogen, F, Cl, cyano, -CH3, -CF3, or -NH2; and all other variables not specifically defined herein are defined as in any of the foregoing embodiments.

[0843] In some embodiments, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts disclosed herein. 3 It is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)R y -C(=O)OR y -OR y -OC(=O)R y or -OC(=O)OR y ;

[0844] R 3 The C1-C6 alkyl or the C2-C6 alkenyl group is optionally substituted with 1 to 3 groups selected from the following: cyano, -C(=O)R y -C(=O)OR y -OR y -OC(=O)R y and -OC(=O)OR y ;where Ry 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.

[0845] In some embodiments, the compounds of any one of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) are selected from compounds 1-457 (Table A below), tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of any of the foregoing.

[0846] In some embodiments, the compounds of any one of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) are selected from compounds 458-532 (Table B below), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of any of the foregoing.

[0847] In some embodiments, the compounds of any one of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) are selected from compounds P1-P225 (Table E below), tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of any of the foregoing.

[0848] Table A. Compounds 1-457

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887] Table B. Compounds 458-532

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895] Table C. Compounds B1-B25

[0896]

[0897]

[0898]

[0899] Table D. Compounds W1-W32

[0900]

[0901]

[0902]

[0903]

[0904] Table E. Predicted compounds P1-P225

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925] Some embodiments of this disclosure include compounds 1-457, 458-532, B1-B25, W1-W32, P1-P225 (e.g., compounds 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433 and 435-457) or derivatives of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe) and (IXa)-(IXe), or tautomers thereof. In some embodiments, the derivative is a silicon derivative wherein at least one carbon atom of a compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, and P1-P225 (e.g., compound 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or a compound of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) has been substituted with silicon. In some embodiments, the derivative is a boron derivative wherein at least one carbon atom of a compound selected from compounds 1-457, 458-532, B1-B25, W1-W32 and P1-P225 (e.g., compound 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433 and 435-457) or a compound of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe) and (IXa)-(IXe) or their tautomers is substituted with boron.In other embodiments, the derivative is a phosphate derivative wherein at least one carbon atom in a compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, and P1-P225 (e.g., compound 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), or their tautomers, is replaced by phosphorus. Since the general properties of silicon, boron, and phosphorus are similar to those of carbon, replacing carbon with silicon, boron, or phosphorus can produce compounds with similar biological activities to the original carbon-containing compounds.

[0926] In some embodiments, the derivative is a silicon derivative in which one carbon atom of a compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, and P1-P225 (e.g., compound 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) and their tautomers has been 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 derivatives of this disclosure may comprise one or more deuterium-substituted hydrogen atoms. For example, one or more hydrogen atoms in the tert-butyl moiety (where carbon has been substituted by silicon) may be substituted with deuterium. In other embodiments, silicon derivatives of compounds selected from compounds 1-457, 458-532, B1-B25, W1-W32 and P1-P225 (e.g., compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433 and 435-457) or compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe) and (IXa)-(IXe) and their tautomers may have silicon incorporated into the heterocycle.

[0927] Examples of silicon derivatives of compounds 1-457 or of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) include the following compounds:

[0928] The undefined variables are defined by any of the following: (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe).

[0929] Examples of borosilicate derivatives of compounds 1-457 or of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) include the following compounds:

[0930]

[0931] In some embodiments, examples of phosphorus derivatives of compounds 1-457 or compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) include the following mixtures:

[0932] The undefined variables are defined by any of the following: (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe).

[0933] In some embodiments, examples of phosphate ester derivatives of formula (I) include the following compounds:

[0934] The variables that are not specifically defined are defined in equation (I).

[0935] In some embodiments, examples of phosphate ester derivatives of formula (I) include the following compounds:

[0936] The variables that are not specifically defined are defined in equation (I).

[0937] Another aspect of this disclosure provides pharmaceutical compositions comprising compounds selected from any of the following formulas: (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), compounds 1-457, compounds 458-532, compounds B1-B25, compounds W1-W32, compounds P1-P225 (e.g., compounds 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), 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 is administered to a patient in need, the pharmaceutical composition comprising at least one compound selected from formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), and compounds 1-457, 458-532, compounds B1-B25, compounds W1-W32, compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0938] 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.

[0939] 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)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 separate composition concurrently with, before, or after a composition comprising at least one additional active agent. In some embodiments, a compound comprising at least one selected from compounds 1-457, compounds 458-532, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), 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 separate composition simultaneously, before, or after a composition comprising at least one additional active agent.

[0940] In some embodiments, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 in the same pharmaceutical composition. In some embodiments, the compound is a compound selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0941] In some embodiments, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided in a method for treating AATD, wherein the method comprises co-administering the compound and an additional active agent. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0942] In some embodiments, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with an additional active agent, are provided for use in a method of treating AATD. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0943] In some embodiments, a method of using an additional active agent to treat AATD is provided, wherein the method comprises co-administering the additional active agent and compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0944] In some embodiments, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compounds and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compounds and the additional active agent are prepared for simultaneous administration. In some embodiments, the compounds and the additional active agent are prepared for sequential co-administration. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0945] In some embodiments, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with an additional active agent, are provided 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 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0946] In some embodiments, a method of treating AATD with an additional active agent is provided, wherein the additional active agent is prepared for administration in combination with compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), 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 compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0947] 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.

[0948] 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 with any other component of the pharmaceutical composition in a harmful manner, its use is contemplated within the scope of this disclosure.

[0949] 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), buffers (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.

[0950] 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.

[0951] 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)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), a tautomer of such compound, a deuterated derivative of such compound and tautomer, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-532, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), 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.

[0952] 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)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe) and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and a pharmaceutically acceptable salt thereof. In some embodiments, the method of modulating α-1-antitrypsin activity includes contacting the α-1-antitrypsin with at least one compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, and P1-P225 (e.g., compound 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0953] 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.

[0954] III. Preparation of Compounds

[0955] All genera, subgenera and specific compound formulas disclosed herein are considered part of this disclosure.

[0956] A. Compound of Formula I

[0957] The compounds disclosed herein may be prepared according to standard chemical practice or as described herein. Throughout the following synthetic schemes and in the description of compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), compounds 1-457, compounds 458-532, compounds B1-B25, compounds W1-W32, compounds P1-P225, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and salts of pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used:

[0958] abbreviation

[0959] BrettPhos Pd G4 = dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tris(propyl-2-yl))phenyl]phenyl]phosphine; methanesulfonic acid; N-methyl-2-phenylaniline; palladium

[0960] DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-2-amino

[0961] DMA = dimethylacetamide

[0962] DMAP = dimethylaminopyridine

[0963] DME = dimethoxyethane

[0964] DMF = dimethylformamide

[0965] DMSO = dimethyl sulfoxide

[0966] EtOH = ethanol

[0967] EtOAc = Ethyl acetate

[0968] HATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (phosphine hexafluoride ion)

[0969] MeOH = methanol

[0970] MP-TMT cleaner resin = macroporous polystyrene-bonded trithiotriazine, resin-bonded 2,4,6-trithiotriazine (TMT) equivalent.

[0971] MTBE = Methyl tert-butyl ether

[0972] NMM = N-methylmorpholine

[0973] NMP = N-methylpyrrolidine

[0974] Pd(dppf)₂Cl₂=[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0975] PdCl2 = Palladium(II) dichloride

[0976] PdCl2(PPh3)2=bis(triphenylphosphine)palladium(II) dichloride

[0977] SFC = Supercritical Fluid Chromatography

[0978] SPhos Pd G3=(2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate

[0979] TBAF = Tetrabutylammonium fluoride

[0980] 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

[0981] tBuXPhos Pd G3=[(2-Di--tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate

[0982] tBuXPhos Pd G4=di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine; dichloromethane; methanesulfonic acid; N-methyl-2-phenyl-aniline palladium(II)

[0983] TEA = Triethylamine

[0984] TFA = Trifluoroacetic acid

[0985] THF = Tetrahydrofuran

[0986] 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

[0987] 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)):

[0988] Option 1

[0989]

[0990] Scheme 1 illustrates a method for preparing compounds of formulas 1-2. PG 1 It is an alcohol protecting group, such as benzyl (Bn), methoxymethyl (MOM), or methyl (Me). 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 under a hydrogen atmosphere using a palladium / carbon catalyst. The reaction can be carried out under high pressure. Solvents such as MeOH, 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 protecting 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 alcohol protecting groups.

