Indole derivatives as alpha-1-antitrypsin modulators for treating alpha-1-antitrypsin deficiency (AATD)

Abstract

Indole derivatives as alpha-l-antitrypsin modulators for treating alpha-l-antitrypsin deficiency (AATD).

Description

wo 2021 / 203023 IIVATIVES AS ALPHA-1 -ANTITRYPSIN MODLPCT / US2021 / 025614 TREATING ALPHA-1 -ANTITRYPSIN DEFICIENCY (AATD)

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 004,717, filed April 3, 2020, the contents of which are incorporated by reference herein in their entirety.

[0002] The disclosure provides compounds that are capable of modulating alpha- 1 antitrypsin (AAT) activity and methods of treating alpha- 1 antitrypsin deficiency (AATD) by administering one or more such compounds.

[0003] AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments for AATD exist, there is currently no cure. AAT is produced primarily in liver cells and secreted into the blood, but it is also made by other cell types including lung epithelial cells and certain white blood cells. AAT inhibits several serine proteases secreted by inflammatory cells (most notably neutrophil elastase [NE], proteinase 3, and cathepsin G) and thus protects organs such as the lung from protease-induced damage, especially during periods of inflammation.

[0004] The mutation most commonly associated with AATD involves a substitution of lysine for glutamic acid (E342K) in the SERPINA1 gene that encodes the AAT protein. This mutation, known as the Z mutation or the Z allele, leads to misfolding of the translated protein, which is therefore not secreted into the bloodstream and can polymerize within the producing cell. Consequently, circulating AAT levels in individuals homozygous for the Z allele ( PiZZ) are markedly reduced; only approximately 15% of mutant Z-AAT protein folds correctly and is secreted by the cell. An additional consequence of the Z mutation is that the secreted Z-AAT has reduced activity compared to wild-type protein, with 40% to 80% of 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 polymerized Z-AAT protein within hepatocytes results in a gain- of-function cytotoxicity that can result in cirrhosis or liver cancer later in life and neonatal liver disease in 12% of patients. This accumulation may spontaneously remit but can be fatal in a small number of children. The deficiency of circulating AAT results in unregulated protease activity that degrades lung tissue over time, resulting in emphysema, a form of chronic obstructive pulmonary disease (COPD). This effect is severe in PiZZ individuals and typically manifests in middle age, resulting in a decline in quality of life and shortened lifespan (mean 68 years of age) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016; 11 : 1663-9). The effect is more pronounced in PiZZ individuals who smoke, resulting in an even further shortened lifespan (58years). (Piitulainen and Tanash, COPD 2015; 12(1):36-41). PiZZ individuals account for the majority of those with clinically relevant AATD lung disease. Accordingly, there is a need for additional and effective treatments for AATD.

[0006] A milder form of AATD is associated with the SZ genotype in which the Z-allele is combined with an S-allele. The S allele is associated with somewhat reduced levels of circulating AAT but causes no cytotoxicity in liver cells. The result is clinically significant lung disease but not liver disease. (Fregonese and Stolk, Orphanet J Rare Dis. 2008; 33:16). As with the ZZ genotype, the deficiency of circulating AAT in subjects with the SZ genotype results in unregulated protease activity that degrades lung tissue over time and can result in emphysema, particularly in smokers.

[0007] The current standard of care for AAT deficient individuals who have or show signs of developing significant lung or liver disease is augmentation therapy or protein replacement therapy. Augmentation therapy involves administration of a human AAT protein concentrate purified from pooled donor plasma to augment the missing AAT. Although infusions of the plasma protein have been shown to improve survival or slow the rate of emphysema progression, augmentation therapy is often not sufficient under challenging conditions such as during an active lung infection. Similarly, although protein replacement therapy shows promise in delaying progression of disease, augmentation does not restore the normal physiological regulation of AAT in patients and efficacy has been difficult to demonstrate. In addition, augmentation therapy requires weekly visits for treatment and augmentation therapy cannot address liver disease, which is driven by the toxic gain-of-function of the Z allele. Thus, there is a continuing need for new and more effective treatments for AATD.

[0008] One aspect of the disclosure provides compounds of Formulae (I), (Ila)-(IIg), (Illa)- (IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)- (Vlle), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives that can be employed in the treatment of AATD. For example, compounds of Formula (I), tautomers thereof, deuterated derivatives of those compounds or tautomers, or pharmaceutically acceptable salts of any of the foregoing, can be depicted as:wherein:, for each of the two occurrences, is a single bond or a double bond, provided that one is a single bond and the other is a double bond;V1and V2are each independently N or -CR2;W1and W2are each independently N or C, provided that one of W1and W2is N and the other is C;U is hydrogen, -OH, -CH3, -NH2, or halogen;X is absent or a bond, -(CRaRb)p-, or -SO2-;Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;Rcand Rd, for each occurrence, are each independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;Ring A is C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10- membered heteroaryl; provided that when W1is N and W2is C, Ring A is not 1, 5,6,7- tetrahydro-4 / / -indol-4-onyl or a tautomer thereof;Ring B is C4-C12 cycloalkyl, Ce or C10 aryl, 5 to 10-membered heteroaryl, or benzyl;Ring C is C3-C12 cycloalkyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10- membered heteroaryl; provided that when Ring C is phenyl, the phenyl is substituted with R4; provided that when Ring C is phenyl, Y cannot be -SO2-; andprovided that when Ring B is benzyl, Ring C cannot be pyridinyl or indolyl;RE, Rr, and RGare each independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -CRP(=N)ORs, -NR"C(=0)Rs, -NR"C(=0)0Rs, -NRpC(=0)NRqRr,-ORs, -0C(=0)Rs, or -0C(=0)NRpRq; wherein: the C1-C6 alkyl or the C2-C6 alkenyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -NRpC(=0)Rs, -NRpC(=0)0Rs, -NRpC(=0)NRqRr, -NRpS(=0)rRs, -ORs, -0C(=0)Rs, -0C(=0)0Rs,-0C(=0)NRpRq, -S(=0)rRs, and -S(=0)rNRpRq; wherein:Rp, Rq, and Rr, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, or 3 to 6-membered heterocyclyl; wherein: the C1-C4 alkyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, Ci- C3alkoxy, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl or the 3 to 6-membered heterocyclyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0(Ci-C2alkyl), -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rs, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C4 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl, the phenyl, or the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl),-N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;R1is halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or -0-(C3-C6 cycloalkyl);R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6alkyl, C2- Ce alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6alkenyl, or the C3-C6cycloalkyl of R2is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rk,-C(=0)0Rk, -C(=0)NRhR‘, -NRhR‘, -NRhC(=0)Rk, -NRhC(=0)0Rk, -NRhC(=0)NR'Rj, -NRhS(=0)sRk-ORk, -0C(=0)Rk, -0C(=0)0Rk,-0C(=0)NRhR‘, -S(=0)sRk, and S(=0)sNRhRi; wherein:Rh, R', and R', for each occurrence, are each independently hydrogen, C1-C4 alkyl, or C3-C6cycloalkyl; wherein: the C1-C4 alkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, Ci- C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rk, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein:-ORkcannot be -OH; the C1-C4 alkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2 alkyl)2; and the C3-C6cycloalkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci- C2alkyl)2;R3and R4, for each occurrence, are each independently halogen, cyano, =0, C1-C6alkyl, Ci-Ce alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -C(=0)NRv0Ry,-C(=0)NRvS(=0)tRy, -NRVRW, -NRvC(=0)Ry, -NRvC(=0)0Ry, -NRvC(=0)NRwRx, -NRvS(=0)tRy, -ORy, -0C(=0)Ry, -0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy,-S(=0)tNRvRw, -S(=0)tNRvC(=0)Ry, -P(=0)RzRz, phenyl, or a 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the Ci-Ce alkenyl, or the C3-C6cycloalkyl of any one of R3and R4is optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -NRVRW, -NRvC(=0)Ry,-NRvC(=0)0Ry, -NRVC (=0)NRwRx, -NRvS(=0 Ry-ORy, -0C(=0)Ry,-0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, and -S(=0)tNRvRw; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, 5 or 6-membered heterocyclyl, or 5 or 6- membered heteroaryl; wherein: the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkyl, Ci- C3 alkoxy, C1-C3haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci- C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Ry, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, a 5 or 6-membered heterocyclyl, or a 5 or 6-membered heteroaryl; whereinthe C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, Ci-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2 alkyl)2; and the C3-C6 cycloalkyl, the phenyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, Ci- C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci- C2 alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rz, for each occurrence, is independently C1-C2 alkyl, -OH, or -0(Ci-C2alkyl); k is an integer selected from 1, 2, and 3; m and n are each independently an integer selected from 0, 1, 2, and 3; p, r, s, and t are each independently an integer selected from 1 and 2; and q is an integer selected from 1, 2, and 3.

[0009] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, U is -OH, -CH3, -NH2, or halogen, and all other variables are as defined for Formula (I).

[0010] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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).

[0011] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, U is -OH, -CH3, -NH2, or 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).

[0012] The compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)- (Ilf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)) are modulators of AAT activity. In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe),(Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives have an EC so of 2.0 mM or less when tested in an AAT Function Assay. In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives have an EC so of less than 0.5 pM when tested in an AAT Function Assay.

[0013] In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (ma)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives have an ICso of 5.0 pM or less when tested in a Z-AAT Elastase Activity Assay. In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf)(e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives have an ICso of less than 2.0 pM when tested in a Z-AAT Elastase Activity Assay.

[0014] In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives have an EC so of 2.0 pM or less when tested in an AAT Function Assay and have an ICso of 5.0 pM or less when tested in a Z-AAT Elastase Activity Assay. In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of thosetautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives have an EC so of less than 0.5 mM when tested in an AAT Function Assay and have an ICso of 5.0 mM or less when tested in a Z-AAT Elastase Activity Assay. In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ha)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives have an EC so of 2.0 pM or less when tested in an AAT Function Assay and have an ICso of less than 2.0 pM when tested in a Z-AAT Elastase Activity Assay. In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ha)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives have an EC so of less than 0.5 pM when tested in an AAT Function Assay and have an ICso of less than 2.0 pM when tested in a Z-AAT Elastase Activity Assay.

[0015] In some embodiments, the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ha)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives are provided for use in the treatment of AATD. In some embodiments, the 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, e.g., 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 those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing and are for use in the treatment of AATD. In one aspect, the compounds of Formulae (I) are selected from Compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457, tautomers of thosecompounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing and are for use in the treatment of AATD.

[0016] In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formulae (I), (Ila)-(IIg), (Illa)- (IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)- (Vlle), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further include at least one additional active pharmaceutical ingredient and / or at least one carrier. These compositions may further include at least one additional active pharmaceutical ingredient. These compositions may further include at least one carrier. These compositions may further include at least one additional active pharmaceutical ingredient and at least one carrier. These compositions may further include at least one additional active pharmaceutical ingredient or at least one carrier.

[0017] In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formulae (I), (Ila)-(IIg), (Illa)- (IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), (Xa)-(Xf), (Xla)-(Xe), and (Xlla)-(XIIe) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)- (Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical compositions 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0018] Another aspect of the disclosure provides methods of treating AATD comprising administering to a subject in need thereof, at least one compound selected from compounds ofFormulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)- (IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing or a pharmaceutical composition comprising the at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the methods comprise 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, e.g., Compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the subject in need of treatment carries the ZZ mutation. In some embodiments, the subject in need of treatment carries the SZ mutation.

[0019] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound selected from compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf)(e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions. In some embodiments, the methods comprise 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, e.g., Compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing with at least one additional active agent either in the same pharmaceutical composition or in a separate composition. In some embodiments, the subject in need of treatment carries the ZZ mutation. In some embodiments, the subject in need of treatment carries the SZ mutation.

[0020] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound selected from compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf)(e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe),(Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions, wherein the additional active agent is alpha-1 antitrypsin protein (AAT) from the blood plasma of healthy human donors. In some embodiments, the methods comprise 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, e.g., Compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing with at least one additional active agent either in the same pharmaceutical composition or in a separate composition, wherein the additional active agent is alpha- 1 antitrypsin protein (AAT) from the blood plasma of healthy human donors.