[0991] Option 2

[0992]

[0993] 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 Boric acid or ester of any suitable alkyl group (e.g., Me, Et) or hydrogen. 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 the halogenation of aromatic rings. For example, N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS) in solvents such as dichloromethane can be used. Compounds of Formula 2-4 can be 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, a catalyst such as Pd2(dba)3 in the presence of a ligand 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.

[0994] Option 3

[0995]

[0996] The method for preparing compounds of formulas 3-4 is shown in scheme 3. PG 2 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.

[0997] Option 4

[0998]

[0999] 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.

[1000] Option 5

[1001]

[1002] 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).

[1003] Option 6

[1004]

[1005] Scheme 6 illustrates a method for preparing indole of formula 2-1. Q 2 and Q 3It is a halogen, such as Br, Cl, or I. E 1 It 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 tBuXPhosPdG3, tBuXPhosPdG, 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).

[1006] Option 7

[1007]

[1008] 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 a suitable alkyl group such as ethyl or methyl. The N-aniline of Formula 7-1 can be arylated with boric acid or ester 7-2 using 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.

[1009] Option 8

[1010]

[1011] 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).

[1012] Option 9

[1013]

[1014] As shown in Scheme 9, any suitable conditions for coupling the compound of Formula 9-1 with the Sonagashira of the alkyne of Formula 9-2 can be used to prepare the compound of Formula 9-3. PG 4 The protecting group is any suitable ester (e.g., benzyl, methyl, tert-butyl), and all other variables are as defined above. Compounds of Formula 9-5 can be prepared from compounds of Formula 9-3 and amines of Formula 9-4 using an amination method with any suitable aryl halide. In some embodiments, the reaction is carried out in the presence of a tBuXPhos Pd G3 catalyst and NaOtBu. Solvents such as m-xylene can be used. Any suitable halogenating agent can be used to prepare compounds of Formula 9-6 from indoles of Formula 9-5. For example, N-iodosuccinimide or N-bromosuccinimide can be used. In some embodiments, compounds of Formula 9-8 can be prepared by Suzuki coupling of compounds of Formula 9-7 with compounds of Formula 9-6 using a suitable palladium catalyst and a base. For example, Pd(dppf)Cl2 and K2CO3 can be used. Compounds of Formula 9-10 can be prepared from compounds of Formula 9-8 using a standard method for removing the ester and alcohol protecting groups, suitable for the protecting groups used in this embodiment.

[1015] Option 10

[1016]

[1017] Scheme 10 relates to a method for preparing compounds of formula 10-7. Q8 It is a halogen, such as Br, I, or Cl. PG 4 These are standard amine protecting groups (e.g., Bn, Boc, CBz). PG 5 The protecting group is an ester, such as Me, Et, or tert-butyl. Compounds of Formula 10-3 can be prepared by Buchwald amination of compounds of Formula 10-1 and amines of Formula 10-2. In some embodiments, a catalyst such as Pd(OAc)2 with a ligand such as dppf can be used. The reaction can be carried out in the presence of a base such as sodium tert-butoxide. Compounds of Formula 10-5 can be prepared from alkynes of Formula 10-3 and Formula 10-4 using any suitable conditions of Larock indole cyclization. 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). Compounds of Formula 10-6 can be prepared from 10-5 using any suitable method for removing the ester protecting group. For example, in PG 5 In the case of a methyl group, a base such as LiOH or NaOH can be used. Any suitable method for removing the nitrogen protecting group can be used to prepare compounds 10⁻⁶ from 10⁻⁶. For example, in PG 4 In the case of benzyl, hydrogenation can be carried out using a palladium / carbon catalyst under a hydrogen atmosphere. In some embodiments, the reaction is carried out in a solvent such as THF.

[1018] Option 11

[1019]

[1020] Scheme 11 refers to an alternative method for preparing compounds of formula 11-3. Ring B is alkyl or alkoxy. The reductive amination reaction between an amine of formula 11-1 and a ketone or aldehyde of formula 11-2 provides a compound of formula 11-3. In some instances, reagents such as sodium triacetoxyborohydride can be used for reductive amination. Solvents such as AcOH can be used. The reaction can be carried out at room temperature. Example

[1021] 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.

[1022] Example 1. Synthesis of the compound

[1023] All specific and general compounds, methods for preparing those compounds, and intermediates disclosed for preparing those compounds are considered part of the disclosure herein.

[1024] A. Synthetic starting materials

[1025] The preparation of S1-S22 describes the synthetic route for the intermediates used to synthesize compounds 1-457.

[1026] Preparation of S1

[1027] 4-Benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (S1)

[1028]

[1029] Step 1. Synthesis of 1-benzyloxy-3-bromo-2-iodobenzene (C2)

[1030] A solution of 3-bromo-2-iodophenol C1 (129 g, 431.6 mmol) in acetone (1.5 L) was stirred for 5 minutes. K2CO3 (75 g, 542.7 mmol), NaI (21 g, 140.1 mmol), and bromomethylbenzene (55 mL, 462.4 mmol) were added. The reaction mixture was stirred at 55 °C for 7 hours. The mixture was then cooled to room temperature, filtered, and washed with acetone (2 × 100 mL). The combined filtrates were concentrated under vacuum. The residue was dissolved in dichloromethane (1.5 L) and washed with water (2 × 100 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (0–50% ethyl acetate / heptane) gave the product as a white solid (162 g, 96%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.54–7.46 (m, 2H), 7.40 (ddd, J = 7.9, 7.0, 1.1 Hz, 2H), 7.37–7.31 (m, 1H), 7.28 (dd, J = 8.0, 1.3 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 6.76 (dd, J = 8.2, 1.3 Hz, 1H), 5.16 (s, 2H).

[1031] Step 2. Synthesis of 4-[2-(2-benzyloxy-6-bromo-phenyl)ethynyl]tetrahydropyran (C3)

[1032] 1-Benzyloxy-3-bromo-2-iodobenzene C2 (200 g, 514.1 mmol), trimethyl(2-tetrahydropyran-4-ylethynyl)silane (140 g, 767.8 mmol), 1,4-dioxane (1200 mL), NEt3 (430 mL, 3.09 mol), TBAF (720 mL of 1 M, 720.0 mmol of THF solution), and water (20 mL, 1.1 mol). The mixture was purged with N2 for 10 minutes, and CuI (11 g, 57.8 mmol) was added. After purging with N2 for another 10 minutes, PdCl2(PPh3)2 (22 g, 31.3 mmol) was added. The mixture was heated at 65 °C for 6.5 hours, the heat was removed, and the mixture was stirred overnight at room temperature. Water (1 L) and saturated NH4Cl (500 mL) were added, the mixture was stirred for 10 minutes, and then divided into two equal portions. Each fraction was extracted with EtOAc (1.5 L), and the organic extract was washed successively with 1 M HCl aqueous solution (1 L) and brine (1 L), then dried (MgSO4), filtered, and concentrated. The two fractions were combined and dissolved in dichloromethane (300 mL). Silica gel chromatography (1.6 kg silica gel, gradient: 0-40% EtOAc / heptane) yielded the product as an amber oil (151 g, 79%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.33–7.25 (m, 2H), 7.25–7.10 (m, 3H), 7.03 (dd, J = 8.1, 1.0 Hz, 1H), 6.89 (t, J = 8.2 Hz, 1H), 6.68 (dd, J = 8.3, 1.0 Hz, 1H), 4.97 (s, 2H), 3.79 (ddd, J = 11.6, 6.9, 3.4 Hz, 2H), 3.40 (ddd, J = 11.2, 7.2, 3.3 Hz, 2H), 2.84 (tt, J = 7.7, 4.2 Hz, 1H), 1.85–1.70 (m, 2H), 1.61 (dtd, J = 13.2, 7.3, 3.2 Hz, 2H).

[1033] Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline (C4)

[1034] A solution of 4-[2-(2-benzyloxy-6-bromo-phenyl)ethynyl]tetrahydropyran C3 (262 g, 705.7 mmol) in m-xylene (3.9 L) was purged with nitrogen for 15 min. NaOtBu (200 g, 2.08 mol) was added, followed by bubbling with N2 for 15 min. 3,4-Difluoroaniline (84 mL) was added, and purging with N2 was continued for 15 min. tBuXPhos Pd G3 (15 g, 18.9 mmol) was added, followed by purging with N2 for another 10 min. The mixture was stirred, and after 90 min, the internal temperature increased from 21 °C to 29 °C. After another 2.5 h, the internal temperature decreased to 24 °C, and the mixture was then heated to 50 °C and held for 45 min. Add an additional tBuXPhosPdG3 (2.0 g, 2.52 mmol), stir the mixture at 50 °C for another 2 hours, pour the reaction mixture onto ice-water (6 L), and then add 2-MeTHF (3 L). After stirring, separate the layers. Wash the organic layer sequentially with water (4 L), 1 M HCl (3 L) aqueous solution, saturated NaHCO3 (3 L) aqueous solution, and brine (3 L). Then dry the organic layer (MgSO4), filter, and concentrate under vacuum. Purify by silica gel chromatography (3 kg silica gel, gradient: 0-40% EtOAc / heptane) to give a 2:1 mixture of product 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline C4 and cyclized product C5 (277 g, 94%) as a brown oil. The mixture was used in subsequent steps without further purification.

[1035] Step 4. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole (C5)

[1036] A solution of 277 g (660.4 mmol) of 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline (a mixture of ~2:1 aniline C4:indole C5) in MeCN (1.9 L) was purged with nitrogen for 15 min. PdCl2 (3.5 g, 19.7 mmol) was added, and the reaction was placed under positive N2 pressure, then heated to 50 °C and maintained for 1 h. The heat was then removed, and the reaction mixture was stirred overnight at room temperature. After 16 hours, the resulting suspension was filtered, the solid was collected, washed with heptane (400 mL), and dried by suction to give ~150 g of a grayish-white solid. The filtrate was concentrated to give ~100 g of a dark oily product, which was purified by silica gel chromatography (1.6 kg silica gel column, gradient: 0-40% EtOAc / heptane) (Note: the compound precipitates on the column, resulting in product loss), yielding another product (~90 g) as a grayish-white solid. This fraction of the product obtained by column chromatography was combined with the product separated from the reaction mixture. The mixture was treated with EtOAc (300 mL), the slurry was heated to reflux, and then heptane (1 L) was added. The mixture was then allowed to stand at room temperature for 2 hours, filtered, and the collected solid was washed with heptane (300 mL). The product was dried under vacuum to give a product (224.6 g) as slightly grayish-white crystals. The filtrate yielded another 8.0 g of grayish-white crystals, which were combined with the first batch of product to give the product 4-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole (232.6 g, 84%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.59–7.51 (m, 2H), 7.48–7.31 (m, 4H), 7.24 (ddd, J = 10.4, 7.0, 2.5 Hz, 1H), 7.14 (dddd, J = 8.7, 4.1, 2.5, 1.6 Hz, 1H), 7.09–7.00 (m, 1H), 6.66 (d, J = 0.7 Hz, 1H), 6.64 (s, 2H), 5.26 (s, 2H), 4.00 (ddd, J = 11.7, 4.2, 1.8 Hz, 2H), 3.37 (td, J = 11.7, 2.4 Hz, 2H), 2.80 (tt, J = 11.4, 4.0 Hz, 1H), 1.95–1.66 (m, 4H). 19F NMR (282MHz, chloroform-d) δ -134.09 (d, J = 21.5Hz), -136.75 (d, J = 21.7Hz). LCMS m / z 419.9 [M+1] + .

[1037] Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (S1)

[1038] 1-Iodopyrrolidine-2,5-dione (96 g, 413.9 mmol) was added in three portions to a solution of 4-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole C5 (159 g, 379.1 mmol) cooled to 0 °C (ice / water bath) in 2.5 L of CH2Cl2 for 10 minutes. The resulting reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was treated with water (600 mL) and 1 M Na2S2O3 (600 mL). The organic layer was separated and washed successively with saturated aqueous solutions of NaHCO3 (~600 mL) and brine (~600 mL each). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was treated with EtOAc (~200 mL) and heated under reflux for 15 minutes to give a suspension. The suspension was treated with heptane (~1 L), and the resulting suspension was slowly cooled to room temperature (overnight) over 14 hours, and then filtered. The collected solid was washed with heptane (100 mL) and then dried in a vacuum oven at 45 °C for 2 hours to give the product as a brown solid (180 g, 86%). 1 HNMR (300MHz, DMSO-d6) δ7.81-7.54(m,4H),7.49-7.37(m,2H),7.37-7.26(m,2H),6.99(t,J=8.1Hz,1H),6.73(d,J=7.9Hz,1H),6.43(d,J=8.2Hz, 1H),5.26(s,2H),3.86(dd,J=11.5,4.1Hz,2H),3.21(ddd,J=12.0,9.8,5 .1Hz,2H),3.06-2.84(m,1H),2.19(dt,J=12.7,4.7Hz,2H),1.56(s,2H). 19 F NMR(282MHz,DMSO-d6)δ-135.42,-135.50,-136.83,-136.91.LCMS m / z 545.21[M+1] + .

[1039] Preparation of S2

[1040] 4-Benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (S2)

[1041]

[1042] Step 1. Synthesis of 3-benzyloxy-2-bromo-4-fluoroaniline C7

[1043] KOtBu (8.68 g, 77.4 mmol) was added to a solution of 3-amino-2-bromo-6-fluorophenol C6 (15.6 g, 75.8 mmol) and chloromethylbenzene (9.6 g, 75.8 mmol) in DMF (120 mL). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with EtOAc, and washed with water. The organic layer was dried and concentrated. The crude product was purified on silica gel (gradient: 10–40% EtOAc / hexane) to give the product. 3-Benzyloxy-2-bromo-4-fluoroaniline (17.8 g, 75%) LCMS m / z 295.94 [M+H] + .

[1044] Step 2. Synthesis of 3-benzyloxy-4-fluoro-2-iodoaniline (C8)

[1045] 3-Benzyloxy-2-bromo-4-fluoroaniline (7.36 g, 24.9 mmol), NaI (15 g, 100.1 mmol), N,N'-dimethylethane-1,2-diamine (780 mg, 8.9 mmol), and CuI (980 mg, 5.146 mmol) were mixed into 1,4-dioxane (60 mL). The reaction mixture was stirred in a sealed container and heated at 140 °C overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL). Column filtration. The filtrate was washed with water and brine, and dried over Na₂SO₄. The solvent was removed, and the crude product was purified on silica gel (220 g column, 10-90% EtOAc / hexane) to obtain the desired product. 3-Benzyloxy-4-fluoro-2-iodoaniline (7.5 g, 84%) LCMS m / z 344.17 [M+H] + .