[0021] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound selected from compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf)(e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions, wherein the additional active agent is recombinant AAT. In some embodiments, the methods comprise 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, or e.g., Compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing with at least one additional active agent either in the same pharmaceutical composition or in a separate composition, wherein the additional active agent is recombinant AAT.

[0022] Also provided are methods of modulating AAT, comprising administering to a subject in need thereof, at least one compound selected from compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf)(e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoingor a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the methods of modulating AAT comprise 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing or a pharmaceutical composition comprising the at least one such compound, tautomer, deuterated derivative or pharmaceutically acceptable salt.

[0023] Another aspect of the disclosure provides Compounds B1-B25 and Compounds W1-W32, as well as tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salts of those compounds, tautomers, or deuterated derivatives that can be employed in the treatment of AATD.

[0024] In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further include at least one additional active pharmaceutical ingredient and / or at least one carrier.

[0025] Another aspect of the disclosure provides methods of treating AATD comprising administering to a subject in need thereof, at least one compound selected from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing or a pharmaceutical composition comprising the at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0026] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound selected from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions. In some embodiments, the subject in need of treatment carries the ZZ mutation. In some embodiments, the subject in need of treatment carries the SZ mutation.

[0027] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound selected from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions, wherein the additional active agent is alpha- 1 antitrypsin protein (AAT) from the blood plasma of healthy human donors.

[0028] In some embodiments, the methods of treatment include administration of at least one additional active agent to the subject in need thereof, either in the same pharmaceutical composition as the at least one compound selected from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as separate compositions, wherein the additional active agent is recombinant AAT.

[0029] Also provided are methods of modulating AAT, comprising administering to a subject in need thereof, at least one compound selected from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing or a pharmaceutical composition comprising the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt.

[0030] Also provided is a compound of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy. In some embodiments, there is provided 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.

[0031] Also provided is a pharmaceutical composition comprising a compound of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and(Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy. In some embodiments, there is provided a pharmaceutical composition 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.

[0032] Also provided is a compound of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy. In some embodiments, there is provided a compound selected from Compounds B1-B25 and Compounds W1-W32, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.

[0033] Also provided is a pharmaceutical composition comprising a compound of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), and tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy. In some embodiments, there is provided a pharmaceutical composition comprising a compound selected from Compounds B1-B25 and Compounds W1-W32, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, for use in therapy.I. Definitions

[0034] The term “AAT” as used herein means alpha- 1 antitrypsin or a mutation thereof, including, but not limited to, the AAT gene mutations such as Z mutations. As used herein, “Z- AAT” means AAT mutants which have the Z mutation.

[0035] As used herein, “mutations” can refer to mutations in the SERPINA1 gene (the gene encoding AAT) or the effect of alterations in the gene sequence on the AAT protein. A “ SERPINA1 gene mutation” refers to a mutation in the SERPINA1 gene, and an “AAT protein mutation” refers to a mutation that results in an alteration in the amino acid sequence of theAAT protein. A genetic defect or mutation, or a change in the nucleotides in a gene in general, results in a mutation in the AAT protein translated from that gene.

[0036] As used herein, a patient who is “homozygous” for a particular gene mutation has the same mutation on each allele.

[0037] As used herein, a patient who has the PiZZ genotype is a patient who is homozygous for the Z mutation in the AAT protein.

[0038] The term “AATD” as used herein means alpha- 1 antitrypsin deficiency, which is a genetic disorder characterized by low circulating levels of AAT.

[0039] The term “compound,” when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure unless otherwise indicated as a collection of stereoisomers (for example, a collection of racemates, a collection of cis / trans stereoisomers, or a collection of ( E) and (Z) stereoisomers), except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this disclosure will depend upon a number of factors including the isotopic purity of reagents used to make the compound and the efficiency of incorporation of isotopes in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto 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.

[0040] Compounds of the disclosure may optionally be substituted with one or more substituents. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an “optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0041] The term “isotopologue” refers to a species in which the chemical structure differs from a specific compound of this disclosure only in the isotopic composition thereof. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C or14C are within the scope of this disclosure.

[0042] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, e.g., 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 present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0043] The term “tautomer,” as used herein, refers to one of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule.

[0044] “Stereoisomer” refers to both enantiomers and diastereomers.

[0045] As used herein, “deuterated derivative” refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom (“D”). It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes, notwithstanding this variation is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivatives described herein. Thus, unless otherwise stated, when a reference is made to a “deuterated derivative” of a compound of the disclosure, at least one hydrogen is replaced with deuterium at well above its natural isotopic abundance (which is typically about 0.015%).In some embodiments, the deuterated derivatives of the disclosure have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5% deuterium incorporation at each designated deuterium) at least 4500, (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation) at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at lease 6333.3 (95% deuterium incorporation, at least 6466.7 (97% deuterium incorporation, or at least 6600 (99% deuterium incorporation).

[0046] The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0047] The term “alkyl” as used herein, means a straight-chain (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or may contain one or more units of saturation, without being fully aromatic. Unless otherwise specified, alkyl groups contain 1-12 alkyl carbon atoms. In some embodiments, alkyl groups contain 1-10 aliphatic carbon atoms. In other embodiments, alkyl groups contain 1-8 aliphatic carbon atoms. In still other embodiments, alkyl groups contain 1-6 alkyl carbon atoms, in other embodiments alkyl groups contain 1-4 alkyl carbon atoms, and in yet other embodiments alkyl groups contain 1-3 alkyl carbon atoms and 1-2 alkyl carbon atoms.

[0048] The term “heteroalkyl” as used herein, refers to aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroalkyl groups may be substituted or unsubstituted, branched or unbranched.

[0049] The term “alkenyl” as used herein, means a straight-chain (i.e., linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain that contains one or more carbon-to- carbon double bonds.

[0050] The terms “cycloalkyl,” “cyclic alkyl,” “carbocyclyl,” and “carbocycle” refer to a fused, spirocyclic, or bridged monocyclic C3-9 hydrocarbon or a fused, spirocyclic, or bridged bicyclic or tricyclic, Cs-i4 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not fully aromatic, wherein any individual ring in said bicyclic ring system has 3-9 members. Typically, a cycloalkyl is completely saturated, while a carbocyclyl may contain one or more units of unsaturation but is not aromatic. In some embodiments, the cycloalkyl or carbocycle group contains 3 to 12 carbon atoms. In some embodiments, the cycloalkyl or carbocycle group contains 3 to 8 carbon atoms. In some embodiments, the cycloalkyl or carbocycle group contains 3 to 6 carbon atoms.

[0051] The term “heterocycle,” “heterocyclyl,” or “heterocyclic” as used herein refers to fused, spirocyclic, or bridged non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members is a heteroatom. In some embodiments, “heterocycle,” “heterocyclyl,” or “heterocyclic” group has 3 to 14 ring members in which one or more ring members is a heteroatom 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 heterocyclyl contains 3 to 12 ring member atoms. In some embodiments, the heterocyclyl contains 3 to 8 ring member atoms. In some embodiments, the heterocyclyl contains 3 to 6 ring member atoms.

[0052] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0053] The term “alkoxy” as used herein, refers to an alkyl group, as previously defined, wherein one carbon of the alkyl group is replaced by an oxygen ("alkoxy") atom, respectively, provided that the oxygen atom is linked between two carbon atoms. A “cyclic alkoxy” refers to a monocyclic, fused, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that contains at least one alkoxy group, but is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8- oxabicyclo[3.2.1]octanyl, and oxepanyl.

[0054] The terms “haloalkyl” and “haloalkoxy” means an alkyl or alkoxy, as the case may be, which is substituted with one or more halogen atoms. The term “halogen” or means F, Cl, Br, or I. In some embodiments, the halogen is selected from F, Cl, and Br. Examples of haloalkyls include -CHF2, -CH2F, -CF3, -CF2-, or perhaloalkyl, such as, -CF2CF3.

[0055] As used herein, “=0” refers to an oxo group.

[0056] As used herein, a “cyano” or “nitrile” groups refers to -O N.

[0057] As used herein, a “hydroxy” group refers to -OH.

[0058] As used herein, “aromatic groups” or “aromatic rings” refer to chemical groups that contain conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer ranging from 0 to 6. Nonlimiting examples of aromatic groups include aryl and heteroaryl groups.

[0059] The term “aryl” refers to monocyclic, bicyclic, and tricyclic ring systems 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, an aryl contains 6 or 10 carbon atoms. A nonlimiting example of an aryl group is a phenyl ring.

[0060] The term "heteroaryl” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 10 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, a heteroaryl contains 6 or 10 ring atoms.

[0061] Examples of useful protecting groups for nitrogen-containing groups, such as amine groups, include, for example, t-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9- fluorenylmethyl carbamate (Fmoc) benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods of adding (aprocess generally referred to as "protecting") and removing (process generally referred to as "deprotecting") such amine protecting groups are well-known in the art and available, for example, in P. J. Kocienski, Protecting Groups, Thieme, 1994, which is hereby incorporated by reference in its entirety and in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999).

[0062] Examples of suitable solvents that may be used in this disclosure include, but not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (CH2CI2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, isopropyl acetate (IP Ac), / c / T-butyl acetate ( / -BuOAc), isopropyl alcohol (IP A), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2 -Me THF), methyl ethyl ketone (MEK), fer / -butanol, diethyl ether (Et20), methyl- / c77-butyl ether (MTBE), 1,4-dioxane, and L - ethyl pyrrolidone (NMP).

[0063] Examples of suitable bases that may be used in this disclosure include, but not limited to, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), A-methylmorpholine (NMM), triethylamine (Ί¾N; TEA), diisopropyl-ethyl amine ( / -PnEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCTB).

[0064] The disclosure includes pharmaceutically acceptable salts of the compounds of the disclosure. A salt of a compound of is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

[0065] The term “pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, etal. J. Pharmaceutical Sciences , 1977, 66, 1- 19.

[0066] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, b-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0067] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0068] The terms “patient” and “subject” are used interchangeably and refer to an animal, including a human.

[0069] The terms “effective dose,” “effective amount,” “therapeutically effective dose,” and “therapeutically effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in AATD or a symptom of AATD, lessening the severity of AATD or a symptom of AATD, and / or reducing the rate of onset or incidence of AATD or a symptom of AATD). The exact amount of an effective dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0070] As used herein, the term “treatment and its cognates (e.g., “treat,” “treating”) refer to improving AATD or its symptoms in a subject, delaying the onset of AATD or its symptoms in a subject, or lessening the severity of AATD or its symptoms in a subject. “Treatment” and its cognates as used herein, include, but are not limited to the following: improved liver and / or spleen function, lessened jaundice, improved lung function, lessened lung diseases and / or pulmonary exacerbations (e.g., emphysema), lessened skin disease (e.g., necrotizing panniculitis), increased growth in children, improved appetite, and reduced fatigue. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to methods and techniques known in the art or subsequently developed.

[0071] The terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Typically, the term “about” refers to a variation of up to 10%, up to 5%, or up to 2% of a stated value.

[0072] Any one or more of the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those 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, the 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, e.g., Compounds 1-142, 144-177, 179-399, 401- 422, 425-433, and 435-457), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, at least one compound chosen from compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf)(e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is 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 those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one compound selected from compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)- (Illb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily. In some embodiments, 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 those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered twice daily. In some embodiments, at least one compound chosen from compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily. In some embodiments, 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 those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered three times daily.

[0073] Any one or more of the compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ha)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. In some embodiments, the 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 thosecompounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0074] Any one or more of Compounds B1-B25 and W1-W32, tautomers of those compounds, deuterated derivatives of those 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 chosen from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one compound selected from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily. In some embodiments, at least one compound chosen from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily.

[0075] Any one or more of Compounds B1-B25 and W1-W32, tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD.

[0076] As used herein, “AAT augmentation therapy” refers to the use of alpha- 1 antitrypsin protein (AAT) from the blood plasma of healthy human donors to augment (increase) the alpha- 1 antitrypsin levels circulating in the blood. “AAT replacement therapy” refers to administration of recombinant AAT.

[0077] In some embodiments, 10 mg to 1,500 mg, 100 mg to 1800 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 a compound of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)- (Vle), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once daily, twice daily, or three times daily. In some embodiments, 10 mg to 1,500 mg, 100 mg to 1800 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) is administered once daily, twice daily, or three times daily.