[1046] Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-iodoaniline (C9)

[1047] 3-Benzyloxy-4-fluoro-2-iodoaniline (2.68 g, 7.810 mmol), (3,4-difluorophenyl)boronic acid (1.82 g, 11.53 mmol), K₂CO₃ (3.2 g, 23.15 mmol), and copper diacetoxy (1.68 g, 9.25 mmol) were mixed in DMSO (20 mL) and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and then... Column filtration. The filtrate was washed with water. The organic layer was dried and concentrated. The crude product was purified on silica gel (120 g column, 10-40% EtOAc / hexane) to give the desired product: 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-iodoaniline (1.8 g, 41%). Calculated LCMS m / z value: 455.87 [M+H] + .

[1048] Step 4. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (C10)

[1049] 3-Benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-iodoaniline (1.8 g, 3.56 mmol), 4-ethynyltetrahydropyran (600 mg, 5.45 mmol), PdCl2(PPh3)2 (400 g, 569.9 mmol), and CuI (110 mg, 0.58 mmol) were mixed into 1,4-dioxane (10 mL) and Et3N (10 mL), and the reaction was degassed with nitrogen for 30 seconds. The reaction was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with EtOAc, and washed with water. The organic layer was dried and concentrated. The crude product was purified on silica gel (4 g column, 10-40% hexane: EtOAc) to obtain the desired product. 3-Benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (1.2 g, 75%) LCMS m / z 438.1 [M+1]+.

[1050] Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl-indole (C11)

[1051] 3-Benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (1.6 g, 3.658 mmol) was dissolved in MeCN (20 mL) and PdCl2 (120 mg, 0.68 mmol). The reaction was heated at 45°C overnight. The reaction was then cooled to room temperature and analyzed by... Column filtration. The crude product was diluted with EtOAc and washed with water. The organic layer was dried and concentrated. The product was purified by silica gel chromatography (40 g column, 10-90% EtOAc / hexane) to obtain 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl-indole (1.4 g, 77%). 1HNMR(400MHz, DMSO-d6)δ7.76(ddd,J=11.2,7.2,2.6Hz,1H),7.68(dt,J=10.6,8.9Hz,1H),7.58-7.49(m,2H),7.47-7.39(m, 2H), 7.39-7.29 (m, 2H), 6.95 (dd, J=11.8, 8.8Hz, 1H), 6.65 (ddd, J=8.8, 3.5, 0.8Hz, 1H), 6.60 (d, J=0.8Hz, 1H), 5.29 (s, 2H). LCMS m / z 438.06[M+1] +

[1052] Step 6. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (S2)

[1053] A solution of 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl-indole (730 mg, 1.33 mmol) in dichloromethane (10 mL) and 1-iodopyrrolidine-2,5-dione (345 mg, 1.533 mmol) was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with EtOAc, and washed with water. The organic layer was dried and concentrated. The crude product was purified on silica gel (4 g column, 10-40% Hex:EtOAc) to give the desired product: 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (720 mg, 81%). 1 H NMR(400MHz,DMSO-d6)δ7.80(ddd,J=11.1,7.3,2.6Hz,1H),7.71(dt,J=10.6,8.9Hz,1H) ,7.64-7.57(m,2H),7.50-7.32(m,4H),7.06(dd,J=11.5,8.9Hz,1H),6.61(dd,J=8.9,3. 7Hz,1H),5.13(s,2H),3.87(dd,J=11.5,4.2Hz,2H),3.22(tdd,J=12.0,7.2,2.0Hz,2H), 2.93(tt,J=12.4,3.6Hz,1H), 2.21(tq,J=16.6,5.7,4.4Hz,2H), 1.58(t,J=10.1Hz,2H). LCMS m / z 563.08[M+H] + .

[1054] Preparation of S3

[1055] 4-Benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (S3)

[1056]

[1057] Step 1. Synthesis of 1-benzyloxy-3-bromo-5-fluoro-2-iodobenzene (C13)

[1058] A mixture of 3-bromo-5-fluoro-2-iodophenol C12 (50 g, 157.8 mmol), bromomethylbenzene (27.8 g, 162.5 mmol), NaI (4 g, 26.7 mmol), and K2CO3 (45 g, 325.6 mmol) in acetone (500 mL) was stirred overnight at room temperature. The reaction mixture was then subjected to… The filtrate was filtered and concentrated to dryness, then purified by silica gel chromatography (gradient: 0-40% CH₂Cl₂ / heptane) to give the product as a white solid. 1-Benzyloxy-3-bromo-5-fluoro-2-iodobenzene (55 g, 81%). LCMS m / z 406.56 [M+1] + .

[1059] Step 2. Synthesis of 4-[2-(2-benzyloxy-6-bromo-4-fluoro-phenyl)ethynyl]tetrahydropyran (C14)

[1060] A solution of 1-benzyloxy-3-bromo-5-fluoro-2-iodobenzene C13 (19 g, 46.7 mmol), PdCl2(PPh3)2 (1.98 g, 2.8 mmol), and CuI (890 mg, 4.673 mmol) in anhydrous DMF (150 mL) was degassed for 10 min. Then, trimethyl(2-tetrahydropyran-4-ylethynyl)silane (9.78 g, 53.64 mmol) and diethylamine (7.22 mL, 69.8 mmol) were added, followed by TBAF (54 mL of 1 M, 54.00 mmol of THF solution). The reaction mixture was stirred overnight at 65 °C. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated to dryness. Purification by silica gel chromatography (gradient: 0-30% EtOAc / heptane) yielded the product as a pale yellow solid. 4-[2-(2-benzyloxy-6-bromo-4-fluoro-phenyl)ethynyl]tetrahydropyran (11.3 g, 62%). 1¹H NMR (400MHz, chloroform-d) δ 7.51–7.42 (m, 2H), 7.41–7.35 (m, 3H), 6.96 (dd, J = 8.1, 2.4 Hz, 1H), 6.61 (dd, J = 10.3, 2.4 Hz, 1H), 5.10 (s, 2H), 3.94 (ddd, J = 11.5, 6.9, 3.3 Hz, 2H), 3.61–3.53 (m, 2H), 2.99 (tt, J = 7.7, 4.2 Hz, 1H), 1.97–1.88 (m, 2H), 1.83–1.72 (m, 2H).

[1061] Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (C15)

[1062] A solution (pale brown solution) of 4-[2-(2-benzyloxy-6-bromo-4-fluoro-phenyl)ethynyl]tetrahydropyran C14 (2 g, 5.14 mmol) and 3,4-difluoroaniline (930 mg, 7.2 mmol) in xylene (30 mL) was purged with nitrogen for 10 min, followed by the addition of NaOtBu (1.5 g, 15.61 mmol) and tBuXPhos Pd G3 (200 mg, 0.25 mmol). The reaction was stirred at room temperature for 2 h. The reaction was cooled to room temperature, and then ice water (20 mL) and EtOAc (50 mL) were added. The organic layer was separated, washed with brine, dried, and concentrated. The product was purified by silica gel chromatography (gradient: 0-30% EtOAc / hexane) to give a pale yellow solid. 3-Benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (2.2 g, 97%). 1¹H NMR (400 MHz, chloroform-d) δ 7.54–7.45 (m, 2H), 7.42 (ddd, J = 7.9, 7.0, 1.1 Hz, 2H), 7.39–7.31 (m, 1H), 7.16 (dt, J = 10.0, 8.8 Hz, 1H), 7.06 (ddd, J = 11.6, 6.9, 2.7 Hz, 1H), 6.92 (dddd, J = 8.5, 4.0, 2.6, 1.6 Hz, 1H), 6.50 (s, 1H), 6.43 (d d,J=11.0,2.3Hz,1H),6.21(dd,J=10.5,2.3Hz,1H),5.13(s,2H),3.94(ddd,J=11.6,6.2,3.5Hz,2H),3.56(dd d,J=11.4,8.0,3.1Hz,2H),3.01(tt,J=8.2,4.1Hz,1H),2.03-1.89(m,2H),1.78(dtd,J=13.3,8.1,3.5Hz,2H). LC-MS m / z438.3[M+1] + .