[0078] In some embodiments, 10 mg to 1,500 mg, 100 mg to 1800 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 a compound selected from compounds of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32), tautomers of those compounds, deuterated derivatives of those compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered once daily, twice daily, or three times daily. In some embodiments, 10 mg to 1,500 mg, 100 mg to 1800 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 of Formulae (Xla)-(XIe) and (Xlla)-(XIIe) (e.g., Compounds B1-B25 and Compounds W1-W32) is administered once daily, twice daily, or three times daily.

[0079] One of ordinary skill in the art would recognize that, when an amount of a compound is disclosed, the relevant amount of a pharmaceutically acceptable salt form of the compound is an amount equivalent to the concentration of the free base of the compound. It is noted that the disclosed amounts of the compounds, tautomers, deuterated derivatives, and pharmaceutically acceptable salts are based upon the free base form of the reference compound. For example, “10 mg of at least one compound chosen from compounds of Formula (I) and pharmaceutically acceptable salts thereof’ includes 10 mg of a compound of Formula (I) and a concentration of a pharmaceutically acceptable salt of compounds of Formula (I) equivalent to 10 mg of compounds of Formula (I).

[0080] As used herein, the term “ambient conditions” means room temperature, open air condition and uncontrolled humidity condition.

[0081] It should be understood that references herein to methods of treatment (e.g., methods of treating AATD) using one or more compounds (e.g., compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf)(e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) should also be interpreted as references to:- one or more compounds (e.g., compounds of Formulae (I), (Ila)-(IIg), (Illa)-(IIIc), (IVa)- (IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds ofFormulae (I), (Ha)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) for use in methods of treating, e.g., AATD; and / or- the use of one or more compounds (e.g., compounds of Formulae (I), (Ila)-(IIg), (Illa)- (IIIc), (IVa)-(IVb), (Va)-(Vc), (Vla)-(VIg), (Vlla)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)- (Vlle), and (IXa)-(IXe)), as well as tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of those compounds) in the manufacture of a medicament for treating, e.g., AATD.Example Embodiments 1:

[0082] Non-limiting embodiments of the present disclosure include:1. A compound represented by the following structural formula:a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: for each of the two occurrences, is a single bond or a double bond, provided that one is a single bond and the other is a double bond;V1and V2are each independently N or -CR2;W1and W2are each independently N or C, provided that one of W1and W2is N and the other is C;U is -OH, -CH3, -NH2, or halogen;X is absent or a bond, -(CRaRb)p-, or -SO2-;Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, halogen, -OH, Ci- Ce alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;Rcand Rd, for each occurrence, are each independently hydrogen, halogen, -OH, Ci- Ce alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;Ring A is C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl; provided that when W1is N and W2is C, Ring A is not 1, 5,6,7- tetrahydro-4 / / -indol-4-onyl or a tautomer thereof;Ring B is C4-C12 cycloalkyl, Ce or C10 aryl, 5 to 10-membered heteroaryl, or benzyl;Ring C is C3-C12 cycloalkyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl; provided that when Ring C is phenyl, the phenyl is substituted with R4; provided that when Ring C is phenyl, Y cannot be -SO2-; and provided that when Ring B is benzyl, Ring C cannot be pyridinyl or indolyl;RE, Rr, and RGare each independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -CRP(=N)ORs, -NR"C(=0)Rs, -NR"C(=0)0Rs, -NRpC(=0)NRqRr,-ORs, -0C(=0)Rs, or -0C(=0)NRpRq; wherein: the C1-C6alkyl or the C2-C6alkenyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -NRpC(=0)Rs, -NRpC(=0)0Rs, -NRpC(=0)NRqRr, -NRpS(=0)rRs, -ORs, -0C(=0)Rs, -0C(=0)0Rs, -0C(=0)NRpRq, -S(=0)rRs, and -S(=0)rNRpRq; wherein:Rp, Rq, and Rr, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, or 3 to 6-membered heterocyclyl; wherein: the C1-C4 alkyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, Ci- C3alkoxy, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl or the 3 to 6-membered heterocyclyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3haloalkyl, C1-C3 haloalkoxy, -C(=0)0(Ci-C2alkyl), -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rs, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C4 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl, the phenyl, or the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;R1is halogen, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or -0-(C3-C6 cycloalkyl);R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6alkyl, C2- Ce alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, -NRhR‘, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6 alkenyl or the C3-C6cycloalkyl of R2is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rk,-C(=0)0Rk, -C(=0)NRhR‘, -NRhR‘, -NRhC(=0)Rk, -NRhC(=0)0Rk, -NRhC(=0)NR'Rj, -NRhS(=0)sRk-ORk, -0C(=0)Rk, -0C(=0)0Rk,-0C(=0)NRhR‘, -S(=0)sRk, and S(=0)sNRhRi; wherein:Rh, R', and R', for each occurrence, are each independently hydrogen, C1-C4 alkyl, or C3-C6cycloalkyl; wherein: the C1-C4 alkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rk, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein:-ORkcannot be -OH; the C1-C4 alkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2 alkyl)2; and the C3-C6cycloalkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl),-C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci- C2 alkyl)2;R3and R4, for each occurrence, are each independently halogen, cyano, =0, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -C(=0)NRv0Ry, -C(=0)NRvS(=0)tRy, -NRVRW, - NRvC(=0)Ry, -NRvC(=0)0Ry, -NRvC(=0)NRwRx, -NRvS(=0)tRy-ORy, -0C(=0)Ry, - 0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, -S(=0)tNRvRw, -S(=0)tNRvC(=0)Ry, - P(=0)RzRz, phenyl, or a 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6alkenyl, or the C3-C6cycloalkyl of any one of R3and R4is optionally substituted with 1 to 3 groups selected from cyano, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -NRVRW, -NRvC(=0)Ry,-NRvC(=0)0Ry, -NRVC (=0)NRwRx, -NRvS(=0 Ry-ORy, -0C(=0)Ry, - 0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, and -S(=0)tNRvRw; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, 5 or 6-membered heterocyclyl, or 5 or 6- membered heteroaryl; wherein: the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano -OH,-NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Ry, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, a 5 or 6-membered heterocyclyl, or a 5 or 6-membered heteroaryl; wherein the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl),-C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl, the phenyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2;Rz, for each occurrence, is independently C1-C2 alkyl, -OH, or -0(Ci-C2alkyl); k is an integer selected from 1, 2, and 3; m and n a are each independently an integer selected from 0, 1, 2, and 3; and p, q, r, s, and t are each independently an integer selected from 1 and 2.2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1 represented by one of the following structural formulae:wherein:U is -OH, -CH3, -NH2, F, or Cl; and wherein all other variables not specifically defined herein are as defined in embodiment 1.3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1 represented by one of the following structural formulae:wherein:U is -OH, -CH3, -NH2, F, or Cl; and wherein all other variables not specifically defined herein are as defined in embodiment 1.4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 1 or embodiment 2 represented by one of the following structural formulae:wherein:U is -OH or -NH2;Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9- membered heterocyclyl, phenyl, or 5 to 9-membered heteroaryl;Ring B is substituted with R1and Ring B is C4-C6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl, or benzyl; andwhen Z is Ring C optionally substituted with R4, Ring C is C4-Cs cycloalkyl, 4 to 8- membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl; and wherein all other variables not specifically defined herein are as defined in embodiment 1 or embodiment 2.5. The 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 formulae:(IVa1) (IVb') wherein:Ring B is substituted with R1and Ring B is cyclohexyl, phenyl, pyridinyl, or benzyl; and wherein all other variables not specifically defined herein are as defined in any one of embodiments 1, 2, and 4.6. The 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:wherein:R1is halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; and k is an integer selected from 1 and 2; and wherein all other variables not specifically defined herein are as defined in any one of embodiments 1, 2, 4, and 5.7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 6, wherein R1is cyano, F, Cl, -CFb, -CHF2, -CF3, -OCH3, or -OCH(CH3)2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 7, wherein at least one R1is F; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 8, wherein:X is absent or a bond, -(CRaRb)-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 9, wherein X is absent or a bond, -CH2-, or -SO2-; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 10, wherein:Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Rcand Rd, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3alkoxy; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 11, wherein Y is absent or a bond, -CH2-, -CHCH3-, - C(CH3)2-, -C(=0)-, or -SO2-; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 12, wherein Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl containing 1 to 3 oxygen atoms, phenyl, or 5 to 9-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 13, wherein Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl containing one or two oxygen atoms, phenyl, or 5 to 9-membered heteroaryl containing one or two nitrogen atoms or one or two oxygen atoms; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 14, wherein Ring A is optionally substituted with R3and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 15, wherein Ring A is optionally substituted with R3and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 16, wherein Z is Ring C, Ring C is optionally substituted with R4, and Ring C is Cri-Cx cycloalkyl; 4 to 8-membered heterocyclyl containing one or two heteroatoms selected from O, N, and S; phenyl; or 5-membered heteroaryl containing one or two heteroatoms selected from O and N; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 17, wherein Z is Ring C, Ring C is optionallyand wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 18, wherein Z is Ring C, Ring C is optionally substituted with (R4)o, and Ring C is selected fromand wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 19, wherein RE, Rr, and RGare each independently hydrogen, halogen, cyano (-CºN), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=0)0Rs, - C(=0)NRpRq, -CRP(=N)ORs, or -ORs; wherein: the C1-C4 alkyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq,-ORs, -0C(=0)Rs, -0C(=0)0Rs, -0C(=0)NRpRq, and -S(=0)2Rs; wherein:Rpand Rq, for each occurrence, are each independently hydrogen, Ci- C2 alkyl, C3-C5 cycloalkyl, or 5 or 6-membered heterocyclyl; wherein: the C1-C2 alkyl of any one of Rpand Rqis optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; the C3-C5 cycloalkyl or the 5 or 6-membered heteroaryl of Rpand Rqis optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH;Rs, for each occurrence, is independently hydrogen, C1-C2 alkyl, or 5 or 6-membered heteroaryl; wherein the C1-C2 alkyl of Rsis optionally substitutedwith 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; wherein: the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 20, wherein RE, Rr, and RGare each independently hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, -C(=0)NRpRq, -CRp(=N)ORs, or -ORs; wherein: the C1-C2 alkyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)NRpRq, -ORs, -0C(=0)NRpRq, and -S(=0)2Rs; wherein:Rpand Rq, for each occurrence, are each independently hydrogen, Ci- C2 alkyl, cyclopentyl, or tetrahydrofuranyl; wherein: the C1-C2 alkyl of any one of Rpand Rqis optionally substituted with 1 to 3 halogen groups selected from F and Cl;Rs, for each occurrence, is independently hydrogen, Ci- C2 alkyl, pyridinyl, or pyrimidinyl; wherein: the C1-C2 alkyl of Rsis optionally substituted with 1 to 3 halogen groups selected from F and Cl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 21, wherein RE, RE, and RGare each independently hydrogen, F, -OH, -CH(OH)CH3, -C(=0)NHCH3, -C(=N)OCH3, -CH3,-CF3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -C2H5, -(CH2)20H, -CH2OCH3,-CH2OC2H5, -(CH2)20CH3, -CH2OCHF2, -(CH2)20CHF2, -CH2C(=0)NH2,-CH2C(=0)N(CH3)2, -CH2S(=0)2CH3, -(CH2)2S(=0)2CH3, -CH2(0)C(=0)NHCH3, -CH2(0)C(=0)N(CH3)C2H5,-CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)NH(cyclopentyl), -CH2(0)C(=0)NH(tetrahydrofuranyl),-CH2(0)(pyridin-2-yl), or -CH2(0)(pyrimidin-2-yl); and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 22, wherein RE, Rr, and RGare each independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, or -CH2OCH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 23 represented by one of the following structural formulae:(Vie'); wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 24 represented by one of the following structural formulae:(Vile'); wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 25 represented by one of the following structural formulae:(Vine'); wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 26 represented by one of the following structural formulae:wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 27, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C6 alkoxy, C1-C6 haloalkyl, -NRhR', or C3-C6 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or C1-C4 alkyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 28, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C4 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C4 alkoxy, C1-C4 haloalkyl, -NRhR', or C3-C5 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or C1-C4 alkyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 29, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C2 haloalkyl, -NRhR‘, or C3-C4 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or -CH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.31. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 30, wherein R2, for each occurrence, is independently hydrogen, F, Cl, cyano, -CH3, -CHF2, -CF3, -NH2, or cyclopropyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 31, wherein R3, for each occurrence, is independently halogen, cyano, =0, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,-C(=0)Ry, -C(=0)ORy, -C(=0)NRvRw, -C(=0)NRORy,-C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C4 alkyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)ORy, and -NRVRW; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or C1-C2 alkyl; wherein the C1-C2 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; andRy, for each occurrence, is independently hydrogen, C1-C4 alkyl, or 5 or 6-memberedheterocyclyl; wherein: the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=0)0H; and the 5 or 6-memberedheterocyclyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, and -C(=0)0H; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 32, wherein R3, for each occurrence, is independently halogen, cyano, =0, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw,-C(=0)NRv0Ry, -C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C4 alkyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -ORyand -C(=0)0Ry; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or C1-C4 alkyl; wherein the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with -OH; andRy, for each occurrence, is independently hydrogen, Ci-C2alkyl, or 6- memberedheterocyclyl; wherein: the Ci-C2alkyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0H; and the 6-memberedheterocyclyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0H;Rz, for each occurrence, is independently -CH3, -OH, or -OCH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 33, wherein R3, for each occurrence, is independently halogen, cyano, =0, Ci-C2alkyl, Ci-C2alkoxy, C1-C4 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw,-C(=0)NRv0Ry, -C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the Ci-C2alkyl of R3is optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0Ry; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or Ci-C2alkyl; wherein the Ci-C2alkyl of any one of Rv, Rw, and Rxis optionally substituted with -OH; andRy, for each occurrence, is independently hydrogen, Ci-C2alkyl, or tetrahydro-2H-pyranyl; wherein: the Ci-C2alkyl of Ryis optionally substituted with -C(=0)0H; and the tetrahydro-2H-pyranyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0H;Rz, for each occurrence, is independently -CH3 or -OH; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 34, wherein R3, for each occurrence, is independently F, Cl, cyano, -OH, =0, -CH3, -OCH3, -CF3, -CH3CN, -C(CH3)2CH2OH, -CH2COOH, - CH20CH3, -C(=0)CHCH30H, -COOH, -C(=0)0(2-tetrahydro-2H-pyranyl), -C(=0)NH2, - C(=0)NH(CH2)20H, -C(=0)NH0H, -C(=0)NHS(=0)2CH3, -NH2, -NHCH3,-OCH2COOH, NHS(=0)2CH3,-S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHC(=0)CH3, or -P(=0)(CH3)2; wherein the 2-tetrahydro-2H-pyranyl in -C(=0)0(2-tetrahydro-2H-pyranyl) is substituted with 1 to 3 groups selected from -OH and -C(=0)0H; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.36. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 35, wherein R4, for each occurrence, is independently halogen, cyano, C1-C6 alkyl, Ci-C6alkoxy, C1-C6 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -ORy, or -S(=0)2Ry; wherein: the C1-C6 alkyl of R4is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)0Ry, and -NRVRW; wherein:Rvand Rw, for each occurrence, are each independently hydrogen or C1-C4 alkyl; andRy, for each occurrence, is independently hydrogen and C1-C4 alkyl; wherein: the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 36, wherein R4, for each occurrence, is independently halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=0)Ry, -C(=0)0Ry, -ORy, or -S(=0)2Ry; wherein: the C1-C4 alkyl of R4is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)0Ry, and -NRVRW; wherein:Rvand Rw, for each occurrence, are each independently hydrogen or C1-C4 alkyl;Ry, for each occurrence, is independently hydrogen or C1-C2 alkyl; wherein: the C1-C2 alkyl of any one of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2; and wherein 0 is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.38. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 37, wherein R4, for each occurrence, is independently cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=0)Ry, -C(=0)0Ry, - ORy, or -S(=0)2Ry; wherein: the C1-C2 alkyl of R4is optionally substituted with cyano, -OH, or -OCH3;Ry, for each occurrence, is independently hydrogen or C1-C2 alkyl; wherein: the C1-C2 alkyl of Ryis optionally substituted with -OCH3; wherein 0 is an integer selected from 0 and 1;and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.39. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 38, wherein R4, for each occurrence, is independently cyano, -OH, -OCH3, -CH3, -C2H5, -CF3, -CH2CN, -CH2OH, -CH2OCH3, -COOH, -C(=0)CH3, - C(=0)0CH3, -C(=0)CH20CH3, -S(=0)2CH3, S(=0)2C2H5, or S(=0)2CF3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.40. A compound selected from Compounds 1-457, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.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 that compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.42. A method of treating alpha- 1 antitrypsin (AAT) deficiency comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments1 to 40, or a therapeutically effective amount of a pharmaceutical composition according to embodiment 41.43. A method of modulating alpha- 1 antitrypsin (AAT) activity comprising the step of contacting said 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 41.44. The method of embodiment 42 or embodiment 43, wherein said therapeutically effective amount of the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is administered in combination with AAT augmentation therapy and / or AAT replacement therapy.