[1063] Step 4. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-tetrahydropyran-4-yl-indole (C16)

[1064] PdCl₂ (600 mg, 3.4 mmol) was added to a solution of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline C15 (14.5 g, 33.0 mmol) in MeCN (150 mL) (a pale brown solution). The reaction was heated at 60 °C for 12 h. The solution was concentrated to dryness and purified by silica gel chromatography (gradient: 0-25% EtOAc / heptane) to give a white solid. 4-Benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-tetrahydropyran-4-ylindole (13.6 g, 94%) LCMS m / z 438.3 [M+1] + .

[1065] Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (S3)

[1066] N-iodosuccinimide (26.4 g, 117.3 mmol) was added to a solution of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-tetrahydropyran-4-yl-indole C16 (46.7 g, 106.8 mmol) in dichloromethane (875 mL) at 3.5 °C (ice-water bath). The mixture was slowly heated to room temperature in an ice-water bath and stirred for 18 h. The reaction mixture was washed successively with 1 M sodium thiosulfate aqueous solution, saturated NaHCO3 aqueous solution, and brine (800 mL each), then dried (MgSO4), filtered, and concentrated. The residue was treated with EtOAc (100 mL), and the resulting suspension was rotated on a rotary evaporator at 75 °C for 1 h. The suspension was treated with heptane (100 mL) and then allowed to stand at room temperature for 2 h. The crystals obtained by filtration were washed with heptane (100 mL) and then dried by suction to give the product, which was a grayish-white solid. 4-Benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (54.6 g, 91%). 1 H NMR(300MHz,DMSO-d6)δ7.82-7.56(m,4H),7.49-7.38(m,2H),7.38-7.26(m, 2H),6.70(dd,J=12.0,2.1Hz,1H),6.24(dd,J=9.4,2.1Hz,1H),5.28(s,2H),3 .85(dd,J=11.4,4.1Hz,2H),3.20(tdd,J=11.7,5.4,2.0Hz,2H),2.91(ddd,J =12.5,8.8,3.7Hz,1H),2.16(dq,J=17.6,7.2,6.2Hz,2H),1.65-1.44(m,2H). 19 F NMR (282MHz, DMSO-d6) δ -116.95, -135.20 (d, J = 22.9Hz), -136.62 (d, J = 22.9Hz). LCMS m / z 563.12[M+1]+.

[1067] Preparation of S4

[1068] 4-Benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (S4)

[1069]

[1070] Step 1. Synthesis of 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol (C17)

[1071] A solution of 1-benzyloxy-3-bromo-5-fluoro-2-iodobenzene C13 (5 g, 12.3 mmol) and 2,2-dimethylbut-3-yn-1-ol (1.8 g, 18.3 mmol) in 1,4-dioxane (40 mL) and Et3N (40 mL) was purged with nitrogen for 10 min, followed by the addition of CuI (157 mg, 0.82 mmol) and PdCl2(PPh3)2 (500 mg, 0.71 mmol). The resulting reaction mixture was heated to 50 °C and stirred overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and partitioned between saturated NH4Cl aqueous solution (~50 mL) and ethyl acetate (~150 mL). After stirring for 10 min, the organic layer was separated, washed with 1N HCl solution (2 x 50 mL), water (30 mL), and brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 0-70% ethyl acetate / heptane) to give the product as a clear, yellow, viscous oil. 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol (4.23 g, 90%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.49 (dtd, J = 6.9, 1.4, 0.7Hz, 2H), 7.46–7.32 (m, 3H), 6.98 (dd, J = 8.0, 2.4Hz, 1H), 6.65 (dd, J = 10.2, 2.4Hz, 1H), 5.12 (s, 2H), 3.49 (d, J = 7.1Hz, 2H), 1.34 (s, 6H). LCMS m / z 377.01 [M+1] + .

[1072] Step 2. Synthesis of 1-benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzene (C18)

[1073] A mixture of 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-1-ol C17 (3.65 g, 9.5 mmol) and iodomethane (1.5 mL, 24.1 mmol) in THF (50 mL) was cooled to 0 °C under nitrogen. NaH (600 mg, 15.0 mmol) was added, the resulting reaction mixture was stirred, and allowed to warm to room temperature. The mixture was poured into water (50 mL), partitioned between saturated NH4Cl solution (~50 mL) and ethyl acetate (~150 mL), and stirred for 10 minutes. The organic layer was separated and washed successively with 1N HCl solution (2 x 50 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over MgSO4, filtered, and concentrated under reduced pressure to give the product as a dark oil that turned into a brown solid under vacuum. 1-Benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzene (3.8 g, 100%). 1 H NMR(400MHz,CD3CN)δ7.51(dtd,J=6.9,1.4,0.7Hz,2H),7.46-7.32(m,3H),7.06(dd,J=8.4,2 .4Hz,1H),6.87(dd,J=10.8,2.4Hz,1H),5.13(s,2H),3.32(s,3H),3.31(s,2H),1.27(s,6H). LCMS m / z390.96[M+1] + .

[1074] Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)aniline (C19)

[1075] To a solution of 1-benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)benzene C18 (667 mg, 1.71 mmol) and 3,4-difluoroaniline (330 mg, 2.56 mmol) in degassed xylene (12 mL), NaOtBu (500 mg, 5.20 mmol) was added, followed by the addition of tBuXPhos Pd G3 (70 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 12 hours, diluted with ice water (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic compounds were concentrated to dryness and purified by silica gel chromatography (gradient: 0–25% EtOAc / heptane) to give the product as a brown oil. 3-Benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)aniline (667 mg, 89%). 1HNMR (400MHz, chloroform-d) δ7.53 (d, J=7.3Hz, 2H), 7.42 (dd, J=8.1, 6.8Hz, 3H), 7.39 -7.33(m,1H),7.16(dt,J=10.4,8.9Hz,1H),7.07(ddd,J=11.8,6.9,2.6Hz,1H) ,7.01-6.89(m,2H),6.46(dt,J=11.1,1.7Hz,1H),6.18(dt,J=10.7,1.5Hz,1H) ,5.14(s,2H),3.41(d,J=1.0Hz,3H),3.37(d,J=1.1Hz,2H),1.43-1.33(m,6H). LCMS m / z 440.42 [M+1] + .

[1076] Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-(2-methoxy-1,1-dimethyl-ethyl)indole (C20)

[1077] PdCl2 (21 mg, 0.12 mmol) was added to a solution of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(4-methoxy-3,3-dimethyl-but-1-ynyl)aniline C19 (515 mg, 1.17 mmol) in MeCN (5 mL). The reaction mixture was stirred at room temperature for 8 hours. The mixture was then diluted with ice water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated to dryness and purified by silica gel chromatography (gradient: 0-25% EtOAc / heptane) to give a white solid. 4-Benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-(2-methoxy-1,1-dimethyl-ethyl)indole (483 mg, 94%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.45–7.38 (m, 2H), 7.38–7.30 (m, 2H), 7.30–7.20 (m, 2H), 7.18–7.10 (m, 1H), 7.06 (dddd, J = 8.5, 4.0, 2.5, 1.6 Hz, 1H), 6.52 (d, J = 0.8 Hz, 1H), 6.29 (dd, J = 11.6, 2.0 Hz, 1H), 5.89 (ddd, J = 9.4, 1.9, 0.7 Hz, 1H), 5.08 (s, 2H), 3.15 (s, 3H), 3.06 (s, 2H), 1.20 (s, 3H), 1.16 (s, 3H). LCMS m / z 440.37 [M+1] + .