[0083] For the avoidance of doubt, features described in connection with Formula (F) may also be combined with features described in connection with Formulae (I), (Ila)-(IIf), (Illa)- (Illb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe).Example Embodiments 2:

[0084] Non-limiting embodiments / clauses of the present disclosure include:1. A compound represented by the following structural formula:a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: for each of the two occurrences, is a single bond or a double bond, provided that one is a single bond and the other is a double bond;V1and V2are each independently N or -CR2;W1and W2are each independently N or C, provided that one of W1and W2is N and the other is C;U is hydrogen, -OH, -CH3, -NH2, or halogen;X is absent or a bond, -(CRaRb)p-, or -SO2-;Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, halogen, -OH, Ci- Ce alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy;Rcand Rd, for each occurrence, are each independently hydrogen, halogen, -OH, Ci- Ce alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy;Ring A is C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl; provided that when W1is N and W2is C, Ring A is not 1, 5,6,7- tetrahydro-4 / / -indol-4-onyl or a tautomer thereof;Ring B is C4-C12 cycloalkyl, Ce or C10 aryl, 5 to 10-membered heteroaryl, or benzyl;Ring C is C3-C12 cycloalkyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl; provided that when Ring C is phenyl, the phenyl is substituted with R4; provided that when Ring C is phenyl, Y cannot be -SO2-; and provided that when Ring B is benzyl, Ring C cannot be pyridinyl or indolyl;RE, Rr, and RGare each independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -CRP(=N)ORs, -NR"C(=0)Rs, -NR"C(=0)0Rs, -NRpC(=0)NRqRr,-ORs, -0C(=0)Rs, or -0C(=0)NRpRq; wherein: the C1-C6alkyl or the C2-C6alkenyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -NRpC(=0)Rs, -NRpC(=0)0Rs, -NRpC(=0)NRqRr, -NRpS(=0)rRs, -ORs, -0C(=0)Rs, -0C(=0)0Rs, -0C(=0)NRpRq, -S(=0)rRs, and -S(=0)rNRpRq; wherein:Rp, Rq, and Rr, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, or 3 to 6-membered heterocyclyl; wherein: the C1-C4 alkyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, Ci- C3alkoxy, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl or the 3 to 6-membered heterocyclyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0(Ci-C2alkyl), -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rs, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein:the C1-C4 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl, the phenyl, or the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;R1is halogen, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or -0-(C3-C6 cycloalkyl);R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6alkyl, C2- Ce alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, -NRhR‘, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6alkenyl or the C3-C6cycloalkyl of R2is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rk,-C(=0)0Rk, -C(=0)NRhR‘, -NRhR‘, -NRhC(=0)Rk, -NRhC(=0)0Rk, -NRhC(=0)NR'Rj, -NRhS(=0)sRk-ORk, -0C(=0)Rk, -0C(=0)0Rk,-0C(=0)NRhR‘, -S(=0)sRk, and S(=0)sNRhRi; wherein:Rh, R', and R', for each occurrence, are each independently hydrogen, C1-C4 alkyl, or C3-C6cycloalkyl; wherein: the C1-C4 alkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rk, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein:-ORkcannot be -OH; the C1-C4 alkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2 alkyl)2; and the C3-C6cycloalkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl),-C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci- C2 alkyl)2;R3and R4, for each occurrence, are each independently halogen, cyano, =0, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -C(=0)NRv0Ry, -C(=0)NRvS(=0)tRy, -NRVRW, - NRvC(=0)Ry, -NRvC(=0)0Ry, -NRvC(=0)NRwRx, -NRvS(=0)tRy-ORy, -0C(=0)Ry, - 0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, -S(=0)tNRvRw, -S(=0)tNRvC(=0)Ry, - P(=0)RzRz, phenyl, or a 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6alkenyl, or the C3-C6cycloalkyl of any one of R3and R4is optionally substituted with 1 to 3 groups selected from cyano, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -NRVRW, -NRvC(=0)Ry,-NRvC(=0)0Ry, -NRVC (=0)NRwRx, - -NRvS(=0 Ry-ORy, -0C(=0)Ry, - 0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, and -S(=0)tNRvRw; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, 5 or 6-membered heterocyclyl, or 5 or 6- membered heteroaryl; wherein: the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano -OH,-NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; andthe C3-C6cycloalkyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Ry, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, a 5 or 6-membered heterocyclyl, or a 5 or 6-membered heteroaryl; wherein the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl),-C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl, the phenyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2;Rz, for each occurrence, is independently C1-C2 alkyl, -OH, or -0(Ci-C2alkyl); k is an integer selected from 1, 2, and 3; m and n a are each independently an integer selected from 0, 1, 2, and 3; p, r, s, and t are each independently an integer selected from 1 and 2; and q is an integer selected from 1, 2, and 3.2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to clause 1 represented by one of the following structural formulae:wherein:U is -OH, -CH3, -NH2, F, or Cl; and wherein all other variables not specifically defined herein are as defined in embodiment 1.3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to clause 1 represented by one of the following structural formulae:wherein:U is -OH, -CH3, -NH2, F, or Cl; and wherein all other variables not specifically defined herein are as defined in embodiment 1.4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to clause 1 or clause 2 represented by one of the following structural formulae:wherein:U is -OH or -NH2;Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9- membered heterocyclyl, phenyl, or 5 to 9-membered heteroaryl;Ring B is substituted with R1and Ring B is C4-C6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl, or benzyl; andwhen Z is Ring C optionally substituted with R4, Ring C is C4-C8 cycloalkyl, 4 to 8- membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl; and wherein all other variables not specifically defined herein are as defined in clause 1 or clause 2.5. The 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 formulae:wherein:Ring B is substituted with R1and Ring B is cyclohexyl, phenyl, pyridinyl, or benzyl; and wherein all other variables not specifically defined herein are as defined in any one of clauses 1, 2, and 4.6. The 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:(Va) (Vb) wherein:R1is halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; and k is an integer selected from 1 and 2; and wherein all other variables not specifically defined herein are as defined in any one of clauses 1, 2, 4, and 5.7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 6, wherein R1is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 7, wherein at least one R1is F; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 8, wherein:X is absent or a bond, -(CRaRb)-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 9, wherein X is absent or a bond, -CH2-, or -SO2-; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 10, wherein:Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Rcand Rd, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.12. The 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 one of the preceding clauses.13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 12, wherein Y is absent or a bond, -CTh-, -CHCH3-, - C(CH3)2-, -C(=0)-, or -SO2-; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 13, wherein Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl containing 1 to 3 oxygen atoms, phenyl, or 5 to 9-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 14, wherein Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl containing one or two oxygen atoms, phenyl, or 5 to 9-membered heteroaryl containing one or two nitrogen atoms or one or two oxygen atoms; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 15, wherein Ring A is optionally substituted with R3andand wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 16, wherein Ring A is optionally substituted with R3andand wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 17, wherein Z is Ring C, Ring C is optionally substituted with R4, and Ring C is Ch-Cx cycloalkyl; 4 to 8-membered heterocyclyl containing one or two heteroatoms selected from O, N, and S; phenyl; or 5-membered heteroaryl containing one or two heteroatoms selected from O and N; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 18, wherein Z is Ring C, Ring C is optionally substitutedand wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 1 to 19, wherein Z is Ring C, Ring C is optionally substituted with (R4)o, and Ring C is selected fromand wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 20, wherein RE, Rr, and RGare each independently hydrogen, halogen, cyano (-CºN), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=0)0Rs, - C(=0)NRpRq, -CRP(=N)ORs, or -ORs; wherein: the C1-C4 alkyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq,-ORs, -0C(=0)Rs, -0C(=0)0Rs, -0C(=0)NRpRq, and -S(=0)2Rs; wherein:Rpand Rq, for each occurrence, are each independently hydrogen, Ci- C2 alkyl, C3-C5 cycloalkyl, or 5 or 6-membered heterocyclyl; wherein: the C1-C2 alkyl of any one of Rpand Rqis optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; the C3-C5 cycloalkyl or the 5 or 6-membered heteroaryl of Rpand Rqis optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH;Rs, for each occurrence, is independently hydrogen, C1-C2 alkyl, or 5 or 6-membered heteroaryl; wherein the C1-C2 alkyl of Rsis optionally substitutedwith 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; wherein: the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 21, wherein RE, Rr, and RGare each independently hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, -C(=0)NRpRq, -CRp(=N)ORs, or -ORs; wherein: the C1-C2 alkyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)NRpRq, -ORs, -0C(=0)NRpRq, and -S(=0)2Rs; wherein:Rpand Rq, for each occurrence, are each independently hydrogen, Ci- C2 alkyl, cyclopentyl, or tetrahydrofuranyl; wherein: the C1-C2 alkyl of any one of Rpand Rqis optionally substituted with 1 to 3 halogen groups selected from F and Cl;Rs, for each occurrence, is independently hydrogen, Ci- C2 alkyl, pyridinyl, or pyrimidinyl; wherein: the C1-C2 alkyl of Rsis optionally substituted with 1 to 3 halogen groups selected from F and Cl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 22, wherein RE, RE, and RGare each independently hydrogen, F, -OH, -CH(OH)CH3, -C(=0)NHCH3, -C(=N)OCH3, -CH3,-CF3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -C2H5, -(CH2)20H, -CH2OCH3,-CH2OC2H5, -(CH2)20CH3, -CH2OCHF2, -(CH2)20CHF2, -CH2C(=0)NH2,-CH2C(=0)N(CH3)2, -CH2S(=0)2CH3, -(CH2)2S(=0)2CH3, -CH2(0)C(=0)NHCH3, -CH2(0)C(=0)N(CH3)C2H5,-CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)NH(cyclopentyl), -CH2(0)C(=0)NH(tetrahydrofuranyl),-CH2(0)(pyridin-2-yl), or -CH2(0)(pyrimidin-2-yl); and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 23, wherein RE, Rr, and RGare each independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, or -CH2OCH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 24 represented by one of the following structural formulae:wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 25 represented by one of the following structural formulae:(Vile); wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 26 represented by one of the following structural formulae:(Vllle); wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 27 represented by one of the following structural formulae:(IXe); wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 28, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C6 alkoxy, C1-C6 haloalkyl, -NRhR', or C3-C6 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or C1-C4 alkyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 29, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C4 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C4 alkoxy, C1-C4 haloalkyl, -NRhR‘, or C3-C5 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or C1-C4 alkyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.31. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 30, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C2 haloalkyl, -NRhR‘, or C3-C4 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or -CH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 31, wherein R2, for each occurrence, is independently hydrogen, F, Cl, cyano, -CH3, -CHF2, -CF3, -NH2, or cyclopropyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 32, wherein R3, for each occurrence, is independently halogen, cyano, =0, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -C(=0)NRORy,-C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C4 alkyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)0Ry, and -NRVRW; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or Ci-C2alkyl; wherein the Ci-C2alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; andRy, for each occurrence, is independently hydrogen, C1-C4 alkyl, or 5 or 6-memberedheterocyclyl; wherein: the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=0)0H; and the 5 or 6-memberedheterocyclyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, and -C(=0)0H; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 33, wherein R3, for each occurrence, is independently halogen, cyano, =0, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw,-C(=0)NRv0Ry, -C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C4 alkyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -ORyand -C(=0)0Ry; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or C1-C4 alkyl; wherein the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with -OH; andRy, for each occurrence, is independently hydrogen, Ci-C2alkyl, or 6- memberedheterocyclyl; wherein:the C1-C2 alkyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0H; and the 6-membered heterocyclyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0H;Rz, for each occurrence, is independently -CH3, -OH, or -OCH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 34, wherein R3, for each occurrence, is independently halogen, cyano, =0, C1-C2 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl,-C(=0)Ry, -C(=0)ORy, -C(=0)NRvRw,-C(=0)NRv0Ry, -C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C2 alkyl of R3is optionally substituted with 1 to 3 groups selected from -OH and -C(=0)ORy; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or C1-C2 alkyl; wherein the C1-C2 alkyl of any one of Rv, Rw, and Rxis optionally substituted with -OH; andRy, for each occurrence, is independently hydrogen, C1-C2 alkyl, or tetrahydro-2H-pyranyl; wherein: the C1-C2 alkyl of Ryis optionally substituted with -C(=0)OH; and the tetrahydro-2H-pyranyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)OH;Rz, for each occurrence, is independently -CH3 or -OH; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.36. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 35, wherein R3, for each occurrence, is independently F, Cl, cyano, -OH, =0, -CH3, -OCH3, -CF3, -CH3CN, -QCft^OHOH, -CH2COOH, -CH2OCH3, - C(=0)CHCH30H, -COOH, -C(=0)0(2-tetrahydro-2H-pyranyl), -C(=0)NH2, - C(=0)NH(CH2)20H, -C(=0)NH0H, -C(=0)NHS(=0)2CH3, -NH2, -NHCH3,-OCH2COOH, NHS(=0)2CH3,-S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHC(=0)CH3, or-P(=0)(CH3)2; wherein the 2-tetrahydro-2H-pyranyl in -C(=0)0(2-tetrahydro-2H-pyranyl) is substituted with 1 to 3 groups selected from -OH and -C(=0)0H; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 36, wherein R4, for each occurrence, is independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -ORy, or -S(=0)2Ry; wherein: the Ci-Ce alkyl of R4is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)0Ry, and -NRVRW; wherein:Rvand Rw, for each occurrence, are each independently hydrogen or C1-C4 alkyl; andRy, for each occurrence, is independently hydrogen and C1-C4 alkyl; wherein: the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.38. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 37, wherein R4, for each occurrence, is independently halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=0)Ry,-C(=0)0Ry, -ORy, or -S(=0)2Ry; wherein: the C1-C4 alkyl of R4is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)0Ry, and -NRVRW; wherein:Rvand Rw, for each occurrence, are each independently hydrogen or C1-C4 alkyl;Ry, for each occurrence, is independently hydrogen or C1-C2 alkyl; wherein: the C1-C2 alkyl of any one of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2; and wherein 0 is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.39. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 38, wherein R4, for each occurrence, is independently cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=0)Ry, -C(=0)0Ry, -ORy, or - S(=0)2Ry; wherein: the C1-C2 alkyl of R4is optionally substituted with cyano, -OH, or -OCH3;Ry, for each occurrence, is independently hydrogen or C1-C2 alkyl; wherein: the C1-C2 alkyl of Ryis optionally substituted with -OCH3; wherein 0 is an integer selected from 0 and 1; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.40. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 39, wherein R4, for each occurrence, is independently cyano, -OH, -OCH3, -CH3, -C2H5, -CF3, -CH2CN, -CH2OH, -CH2OCH3, -COOH, -C(=0)CH3, - C(=0)0CH3, -C(=0)CH20CH3, -S(=0)2CH3, S(=0)2C2H5, or S(=0)2CF3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.41. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 40, wherein U is -OH, -CH3, -NH2, or halogen; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.42. The 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 one of the preceding clauses.43. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 40, wherein U is halogen; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.44. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to 40, wherein U is fluoro; and wherein all other variables not specifically defined herein are as defined in any one of the preceding clauses.45. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according 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 one of the preceding clauses.46. A compound selected from Compounds 1-457, Compounds 458-532, Compounds B1-B25, Compounds W1-W32, and Compounds P1-P225, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.47. A compound selected from Compounds 1-457, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.48. A compound selected from Compounds 458-532, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.49. A compound selected from Compounds B1-B25 and Compounds W1-W32, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.50. A compound selected from Compounds P1-P225, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.51. A pharmaceutical composition comprising at least one compound according to any one of clauses 1 to 50, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.52. A method of treating alpha- 1 antitrypsin (AAT) deficiency comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of clauses 1 to50, or a therapeutically effective amount of a pharmaceutical composition according to clause51.53. A method of modulating alpha- 1 antitrypsin (AAT) activity comprising the step of contacting said 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 51.54. The method of clause 52 or clause 53, wherein said therapeutically effective amount of the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is administered in combination with AAT augmentation therapy and / or AAT replacement therapy.II. Compounds and Compositions

[0085] In some embodiments, a compound of the disclosure is a compound of Formula (I):a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein: for each of the two occurrences, is a single bond or a double bond, provided that one is a single bond and the other is a double bond;V1and V2are each independently N or -CR2;W1and W2are each independently N or C, provided that one of W1and W2is N and the other is C;U is hydrogen, -OH, -CH3, -NH2, or halogen;X is absent or a bond, -(CRaRb)p-, or -SO2-;Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, halogen, -OH, Ci- Ce alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;Rcand Rd, for each occurrence, are each independently hydrogen, halogen, -OH, Ci- Ce alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;Ring A is C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl; provided that when W1is N and W2is C, Ring A is not 1, 5,6,7- tetrahydro-4 / / -indol-4-onyl or a tautomer thereof;Ring B is C4-C12 cycloalkyl, Ce or C10 aryl, 5 to 10-membered heteroaryl, or benzyl;Ring C is C3-C12 cycloalkyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl; provided that when Ring C is phenyl, the phenyl is substituted with R4; provided that when Ring C is phenyl, Y cannot be -SO2-; and provided that when Ring B is benzyl, Ring C cannot be pyridinyl or indolyl;RE, Rr, and RGare each independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -CRp(=N)ORs, -NRpC(=0)Rs, -NRpC(=0)0Rs, -NRpC(=0)NRqRr,-ORs, -0C(=0)Rs, or -0C(=0)NRpRq; wherein: the C1-C6 alkyl or the C2-C6 alkenyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rs,-C(=0)0Rs, -C(=0)NRpRq, -NRpC(=0)Rs, -NRpC(=0)0Rs,-NRpC(=0)NRqRr, -NRpS(=0)rRs, -ORs, -0C(=0)Rs, -0C(=0)0Rs,-0C(=0)NRpRq, -S(=0)rRs, and -S(=0)rNRpRq; wherein:Rp, Rq, and Rr, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, or 3 to 6-membered heterocyclyl; wherein:the C1-C4 alkyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkoxy, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl or the 3 to 6-membered heterocyclyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0(Ci-C2alkyl), -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rs, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C4 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl, the phenyl, or the 5 or 6-membered of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3alkyl, Ci- C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;R1is halogen, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or -0-(C3-C6cycloalkyl) such as -O-(cyclopropyl) or -O-(cyclobutyl);R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6alkyl, C2- Ce alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the Ci-Ce alkenyl or the C3-C6cycloalkyl of R2is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rk,-C(=0)0Rk, -C(=0)NRhR‘, -NRhR‘, -NRhC(=0)Rk, -NRhC(=0)0Rk, -NRhC(=0)NR'Rj, -NRhS(=0)sRk-ORk, -0C(=0)Rk, -0C(=0)0Rk,-0C(=0)NRhR‘, -S(=0)sRk, and S(=0)sNRhRi; wherein:Rh, R', and R', for each occurrence, are each independently hydrogen, C1-C4 alkyl, or C3-C6cycloalkyl; wherein: the C1-C4 alkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen,cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, Ci- C3alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci- C2 alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rk, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein:-ORkcannot be -OH; the C1-C4 alkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2 alkyl)2; and the C3-C6 cycloalkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl),-C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci- C2 alkyl)2;R3and R4, for each occurrence, are each independently halogen, cyano, =0, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -C(=0)NRv0Ry,-C(=0)NRvS(=0)tRy, -NRVRW, -NRvC(=0)Ry, -NRvC(=0)0Ry, -NRvC(=0)NRwRx, -NRvS(=0)tRy, -ORy, -0C(=0)Ry, -0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy,-S(=0)tNRvRw, -S(=0)tNRvC(=0)Ry, -P(=0)RzRz, phenyl, or a 5 or 6-membered heteroaryl; wherein: the C1-C6 alkyl, the C2-C6 alkenyl, or the C3-C6 cycloalkyl of any one of R3and R4is optionally substituted with 1 to 3 groups selected from cyano, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -NRVRW, -NRvC(=0)Ry,-NRvC(=0)0Ry, -NRVC (=0)NRwRx, -NRvS(=0),Ry-OR', -0C(=0)R-\ - 0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, and -S(=0)tNRvRw; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 5 or 6-membered heterocyclyl, or 5 or 6- membered heteroaryl; wherein: the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano -OH,-NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6 cycloalkyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Ry, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, phenyl, a 5 or 6-membered heterocyclyl, or a 5 or 6-membered heteroaryl; wherein the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl, the phenyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2;Rz, for each occurrence, is independently C1-C2 alkyl, -OH, or -0(Ci-C2alkyl); k is an integer selected from 1, 2, and 3; m and n are each independently an integer selected from 0, 1, 2, and 3; p, r, s, and t are each independently an integer selected from 1 and 2; and q is an integer selected from 1, 2, and 3.