[1078] Step 6. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (S4)

[1079] 4-Benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-(2-methoxy-1,1-dimethyl-ethyl)indole C20 (357 mg, 0.81 mmol) was added to dichloromethane (5 mL) with N-iodosuccinimide (190 mg, 0.84 mmol) and stirred for 1 hour. The mixture was concentrated to dryness and purified by silica gel chromatography (gradient: 0-25% EtOAc / hexane) to give the product as a white solid. 4-Benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (432 mg, 93%). LCMS m / z 565.3 [M+1] + .

[1080] Preparation of S5

[1081] 4-Benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (S5)

[1082]

[1083] Step 1. Synthesis of 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol (C21)

[1084] In a 3L, 3-necked RB flask equipped with a top-mounted stirrer, temperature probe, reflux condenser, and nitrogen inlet, a solution of 1,4-dioxane (1.1L) containing 1-benzyloxy-3-bromo-2-iodobenzene C2 (160g, 411.3mmol) and 2,2-dimethylbut-3-yn-1-ol (51g, 519.6mmol) was added and stirred for 5 minutes. Then, N-isopropylprop-2-amine (370mL, 2.64mol) was added. The reaction mixture was purged with nitrogen for approximately 15 minutes, followed by the addition of cuprous iodide (3.7g, 19.4mmol) and PdCl2 (12.5g, 17.8mmol). The resulting reaction mixture was heated to 50°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and poured into water (300mL). A saturated aqueous solution of NH4Cl (approximately 400mL) was added, followed by ethyl acetate (approximately 2L), and the mixture was stirred for 15 minutes. The organic layer was separated, washed with 1N HCl solution (2 x 200 mL) and brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure.

[1085] The product was purified by silica gel chromatography (gradient: 0-50% ethyl acetate / heptane) to obtain a yellow solid: 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol (130 g, 88%). 1 HNMR(400MHz, chloroform-d)δ7.48(ddt,J=7.4,1.5,0.7Hz,2H),7.44-7.37(m,2H),7.36-7.29(m,1H),7.19(dd,J=8.1,1.0Hz,1H), 7.08(t,J=8.2Hz,1H),6.86(dd,J=8.3,1.0Hz,1H),5.13(s,2H),3.48(d,J=7.2Hz,2H),2.12(t,J=7.2Hz,1H),1.33(s,6H). LCMS m / z 359.02[M+1] + .

[1086] Step 2. Synthesis of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethyl-silane (C22)

[1087] A solution of 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-1-ol C21 (130 g, 361.9 mmol) in DMF (850 mL) was added to a 3 L, 3-necked RB flask equipped with a top stirrer, temperature probe, reflux condenser, and nitrogen inlet. The mixture was stirred at ambient temperature for 5 min, and then imidazole (64 g, 940.1 mmol) and TBSCl (64 g, 424.6 mmol) were added (observed Tmax = 31 °C). The reaction mixture was poured into ice / water (~1 L) and extracted with MTBE (2 x 1 L). The organic phase was washed with 1 N HCl (2 x 200 mL) and brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column: 1.5 kg Isco, gradient: 0-50% ethyl acetate / heptane) to give the product as a clear, pale yellow oil. [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethyl-silane (164g, 96%). 1HNMR (400MHz, chloroform-d) δ7.55-7.44(m,2H),7.42-7.35(m,2H),7.35-7.28(m,1H),7.19(dd,J=8.1,1.0Hz,1H),7.04 (t,J=8.2Hz,1H),6.83(dd,J=8.4,1.0Hz,1H),5.12(s,2H),3.59(s,2H),1.31(s,6H),0.90(s,9H),0.05(s,6H).

[1088] Step 3. Synthesis of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(3,4-difluorophenyl)aniline (C23)

[1089] [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-alkynoxy]-tert-butyl-dimethyl-silane C22 (11 g, 23.2 mmol) and 3,4-difluoroaniline (3.27 g, 25.33 mmol) in xylene (60 mL) were added under nitrogen atmosphere with NaOtBu (6 g, 62.4 mmol), followed by tBuXPhos Pd G3 (315 mg, 0.40 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and saturated NH4Cl and extracted with EtOAc (x 2). The combined organic compounds were concentrated to dryness and purified by silica gel chromatography (column: 220 g silica gel, gradient: 0-50% EtOAc / heptane) to give the product as a yellow oil. 3-Benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(3,4-difluorophenyl)aniline (11.6 g, 96%). 1 H NMR (400MHz, chloroform-d) δ7.49 (ddt, J = 7.4, 1.3, 0.7Hz, 2H), 7.38-7.32 (m, 2H), 7.31-7.25 (m, 1H), 7.10-6.96 (m, 3H), 6.86-6.8 0(m,1H),6.70(dd,J=8.3,0.8Hz,1H),6.43-6.39(m,2H),5.11(s,2H),3.53(s,2H),1.28(s,6H),0.84(s,9H),0.00(s,6H). LCMS m / z 522.52[M+1] + .

[1090] Step 4. Synthesis of 2-[4-benzyloxy-1-(3,4-difluorophenyl)indol-2-yl]-2-methyl-prop-1-ol (C24)

[1091] A solution of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-1-ynyl]-N-(3,4-difluorophenyl)aniline C23 (11.6 g, 22.2 mmol) in MeOH (100 mL) and EtOAc (50.7 mL) was purged with nitrogen for 1 hour. PdCl2(CH3CN)2 (336 mg, 1.30 mmol) was added, and the mixture was heated to 60 °C overnight. The reaction was concentrated under reduced pressure and then purified by silica gel chromatography (gradient: 0-75% EtOAc / heptane) to give a white solid. 2-[4-benzyloxy-1-(3,4-difluorophenyl)indol-2-yl]-2-methyl-prop-1-ol (8.2 g, 91%). 1 H NMR (400MHz, chloroform-d) δ7.55(dt,J=6.3,1.4Hz,2H),7.48-7.41(m,2H),7.41-7.31(m,2H),7.31-7.24(m,3H),7.22-7.15(m,1H),7.02(t,J=8.0Hz ,1H),6.74(d,J=0.8Hz,1H),6.63(d,J=7.8Hz,1H),6.33(d,J=8.2Hz,1H),5.26(s,2H),3.53(dd,J=6.0,1.6Hz,2H),1.28(s,3H),1.27(s,3H). LCMS m / z 408.37[M+1] + .

[1092] Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indole (C25)

[1093] At 0 °C, 2-[4-benzyloxy-1-(3,4-difluorophenyl)indol-2-yl]-2-methyl-prop-1-ol C24 (500 mg, 1.23 mmol) and MeI (120 μL, 1.928 mmol) in THF (5 mL) were added in a single addition of NaH (60 mg, 60% w / w, 1.5 mmol), and the mixture was warmed to room temperature. After 1 hour, the reaction was complete. Water (5 mL) and saturated NH4Cl (5 mL) were added to the reaction mixture, and the mixture was then extracted with EtOAc (3 x 5 mL). The combined organic fractions were washed with brine (1 x 2 mL), dried over MgSO4, and concentrated to give 4-benzyloxy-1-(3,4-difluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indol (509 mg, 99%). 1¹H NMR (400MHz, chloroform-d) δ 7.52–7.45 (m, 2H), 7.42–7.34 (m, 2H), 7.33–7.17 (m, 3H), 7.13 (dddd, J = 8.6, 4.0, 2.5, 1.6 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.63 (d, J = 0.9 Hz, 1H), 6.54 (dd, J = 7.8, 0.6 Hz, 1H), 6.25 (dt, J = 8.3, 0.7 Hz, 1H), 5.18 (s, 2H), 3.20 (s, 3H), 3.14 (s, 2H), 1.26–1.20 (m, 6H). LCMS m / z calculated value 421.18533, measured value 422.37 [M+H]. + .

[1094] Step 6. 4-Benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (S5)

[1095] A solution of 4-benzyloxy-1-(3,4-difluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indole C25 (518.4 mg, 1.23 mmol) in dichloromethane (5 mL) was added to NIS (290 mg, 1.29 mmol) and stirred for 2 hours. The mixture was concentrated and dissolved in dichloromethane. The product was purified by silica gel chromatography (gradient: 0-20% EtOAc / hexane) to obtain a white solid. 4-Benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (675 mg, 98%) 1 ¹H NMR (400MHz, chloroform-d) δ 7.65 (ddt, J = 7.4, 1.3, 0.7Hz, 2H), 7.48–7.39 (m, 2H), 7.39–7.35 (m, 1H), 7.34–7.28 (m, 1H), 7.26–7.18 (m, 1H), 7.13 (dddd, J = 8.5, 4.0, 2.5, 1.6Hz, 1H), 6.97 ( dd,J=8.3,7.9Hz,1H),6.63(dd,J=7.9,0.8Hz,1H),6.28(dd,J=8.3,0.7Hz,1H),5.26(s, 2H), 3.79 (d, J = 9.1Hz, 1H), 3.71 (d, J = 9.1Hz, 1H), 1.59 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H). LCMS m / z 547.28[M+H] + .

[1096] Preparation of S6

[1097] 1-(3-Chloro-4-fluoro-phenyl)-3-iodo-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole (S6)

[1098]

[1099] Step 1. Synthesis of 1-bromo-2-iodo-3-(methoxymethoxy)benzene (C27)

[1100] To a solution of 3-bromo-2-iodophenol C26 (5.2 g, 17.40 mmol) and DIPEA (4.5 mL, 25.8 mmol) in dichloromethane (50 g), a solution of chloro(methoxy)methane (1.6 mL, 21.1 mmol) in dichloromethane (10 mL) was added dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. NH4Cl (20 mL) aqueous solution and water (10 mL) were added, and the mixture was stirred for 5 minutes. The organic layer was separated, dried over sodium sulfate, and concentrated to give the product as a brown liquid, which was used directly in the next step. 1-Bromo-2-iodo-3-(methoxymethoxy)benzene (6.1 g, 100%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.34 (dd, J = 8.0, 1.3Hz, 1H), 7.18 (t, J = 8.1Hz, 1H), 6.99 (dd, J = 8.3, 1.3Hz, 1H), 5.26 (s, 2H), 3.53 (s, 3H). LCMS m / z 342.22 [M+H] + .

[1101] Step 2. Synthesis of 4-[2-[2-bromo-6-(methoxymethoxy)phenyl]ethynyl]tetrahydropyran (C28)

[1102] Water (250 μL, 13.9 mmol) was added to a solution of 1-bromo-2-iodo-3-(methoxymethoxy)benzene 27 (2 g, 5.8 mmol) and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (1.28 g, 7.02 mmol) in DMF (11 mL) and triethylamine (11 mL), and the mixture was purged with nitrogen for 15 min. CsF (2 g, 13.17 mmol), PdCl2(PPh3)2 (245 mg, 0.35 mmol), and CuI (115 mg, 0.60 mmol) were added, and the reaction was heated to 90 °C overnight. The mixture was cooled, and triethylamine was removed under vacuum. Ice-water (100 mL) was added, and the mixture was extracted with diethyl ether (3 x 100 mL). The organic layer was washed with water (200 mL), then with brine (200 mL), and concentrated. The product was purified by silica gel chromatography (gradient: 0-30% ethyl acetate / heptane) to obtain a pale yellow oil. 4-[2-[2-bromo-6-(methoxymethoxy)phenyl]-ethynyl]tetrahydropyran (1.43 g, 75%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.24 (dd, J = 7.2, 1.8Hz, 1H), 7.11–7.01 (m, 2H), 5.23 (s, 2H), 4.02 (ddd, J = 11.5, 7.0, 3.4Hz, 2H), 3.62 (ddd, J = 11.1, 7.2, 3.3Hz, 2H), 3.51 (s, 3H), 3.01 (tt, J = 7.7, 4.2Hz, 1H), 2.01–1.91 (m, 2H), 1.87–1.77 (m, 2H). LCMS m / z 325.09 [M+H] + .

[1103] Step 3. N-(3-chloro-4-fluoro-phenyl)-3-(methoxymethoxy)-2-(2-tetrahydropyran-4-ylethynyl)aniline (C29) and 1-(3-chloro-4-fluoro-phenyl)-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole (C30)

[1104] A solution of 4-[2-[2-bromo-6-(methoxymethoxy)phenyl]ethynyl]tetrahydro-pyran C28 (1.5 g, 4.61 mmol) and 3-chloro-4-fluoroaniline (940 mg, 6.46 mmol) in xylene (30 mL) was degassed for 5 min. Sodium tert-butoxide (1.33 g, 13.8 mmol) was added, and the solution was degassed again for 5 min. tBuXPhosPd G3 (529.6 mg, 0.66 mmol) was added, and the reaction was stirred at room temperature for 3 h. Ice water (50 mL) and EtOAc (50 mL) were added. After stirring for 5 min, the aqueous layer was separated and washed with EtOAc (20 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Purification was performed by silica gel chromatography (gradient: 0-40% EtOAc / heptane) to give products C29 and C30. N-(3-chloro-4-fluoro-phenyl)-3-(methoxymethoxy)-2-(2-tetrahydropyran-4-ylethynyl)aniline C29 (1.39 g, 75%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.25 (dd, J = 6.3, 2.7Hz, 1H), 7.11 (t, J = 8.5Hz, 2H), 7.05 (ddd, J = 8.9, 4.2, 2.7Hz, 1H), 6.78 (dd, J = 8.3, 0.8Hz, 1H), 6.63 (dd, J = 8.3, 0.8Hz, 1H), 6.36 (s, 1H), 5. 27(s,2H),4.00(ddd,J=11.6,6.0,3.6Hz,2H),3.62(ddd,J=11.5,8.3,3.0Hz,2H),3.55(s ,3H),3.02(tt,J=8.3,4.1Hz,1H),2.05-1.94(m,2H),1.82(dtd,J=13.4,8.3,3.6Hz,2H). LCMS m / z 390.27[M+H] + .

[1105] 1-(3-chloro-4-fluoro-phenyl)-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole C30 (0.37 g, 19%). 1H NMR (400MHz, chloroform-d) δ7.21 (dd, J=6.3, 2.7Hz, 1H), 7.14-7.01 (m, 4H), 6.97 (ddt, J=8.9, 4.0, 2.2Hz, 1H), 6.79 (dd, J=8.3, 0.8Hz, 1H), 6.68 (ddd, J=8.7, 4.1, 2.6Hz, 1H), 6.58 (dd, J=8.3, 0.9Hz, 1H), 6. 34(s,1H),5.79(d,J=2.7Hz,1H),5.26(s,2H),4.00(ddd,J=11.6,6.0,3.6Hz,2H),3.61(ddd,J=11. 5,8.2,3.1Hz,2H),3.55(s,3H),3.02(tt,J=8.3,4.1Hz,1H),2.06-1.93(m,2H),1.89-1.77(m,2H).