[0086] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, U is -OH, -CH3, -NH2, or halogen, and all other variables are as defined for Formula (I).

[0087] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, U is hydrogen, and all other variables are as defined for Formula (I).

[0088] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, U is -OH, and all other variables are as defined for Formula (I).

[0089] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, U is halogen, and all other variables are as defined for Formula (I).

[0090] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, U is fluoro, and all other variables are as defined for Formula (I).

[0091] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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).

[0092] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, U is -OH, -CH3, -NH2, or 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).

[0093] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, V2is -CR2, wherein R2is halogen, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0094] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, V2is -CR2, wherein R2is fluoro, wherein allother variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0095] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, V1is -CR2, wherein R2is halogen, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0096] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, V1is -CR2, wherein R2is fluoro, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0097] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Ila) or Formula (lib):wherein:U is -OH, -CHS, -NH2, F, or Cl; and wherein all other variables not specifically defined herein are as defined in Formula (I).

[0098] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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 preceding embodiment.

[0099] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (He), Formula (lid), Formula (He), or Formula (Ilf):wherein:U is -OH, -CH3, -NH2, F, or Cl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0100] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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 preceding embodiments.

[0101] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Ilg):wherein all other variables not specifically defined herein are as defined in Formula (I).

[0102] For example, in some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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 one of the preceding embodiments.

[0103] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Ilia) or Formula(mb):(Ilia) (Illb) wherein:U is -OH or -NH2;Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9- membered heterocyclyl, phenyl, or 5 to 9-membered heteroaryl;Ring B is substituted with R1and Ring B is C4-C6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl, or benzyl; and when Z is Ring C optionally substituted with R4, Ring C is C4-C8 cycloalkyl, 4 to 8- membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0104] For example, in some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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 one of the preceding embodiments.

[0105] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (IIIc):wherein:Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9- membered heterocyclyl, phenyl, or 5 to 9-membered heteroaryl;Ring B is substituted with R1and Ring B is C4-C6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl, or benzyl; and when Z is Ring C optionally substituted with R4, Ring C is C4-C8 cycloalkyl, 4 to 8- membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0106] For example, in some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, p, q, r, s, and t are each independently aninteger selected from 1 and 2, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0107] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3 carbocyclyl, C4 carbocyclyl, or Ci carbocyclyl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0108] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is phenyl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0109] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0110] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring B is substituted with R1and Ring B is phenyl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0111] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (IVa) or Formula (IVb):wherein:Ring B is substituted with R1and Ring B is cyclohexyl, phenyl, pyridinyl, or benzyl; or Ring B is substituted with R1and Ring B is cyclohexyl, phenyl, or benzyl;and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0112] For example, in some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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 one of the preceding embodiments.

[0113] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Va) or Formula (Vb):wherein:R1is halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; and k is an integer selected from 1 and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0114] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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 one of the preceding embodiments.

[0115] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Vc):wherein:R1is halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; and k is an integer selected from 1 and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0116] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, 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 preceding embodiments.

[0117] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R1is cyano, F, Cl, -CFb, -CHF2, -CF3, - OCH3, or -OCH(CH3)2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0118] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, at least one R1is F; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0119] In some embodiments, in the compound, deuterated derivative, pharmaceutically acceptable salt, or tautomer of the disclosure, X is absent or a bond, -(CRaRb)-, or -SO2-; Raand Rb, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or Ci- C3 alkoxy; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0120] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, X is absent or a bond, -CH2-, or -SO2-; and allother variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0121] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Y is absent or a bond, -(CRcRd)q-,-C(=0)-, or -SO2-; Rcand Rd, for each occurrence, are each 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 one of the preceding embodiments.

[0122] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Y is absent or a bond, -CH2-, -CHCH3-, -C(CH3)2-, -C(=0)-, or -SO2-; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0123] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl containing 1 to 3 oxygen atoms, phenyl, or 5 to 9-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0124] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl containing one or two oxygen atoms, phenyl, or 5 to 9-membered heteroaryl containing one or two nitrogen atoms or one or two oxygen atoms; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0125] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3andand all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0126] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3andand all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0127] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, wherein Z is Ring C, Ring C is optionallyand all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0128] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Z is Ring C, Ring C is optionally substitutedembodiments.

[0129] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, RE, Rr, and RGare each independently hydrogen, halogen, cyano , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=0)ORs, - C(=0)NRpRq, -CRP(=N)ORs, or -ORs; wherein: the C1-C4 alkyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rs, -C(=0)ORs, -C(=0)NRpRq, -ORs,-OC(=0)Rs, -OC(=0)ORs, -OC(=0)NRpRq, and -S(=0)2Rs; wherein:Rpand Rq, for each occurrence, are each independently hydrogen, Ci- C2 alkyl, C3-C5 cycloalkyl, or 5 or 6-membered heterocyclyl; wherein the Ci- C2 alkyl of any one of Rpand Rqis optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; wherein: the C3-C5 cycloalkyl or the 5 or 6-membered heteroaryl of any one of Rpand Rqis optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH;Rs, for each occurrence, is independently hydrogen, C1-C2 alkyl, or 5 or 6-membered heteroaryl; wherein: the C1-C2 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0130] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, RE, RE, and RGare each independently hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, -C(=0)NRpRq, -CRp(=N)ORs, or -ORs; wherein: the C1-C2 alkyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)NRpRq, -ORs, -OC(=0)NRpRq, and -S(=0)2Rs; wherein:Rpand Rq, for each occurrence, are each independently hydrogen, Ci- C2 alkyl, cyclopentyl, or tetrahydrofuranyl; wherein: the C1-C2 alkyl of any one of Rpand Rqis optionally substituted with 1 to 3 halogen groups selected from F and Cl;Rs, for each occurrence, is independently hydrogen, C1-C2 alkyl, pyridinyl, or pyrimidinyl; wherein:the C1-C2 alkyl of Rsis optionally substituted with 1 to 3 halogen groups selected from F and Cl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0131] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, RE, Rr, and RGare each independently hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=0)NHCH3, -C(=N)OCH3, -CH3, -CH2F, - CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)20CH3, - CH2OCHF2, -CH2C(=0)NH2, -CH2C(=0)N(CH3)2, -CH2S(=0)2CH3,-(CH2)2S(=0)2CH3, -CH2(0)C(=0)NHCH3, -CH2(0)C(=0)N(CH3)C2H5, -CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)NH(cyclopentyl), -CH2(0)C(=0)NH(tetrahydrofuranyl), -CH2(0)(pyridin-2-yl), -CH2(0)(pyrimidin-2-yl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0132] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, RE, RE, and RGare each independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH20CH3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0133] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Via), Formula (VIb), Formula (Vic), Formula (VId), or Formula (Vie):wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments. In some embodiments, o is an integer selected from 0, 1, and 2.

[0134] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Vlf) or Formula (VIg):wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments. In some embodiments, o is an integer selected from 0, 1, and 2.

[0135] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independentlyhydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=0)NHCH3, -C(=N)OCH3, -CH3, -CH2F, - CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)20CH3, - CH2OCHF2, -CH2C(=0)NH2, -CH2C(=0)N(CH3)2, -CH2S(=0)2CH3,-(CH2)2S(=0)2CH3, -CH2(0)C(=0)NHCH3, -CH2(0)C(=0)N(CH3)C2H5, -CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)NH(cyclopentyl), -CH2(0)C(=0)NH(tetrahydrofuranyl), -CH2(0)(pyridin-2-yl), -CH2(0)(pyrimidin-2-yl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0136] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH20CH3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0137] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -QHOQH; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0138] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Vila), Formula (Vllb), Formula (Vile), Formula (Vlld), or Formula (Vile):wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments. In some embodiments, o is an integer selected from 0, 1, and 2.

[0139] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Vllf) or Formula (Vllg):wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments. In some embodiments, o is an integer selected from 0, 1, and 2.

[0140] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl, phenyl, or 5 to 9-membered heteroaryl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0141] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3 carbocyclyl, C4 carbocyclyl, or Ci carbocyclyl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0142] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is phenyl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0143] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0144] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=0)NHCH3, -C(=N)OCH3, -CH3, -CH2F, - CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)20CH3, -CH2OCHF2, -CH2C(=0)NH2, -CH2C(=0)N(CH3)2, -CH2S(=0)2CH3,-(CH2)2S(=0)2CH3, -CH2(0)C(=0)NHCH3, -CH2(0)C(=0)N(CH3)C2H5, -CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)NH(cyclopentyl), -CH2(0)C(=0)NH(tetrahydrofuranyl), -CH2(0)(pyridin-2-yl), -CH2(0)(pyrimidin-2-yl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0145] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0146] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -CH20CH3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0147] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Villa), Formula (Vlllb), Formula (VIIIc), Formula (Vllld), or Formula (Vllle):(Vllle); wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0148] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (IXa), Formula (IXb), Formula (IXc), Formula (IXd), or Formula (IXe):wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0149] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C6 alkoxy, C1-C6 haloalkyl, -NRhR‘, or C3-C6 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or Ci- C4 alkyl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0150] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C4 alkyl (optionally substituted with 1 to 3 groups selectedfrom cyano, -OH, -OCH3, and -NH2), C1-C4 haloalkyl, -NRhR‘, or C3-C5 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or C1-C2 alkyl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0151] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), -NRhR‘, or C3-C4 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or -CH3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0152] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R2, for each occurrence, is independently hydrogen, F, Cl, cyano, -CH3, -CF3, -NH2, or cyclopropyl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0153] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R3, for each occurrence, is independently halogen, cyano, =0, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,-C(=0)Ry, -C(=0)ORy, -C(=0)NRvRw, -C(=0)NRORy,-C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C4 alkyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)ORy, and -NRVRW; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or C1-C2 alkyl; wherein the C1-C2 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; andRy, for each occurrence, is independently hydrogen, C1-C4 alkyl, or 5 or 6-memberedheterocyclyl; wherein: the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=0)OH; and the 5 or 6-memberedheterocyclyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, and -C(=0)OH; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0154] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R3, for each occurrence, is independently halogen, cyano, =0, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,-C(=0)Ry, -C(=0)ORy, -C(=0)NRvRw,-C(=0)NRv0Ry, -C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C4 alkyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -ORyand -C(=0)ORy; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or C1-C4 alkyl; wherein the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with -OH; andRy, for each occurrence, is independently hydrogen, Ci-C2alkyl, or 6- memberedheterocyclyl; wherein: the Ci-C2alkyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)OH; and the 6-membered heterocyclyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)OH;Rz, for each occurrence, is independently -CH3, -OH, or -OCH3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0155] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R3, for each occurrence, is independently halogen, cyano, =0, Ci-C2alkyl, Ci-C2alkoxy, C1-C4 haloalkyl,-C(=0)Ry, -C(=0)ORy, -C(=0)NRvRw,-C(=0)NRv0Ry, -C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the Ci-C2alkyl of R3is optionally substituted with 1 to 3 groups selected from -OH and -C(=0)ORy; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or Ci-C2alkyl; wherein the Ci-C2alkyl of any one of Rv, Rw, and Rxis optionally substituted with -OH; andRy, for each occurrence, is independently hydrogen, Ci-C2alkyl, or tetrahydro-2H-pyranyl; wherein: the Ci-C2alkyl of Ryis optionally substituted with -C(=0)OH; and the tetrahydro-2H-pyranyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)OH;Rz, for each occurrence, is independently -CH3 or -OH; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0156] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R3, for each occurrence, is independently F, Cl, cyano, -OH, =0, -CH3, -OCH3, -CF3, -CH3CN, -QCft^OHOH,-CH2COOH, -CH2OCH3, -C(=0)CHCH3OH, -COOH, -C(=0)0(2-tetrahydro-2H-pyranyl), - C(=0)NH2, -C(=0)NH(CH2)20H, -C(=0)NHOH, -C(=0)NHS(=0)2CH3,-NH2, -NHCH3, NHS(=0)2CH3, -OCH2COOH, -S(=0)2CH3, -S(=0)2NH2, - S(=0)2NHC(=0)CH3, or-P(=0)(CH3)2; wherein the 2-tetrahydro-2H-pyranyl in -C(=0)0(2-tetrahydro-2H-pyranyl) is substituted with 1 to 3 groups selected from -OH and - C(=0)OH; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0157] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R4, for each occurrence, is independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=0)Ry,-C(=0)ORy, -ORy, or -S(=0)2Ry; wherein: the C1-C6 alkyl of R4is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)ORy, and -NRVRW; wherein:Rvand Rw, for each occurrence, are each independently hydrogen or C1-C4 alkyl; andRy, for each occurrence, is independently hydrogen and C1-C4 alkyl; wherein: the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0158] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure R4, for each occurrence, is independently halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=0)Ry,-C(=0)ORy, -ORy, or -S(=0)2Ry; wherein: the C1-C4 alkyl of R4is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)ORy, and -NRVRW; wherein:Rvand Rw, for each occurrence, are each independently hydrogen or C1-C4 alkyl;Ry, for each occurrence, is independently hydrogen or C1-C2 alkyl; wherein: the C1-C2 alkyl of any one of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2; and wherein m is an integer selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0159] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R4, for each occurrence, is independently cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=0)Ry, -C(=0)ORy, -ORy, or - S(=0)2Ry; wherein: the C1-C2 alkyl of R4is optionally substituted with cyano, -OH, or -OCH3;Ry, for each occurrence, is independently hydrogen or C1-C2 alkyl; wherein the C1-C2 alkyl of Ryis optionally substituted with -OCH3; wherein m is an integer selected from 0 and 1; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0160] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R4, for each occurrence, is independently cyano, -OH, -OCH3, -CH3, -C2H5, -CH2CN, -CH2OH, -CH2OCH3,-COOH, -C(=0)CH3, -C(=0)0CH3, -C(=0)CH20CH3, -S(=0)2CH3, S(=0)2C2H5, or S(=0)2CF3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0161] In some embodiments, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure is represented by Formula (Xa), Formula (Xb), Formula (Xc), Formula (Xd), Formula (Xe), or Formula (Xf):wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments. In some embodiments, o is an integer selected from 0, 1, and 2.

[0162] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl, phenyl, or 5 to 9-membered heteroaryl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0163] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3 carbocyclyl, C4 carbocyclyl, or Ci carbocyclyl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0164] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is phenyl, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0165] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0166] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=0)NHCH3, -C(=N)OCH3, -CH3, -CH2F, - CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)20CH3, - CH2OCHF2, -CH2C(=0)NH2, -CH2C(=0)N(CH3)2, -CH2S(=0)2CH3,-(CH2)2S(=0)2CH3, -CH2(0)C(=0)NHCH3, -CH2(0)C(=0)N(CH3)C2H5, -CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)NH(cyclopentyl), -CH2(0)C(=0)NH(tetrahydrofuranyl), -CH2(0)(pyridin-2-yl), -CH2(0)(pyrimidin-2-yl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0167] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH20CH3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0168] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -QHOQH; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0169] In some embodiments, a compound of the disclosure is a compound of Formula (XIa), Formula (Xlb), Formula (XIc), Formula (Xld), Formula (Xle), or Formula (Xlf):a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:U is hydrogen or -OH;X is absent or a bond, -(CRaRb)p-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, halogen, -OH, Ci- Ce alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy;RE, Rr, and RGare each independently hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -CRP(=N)ORs, -NR"C(=0)Rs, -NR"C(=0)0Rs, -NRpC(=0)NRqRr,-ORs, -0C(=0)Rs, or -0C(=0)NRpRq; wherein:the C1-C6alkyl or the C2-C6alkenyl of any one of RE, Rr, and RGis optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -NR"C(=0)Rs, -NR"C(=0)0Rs, -NRpC(=0)NRqRr, -NRpS(=0)rRs, -ORs, -0C(=0)Rs, -0C(=0)0Rs,-0C(=0)NRpRq, -S(=0)rRs, and -S(=0)rNRpRq; wherein:Rp, Rq, and Rr, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3 to 6-membered heterocyclyl; wherein: the C1-C4 alkyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, Ci- C3alkoxy, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl or the 3 to 6-membered heterocyclyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0(Ci-C2alkyl), -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rs, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C4 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl, the phenyl, or the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl),-N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;R1is halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or -0-(C3-C6cycloalkyl);R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6alkyl, C2- Ce alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6alkenyl, or the C3-C6cycloalkyl of R2is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rk,-C(=0)0Rk, -C(=0)NRhR‘, -NRhR', -NRhC(=0)Rk, -NRhC(=0)0Rk, -NRhC(=0)NR'Rj, -NRhS(=0)sRk, -ORk, -0C(=0)Rk, -0C(=0)0Rk,-0C(=0)NRhR‘, -S(=0)sRk, and S(=0)sNRhRi; wherein:Rh, R', and R', for each occurrence, are each independently hydrogen, C1-C4 alkyl, or C3-C6cycloalkyl; wherein: the C1-C4 alkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, Ci- C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rk, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein:-ORkcannot be -OH; the C1-C4 alkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH,-NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2 alkyl)2; and the C3-C6cycloalkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci- C2 alkyl)2;R3and R4, for each occurrence, are each independently halogen, cyano, =0, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, - C(=0)Ry, -C(=0)ORy, -C(=0)NRvRw, -C(=0)NRv0Rv,-C(=0)NRvS(=0)tRy, -NRVRW, -NRvC(=0)Ry, -NRvC(=0)ORy, -NRvC(=0)NRwRx,-NRvS(=0)tRy, -OR', -0C(=0)Ry, -0C(=0)0R-\ -0C(=0)NRvRw, -S(=0),Ry,-S(=0)tNRvRw, -S(=0)tNRvC(=0)Ry, -P(=0)RzRz, phenyl, or a 5 or 6-membered heteroaryl; wherein: the Ci-Ce alkyl, the C2-C6alkenyl, or the C3-C6cycloalkyl of any one of R3and R4is optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -NRVRW, -NRvC(=0)Ry,-NRvC(=0)0Ry, -NRVC (=0)NRwRx, -NRvS(=0 Ry-ORy, -0C(=0)Ry,-0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, and -S(=0)tNRvRw; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, 5 or 6-membered heterocyclyl, or 5 or 6- membered heteroaryl; wherein: the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, Ci- C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, - C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and - C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Ry, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, a 5 or 6-membered heterocyclyl, or a 5 or 6-membered heteroaryl; wherein the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2 alkyl)2; and the C3-C6 cycloalkyl, the phenyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of Ryis optionallysubstituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, Ci- C3haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), - C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(CI-C2alkyl)2;Rz, for each occurrence, is independently C1-C2 alkyl, -OH, or -0(Ci-C2alkyl); k is an integer selected from 1, 2, and 3; and0, p, r, s, and t are each independently an integer selected from 1 and 2.

[0170] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=0)NHCH3, -C(=N)OCH3, -CH3, -CH2F, - CH2CN, -(CH2)2CN, -CH2OH, -(CH2)20H, -CH2OCH3, -CH2OC2H5, -(CH2)20CH3, - CH2OCHF2, -CH2C(=0)NH2, -CH2C(=0)N(CH3)2, -CH2S(=0)2CH3,-(CH2)2S(=0)2CH3, -CH2(0)C(=0)NHCH3, -CH2(0)C(=0)N(CH3)C2H5, -CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)NH(cyclopentyl), -CH2(0)C(=0)NH(tetrahydrofuranyl), -CH2(0)(pyridin-2-yl), -CH2(0)(pyrimidin-2-yl; and all other variables not specifically defined herein are as defined in Formula (XIa), Formula (Xlb), Formula (XIc), Formula (Xld), Formula (Xle), or Formula (Xlf).

[0171] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are as defined in Formula (XIa), Formula (Xlb), Formula (XIc), Formula (Xld), Formula (Xle), or Formula (Xlf).

[0172] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R1is cyano, F, Cl, -CH3, -CHF2, -CF3, - OCH3, or -OCH(CH3)2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0173] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, at least one R1is F; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0174] In some embodiments, in the compound, deuterated derivative, pharmaceutically acceptable salt, or tautomer of the disclosure, X is absent or a bond, -(CRaRb)-, or -SO2-; Raand Rb, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or Ci-C3 alkoxy; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0175] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, X is absent or a bond, -CH2-, or -SO2-; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0176] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R2, for each occurrence, is independently hydrogen, F, Cl, cyano, -CFb, -CF3, or -NFh; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0177] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R3is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=0)Ry, -C(=0)ORy, -ORy, -OC(=0)Ry, or - OC(=0)ORy; the C1-C6 alkyl or the C2-C6 alkenyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Ry, -C(=0)ORy, -ORy, -OC(=0)Ry, and -OC(=0)ORy; wherein Ry, for each occurrence, is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0178] In some embodiments, a compound of the disclosure is a compound of Formula (Xlla), Formula (Xllb), Formula (XIIc), Formula (Xlld), Formula (Xlle), or Formula (Xllf):(Xlle) (Xllb), a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:U is hydrogen or -OH;Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Rcand Rd, for each occurrence, are each independently hydrogen, halogen, -OH, Ci- Ce alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy;Ring A is C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl;RE, Rr, and RGare each independently hydrogen, halogen, cyano, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -CRP(=N)ORs, -NR"C(=0)Rs, -NR"C(=0)0Rs, -NRpC(=0)NRqRr,-ORs, -0C(=0)Rs, or -0C(=0)NRpRq; wherein: the C1-C6alkyl or the C2-C6alkenyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -NRpC(=0)Rs, -NRpC(=0)0Rs, -NRpC(=0)NRqRr, -NRpS(=0)rRs, -ORs, -0C(=0)Rs, -0C(=0)0Rs, -0C(=0)NRpRq, -S(=0)rRs, and -S(=0)rNRpRq; wherein:Rp, Rq, and Rr, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, or 3 to 6-membered heterocyclyl; wherein:the C1-C4 alkyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, Ci- C3alkoxy, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl or the 3 to 6-membered heterocyclyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0(Ci-C2alkyl), -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rs, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C4 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl, the phenyl, or the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl),-N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6alkyl, C2- Ce alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6alkenyl, or the C3-C6cycloalkyl of R2is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rk,-C(=0)0Rk, -C(=0)NRhR‘, -NRhR‘, -NRhC(=0)Rk, -NRhC(=0)0Rk, -NRhC(=0)NR'Rj, -NRhS(=0)sRk-ORk, -0C(=0)Rk, -0C(=0)0Rk,-0C(=0)NRhR‘, -S(=0)sRk, and S(=0)sNRhRi; wherein:Rh, R', and R', for each occurrence, are each independently hydrogen, C1-C4 alkyl, or C3-C6cycloalkyl; wherein: the C1-C4 alkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkyl, Ci- C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rk, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein:-ORkcannot be -OH; the C1-C4 alkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), -N(CI-C2alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2alkyl), - N(CI-C2alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci- C2alkyl)2;R3and R4, for each occurrence, are each independently halogen, cyano, =0, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -C(=0)NRv0Ry,-C(=0)NRvS(=0)tRy, -NRVRW, -NRvC(=0)Ry, -NRvC(=0)0Ry, -NRvC(=0)NRwRx, -NRvS(=0)tRy, -ORy, -0C(=0)Ry, -0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, -S(=0)tNRvRw, -S(=0)tNRvC(=0)Ry, -P(=0)RzRz, phenyl, or a 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6 alkenyl, or the C3-C6cycloalkyl of any one of R3and R4is optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -NRVRW, -NRvC(=0)Ry,-NRvC(=0)0Ry, -NRVC (=0)NRwRx, -NRvS(=0 Ry-ORy, -0C(=0)Ry, -0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, and -S(=0)tNRvRw; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, 5 or 6-membered heterocyclyl, or 5 or 6- membered heteroaryl; wherein: the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, Ci- C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, - C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and - C(=0)N(CI-C2alkyl)2; and the C3-C6 cycloalkyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Ry, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, phenyl, a 5 or 6-membered heterocyclyl, or a 5 or 6-membered heteroaryl; wherein the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, - C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2 alkyl)2; and the C3-C6cycloalkyl, the phenyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, Ci- C3 haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), - C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(CI-C2alkyl)2;Rz, for each occurrence, is independently C1-C2 alkyl, -OH, or -0(Ci-C2alkyl); n is integer selected from 0, 1, 2, and 3; ando, q, r, s, and t are each independently an integer selected from 1 and 2.