[1106] Step 4. Synthesis of 1-(3-chloro-4-fluoro-phenyl)-3-iodo-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole (S6)

[1107] N-iodosuccinimide (755 mg, 3.36 mmol) was added to a solution of 1-(3-chloro-4-fluoro-phenyl)-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole C30 in dichloromethane (20 mL). The reaction mixture was stirred for 30 minutes. The mixture was then diluted with water, and the organic layer was concentrated to dryness. The product was purified by silica gel chromatography (gradient: 0-25% EtOAc / heptane) as a white solid, which was used in the next step. 1-(3-chloro-4-fluoro-phenyl)-3-iodo-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole (1.38 g, 83%) 1 ¹H NMR (400 MHz, chloroform-d) δ 7.43–7.37 (m, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 7.21 (ddd, J = 8.7, 4.2, 2.4 Hz, 1H), 7.05 (td, J = 8.1, 2.4 Hz, 1H), 6.81 (ddd, J = 7.9, 4.4, 0.8 Hz, 1H), 6.53 (ddd, J = 14 .5,8.3,0.7Hz,1H),5.36(s,2H),4.02(dd,J=11.5,4.6Hz,2H),3.63(d,J=3.9Hz,3H),3.39( tdd,J=11.9,5.6,2.0Hz,2H),3.11(tt,J=12.5,3.6Hz,1H),2.55-2.17(m,2H),1.60(s,2H). LCMS m / z 515.32[M+H]+ .

[1108] Preparation of S7

[1109] 4-Benzyloxy-6-fluoro-1-(4-fluoro-3-methyl-phenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (S7)

[1110]

[1111] Step 1. Synthesis of 4-[2-(2-bromo-4-fluoro-6-methoxy-phenyl)ethynyl]tetrahydropyran (C34)

[1112] In a 5L 3-necked RB flask equipped with a top stirrer, temperature probe, and nitrogen inlet, add a solution of 1,4-dioxane (1.5L) containing 1-bromo-5-fluoro-2-iodo-3-methoxy-benzene C33 (264g, 797.8mmol) and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (250g, 1.3mol). Stir the mixture for 5 minutes, then add iPrNH2 (650mL, 4.64mol), followed by CuI (6g, 31.5mmol), PdCl2(PPh3)2 (22g, 31.3mmol), and TBAF hydrate (300g, 950.8mmol). Warm the reaction mixture to 60°C and maintain this temperature for 12 hours. Cool the reaction mixture to room temperature and pour it onto a mixture of water (~1L), saturated NH4Cl aqueous solution (~2L), and ethyl acetate (~3L), then stir for 10 minutes. The organic phase was separated and washed successively with 1N HCl solution (2 x 500 mL) and brine (500 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (gradient: 0-30% ethyl acetate / heptane) to give a yellow solid (151 g, 60% yield).

[1113] The mixed fractions were purified by passing them through a separate silica gel column (gradient: 0-50% ethyl acetate / heptane) to give another product (50 g, 20% yield). The purified product batches (151 g + 50 g) were combined and dried under vacuum to give 4-[2-(2-bromo-4-fluoro-6-methoxy-phenyl)ethynyl]tetrahydropyran (200 g, 80%) as a yellow solid. 1¹H NMR (400MHz, DMSO-d⁶ chloroform-d) δ 6.95 (dd, J = 8.0, 2.4Hz, 1H), 6.57 (dd, J = 10.4, 2.4Hz, 1H), 4.01 (ddd, J = 11.6, 6.9, 3.4Hz, 2H), 3.86 (s, 3H), 3.61 (ddd, J = 11.2, 7.3, 3.3Hz, 2H), 3.00 (dq, J = 7.7, 3.8Hz, 1H), 2.03–1.90 (m, 2H), 1.81 (dtd, J = 13.1, 7.4, 3.1Hz, 2H). 19 F NMR (376MHz, chloroform-d) δ -108.45. LCMS m / z 314.97 [M+1] + .

[1114] Step 2. Synthesis of 5-fluoro-N-(4-fluoro-3-methyl-phenyl)-3-methoxy-2-(2-tetrahydro-pyran-4-ylethynyl)aniline (C35)

[1115] A solution of 4-[2-(2-bromo-4-fluoro-6-methoxy-phenyl)ethynyl]tetrahydropyran C34 (92 g, 293.8 mmol), 4-fluoro-3-methylaniline (55.2 g, 441.1 mmol), tBuXPhos (3.75 g, 8.83 mmol), and NaOtBu (70.6 g, 734.6 mmol) in m-xylene (1.3 L) was purged with nitrogen for 10 min. tBuXPhos Pd G3 (7.01 g, 8.83 mmol) was added, and the mixture was heated to 60 °C and maintained for 3 h. The mixture was cooled, and then NH4Cl (1 L) and HCl (64 mL of 6 M, 384.0 mmol) were added, and the mixture was stirred overnight. The mixture was extracted with EtOAc (x 2), and the organic layer was concentrated. The product was purified by silica gel chromatography (gradient: 0-90% EtOAc / heptane) to obtain a black oily substance, 5-fluoro-N-(4-fluoro-3-methyl-phenyl)-3-methoxy-2-(2-tetrahydropyran-4-ylethynyl)aniline (98g, 93%). 1H NMR (300MHz, chloroform-d) δ6.87-6.76(m,3H),6.24(s,1H),6.13(dd,J=11.2,2.3Hz,1H),5.90(dd,J=10.7,2.3Hz,1H),3.80(ddd,J=11.6,5.6,3.6Hz, 2H),3.68(s,3H),3.40(ddd,J=11.5,8.4,3.0Hz,2H),2.82(tt,J=8.4,4 .1Hz,1H),2.11(d,J=1.8Hz,3H),1.86-1.73(m,2H),1.71-1.54(m,2H). LCMS m / z 358.22[M+1] + .

[1116] Step 3. Synthesis of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-4-methoxy-2-tetrahydropyran-4-yl-indole (C36)

[1117] PdCl2 (2.08 g, 11.7 mmol) was added to a solution of 5-fluoro-N-(4-fluoro-3-methyl-phenyl)-3-methoxy-2-(2-tetrahydropyran-4-ylethynyl)aniline C35 (98 g) in MeCN (1 L). The mixture was heated to 60 °C overnight. The mixture was then concentrated to dryness and MBTE (300 mL) was added. After stirring for 10 min, the mixture was filtered to give a solid product (40 g). The black filtrate was purified by silica gel chromatography (gradient: 0-60% EtOAc in dichloromethane) to give an additional 33 g of product. The two product batches were combined to provide a single batch of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-4-methoxy-2-tetrahydropyran-4-yl-indole (73 g, 70%). 1 ¹H NMR (300MHz, chloroform-d) δ 7.15 (td, J = 8.2, 7.6, 4.2Hz, 3H), 6.49 (s, 1H), 6.42–6.24 (m, 2H), 3.97 (s, 5H), 3.35 (td, J = 11.6, 2.7Hz, 2H), 2.76 (ddd, J = 15.4, 11.2, 4.4Hz, 1H), 2.38 (d, J = 1.8Hz, 3H), 1.90–1.64 (m, 4H). LCMS m / z 358.12 [M+1] + .

[1118] Step 4. Synthesis of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole-4-ol (C37)

[1119] In a 1 L 3-necked RB flask, a solution of 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-4-methoxy-2-tetrahydropyran-4-yl-indole C36 (15.1 g, 42.3 mmol) in dichlorom...

Claims

1. A compound selected from the group consisting of and pharmaceutically acceptable salts thereof.

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

3. Use of at least one compound or a pharmaceutically acceptable salt according to claim 1 or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the treatment of alpha- 1 antitrypsin (AAT) deficiency in a patient in need thereof.

4. Use according to claim 3, wherein the at least one compound or a pharmaceutically acceptable salt or the pharmaceutical composition is administered in combination with AAT augmentation therapy and / or AAT replacement therapy.

5. Use of at least one compound or a pharmaceutically acceptable salt according to claim 1 or a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the modulation of alpha- 1 antitrypsin (AAT) activity.

6. Use according to claim 5, wherein the at least one compound or a pharmaceutically acceptable salt or the pharmaceutical composition is administered in combination with AAT augmentation therapy and / or AAT replacement therapy.

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