[0179] In some embodiments, U is -OH.

[0180] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl, phenyl, or 5 to 9-membered heteroaryl, wherein all other variables not specifically defined herein are as defined in Formula (Xlla), Formula (Xllb), Formula (XIIc), Formula (Xlld), or Formula (Xlle).

[0181] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is C3 carbocyclyl, C4 carbocyclyl, or Ci carbocyclyl, wherein all other variables not specifically defined herein are as defined in Formula (Xlla), Formula (Xllb), Formula (XIIc), Formula (Xlld), or Formula (Xlle).

[0182] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is phenyl, wherein all other variables not specifically defined herein are as defined in Formula (Xlla), Formula (Xllb), Formula (XIIc), Formula (Xlld), or Formula (Xlle).

[0183] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Ring A is optionally substituted with R3and Ring A is pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, wherein all other variables not specifically defined herein are as defined in Formula (Xlla), Formula (Xllb), Formula (XIIc), Formula (Xlld), or Formula (Xlle).

[0184] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independently hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=0)NHCH3, -C(=N)OCH3, -CH3, -CH2F, - CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)20CH3, - CH2OCHF2, -CH2C(=0)NH2, -CH2C(=0)N(CH3)2, -CH2S(=0)2CH3,-(CH2)2S(=0)2CH3, -CH2(0)C(=0)NHCH3, -CH2(0)C(=0)N(CH3)C2H5, -CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)NH(cyclopentyl), -CH2(0)C(=0)NH(tetrahydrofuranyl), -CH2(0)(pyridin-2-yl), -CH2(0)(pyrimidin-2-yl); and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0185] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, Rrand RGare each independentlyhydrogen, F, -CH(OH)CH3, -CFb, -CH2CN, -CH2OH, and -CH2OCH3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0186] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R1is cyano, F, Cl, -CFb, -CHF2, -CF3, - OCH3, or -OCH(CH3)2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0187] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, at least one R1is F; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0188] In some embodiments, in the compound, deuterated derivative, pharmaceutically acceptable salt, or tautomer of the disclosure, X is absent or a bond, -(CRaRb)-, or -SO2-; Raand Rb, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or Ci- C3 alkoxy; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0189] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, X is absent or a bond, -CH2-, or -SO2-; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0190] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R2, for each occurrence, is independently hydrogen, F, Cl, cyano, -CFb, -CF3, or -NFh; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0191] In some embodiments, in the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the disclosure, R3is C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=0)Ry, -C(=0)ORy, -ORy, -OC(=0)Ry, or - OC(=0)ORy; the C1-C6 alkyl or the C2-C6 alkenyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Ry, -C(=0)ORy, -ORy, -OC(=0)Ry, and -OC(=0)ORy; wherein Ry, for each occurrence, is independently hydrogen or C1-C4 alkyl; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0192] In some embodiments, the compound of any one of Formulae (I), (Ila)-(IIf), (Illa)- (Illb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) is selected from Compounds 1-457 (Table A below) and tautomers of those compounds, deuterated derivativesof those tautomers and compounds, and pharmaceutically acceptable salt of any of the foregoing.

[0193] In some embodiments, the compound of any one of Formulae (I), (Ila)-(IIf), (Illa)- (Illb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) is selected from Compounds 458-532 (Table B below) and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salt of any of the foregoing.

[0194] In some embodiments, the compound of any one of Formulae (I), (Ila)-(IIf), (Illa)- (Illb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) is selected from Compounds P1-P225 (Table E below) and tautomers of those compounds, deuterated derivatives of those tautomers and compounds, and pharmaceutically acceptable salt of any of the foregoing.Table A. Compounds 1-457Table B. Compounds 458-532Table C. Compounds B1-B25Table D. Compounds W1-W32Table E. Prophetic Compounds P1-P225

[0195] Some embodiments of the disclosure include derivatives of Compounds 1-457, Compounds 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) or compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) or tautomers thereof. In some embodiments, the derivatives are silicon derivatives in which at least one carbon atom in a compound 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) or compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)- (Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) has been replaced by silicon. In some embodiments, the derivatives are boron derivatives, in which at least one carbon atom in a compound 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) or compounds of Formulae (I), (Ila)- (Ilf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) or tautomers thereof has been replaced by boron. In other embodiments, the derivatives arephosphate derivatives, in which at least one carbon atom in a compound selected from Compounds 1-457, Compounds 458-532, Compounds B1-B25, Compounds W1-W32, and Compounds PI -P225 (e.g., Compounds 1-457, or e.g., Compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)- (IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) or tautomers thereof has been replaced by phosphorus. Because the general properties of silicon, boron, and phosphorus are similar to those of carbon, replacement of carbon by silicon, boron, or phosphorus can result in compounds with similar biological activity to a carbon containing original compound.

[0196] In some embodiments, the derivative is a silicon derivative in which one carbon atom in a compound 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) or compounds of Formulae (I), (Ila)- (Ilf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) and tautomers thereof has been replaced by silicon. In other embodiments, two carbon atoms have been replaced by silicon. The carbon replaced by silicon may be a non-aromatic carbon. In some embodiments, a quaternary carbon atom of a tert-butyl moiety may be replaced by silicon. In some embodiments, the silicon derivatives of the disclosure may include one or more hydrogen atoms replaced by deuterium. For example, one or more hydrogens of a tert-butyl moiety in which the carbon has been replaced by silicon, may be replaced by deuterium. In other embodiments, a silicon derivative of a compound 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) or compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)- (Vle), (Vlla)-(VIIe), and (IXa)-(IXe) and tautomers thereof may have silicon incorporated into a heterocycle ring.

[0197] In some embodiments, examples of silicon derivatives of Compounds 1-457 or compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)- (Vlle), and (IXa)-(IXe) include the following compounds:wherein the variables not specifically defined are as defined in any one of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe).

[0198] In some embodiments, examples of boron derivatives of Compounds 1-457 or compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)- (Vlle), and (IXa)-(IXe) include the following compounds:

[0199] In some embodiments, examples of phosphate derivatives of Compounds 1-457 or compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)- (Vlle), and (IXa)-(IXe) include the following compounds:wherein the variables not specifically defined are as defined in any one of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe).

[0200] In some embodiments, examples of phosphate derivatives of Formula (I) include the following compounds:Formula (I).

[0201] In some embodiments, examples of phosphate derivatives of Formula (I) include the following compounds:, wherein the variables not specifically defined are as defined in Formula (I).

[0202] Another aspect of the disclosure provides pharmaceutical compositions comprising a compound selected from compounds according to any of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(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 e.g., Compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435- 457), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition comprising at least one compound chosen from Formulae (I), (Ila)- (Ilf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe) and Compounds 1-457, Compounds 458-532, Compounds B1-B25, Compounds W1-W32, Compounds PI -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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing is administered to a patient in need thereof.

[0203] A pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants.In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0204] It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include at least one other active agent. Alternatively, a pharmaceutical composition comprising at least one compound of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)- (Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuteratedderivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one additional active agent. In some embodiments, a pharmaceutical composition comprising at least one compound selected from Compounds 1-457, Compounds 458-532, Compounds B1-B25, Compounds W1-W32, and Compounds PI -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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising at least one additional active agent.

[0205] In some embodiments, a compound of Formula (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)- (IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is combined with at least one additional active agent for simultaneous, separate, or sequential use in the treatment of AATD. In some embodiments, when the use is simultaneous, the compound of Formula (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and the at least one additional active agent are in separate pharmaceutical compositons. In some embodiments, when the use is simultaneous, the compound of Formula (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and the at least one additional active agent are together in the same pharmaceutical composition. In some embodiments, the compound is a compound selected from Compounds 1-457, 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0206] In some embodiments, a compound of Formula (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)- (IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is provided for use in a method of treating AATD, wherein the method comprises co-administering the compound and an additional active agent. In some embodiments,the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compound is selected from Compounds 1-457, 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0207] In some embodiments, a combination of a compound of Formula (I), (Ila)-(IIf), (Illa)- (Illb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and an additional active agent, is 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 compound is selected from Compounds 1-457, Compounds 458-531, Compounds B1-B25, Compounds W1-W32, and Compounds PI -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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0208] In some embodiments, an additional active agent is provided for use in a method of treating AATD, wherein the method comprises co-administrating the additional active agent and a compound of Formula (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)- (Vlle), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those 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-administeredsequentially. In some embodiments, the compound is 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0209] In some embodiments, a compound of Formula (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)- (IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is provided for use in a method of treating AATD, wherein the compound is prepared for administration in combination with an additional active agent. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential administration. In some embodiments, the compound is selected from Compounds 1-457, 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0210] In some embodiments, a combination of a compound of Formula (I), (Ila)-(IIf), (Illa)- (Illb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and an additional active agent, is provided for use in a method of treating AATD. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential administration. In some embodiments, the compound is selected from Compounds 1-457, 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 those compounds,deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0211] In some embodiments, an additional active agent is provided for use in a method of treating AATD, wherein the additional active agent is prepared for administration in combination with a compound of Formula (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound and the additional active agent are prepared for administration in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are prepared for simultaneous administration. In some embodiments, the compound and the additional active agent are prepared for sequential administration. In some embodiments, the compound is selected from Compounds 1-457, 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0212] In some embodiments, the additional active agent is selected the group consisting of alpha- 1 antitrypsin protein (AAT) from the blood plasma of healthy human donors and recombinant AAT. In some embodiments, the additional active agent is alpha- 1 antitrypsin protein (AAT) from the blood plasma of healthy human donors. In some embodiments, the additional active agent is alpha- 1 antitrypsin protein (AAT) from the blood plasma of healthy human donors.

[0213] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology , eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions andknown techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure.

[0214] Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as com starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

[0215] In another aspect of the disclosure, the compounds and the pharmaceutical compositions, described herein, are used to treat AATD. In some embodiments, the subject in need of treatment with the compounds and compositions of the disclosure carries the ZZ mutation. In some embodiments, the subject in need of treatment with the compounds and compositions of the disclosure carries the SZ mutation.

[0216] In some embodiments, the methods of the disclosure comprise administering to a patient in need thereof a compound chosen from any of the compounds of Formulae (I), (Ila)- (Ilf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound is 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 those compounds, deuteratedderivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, said patient in need thereof has a Z mutation in the alpha- 1 antitrypsin gene. In some embodiments said patient in need thereof is homozygous for the Z- mutation in the alpha- 1 antitrypsin gene.

[0217] Another aspect of the disclosure provides methods of modulating alpha-1 antitrypsin activity comprising the step of contacting said alpha- 1 -antitrypsin with at least one compound of Formulae (I), (Ha)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the methods of modulating alpha- 1 antitrypsin activity comprising the step of contacting said alpha- 1 -antitrypsin with at least one compound 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 those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0218] In some embodiments, the methods of modulating alpha-1 antitrypsin activity take place in vivo. In some embodiments, the methods of modulating alpha- 1 antitrypsin activity take place ex vivo and said alpha- 1 -antitrypsin is from a biological sample obtained from a human subject. In some embodiments, the methods of modulating AAT take place in vitro and said alpha- 1 -antitrypsin is 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.III. Preparation of Compounds

[0219] All the generic, subgeneric, and specific compound formulae disclosed herein are considered part of the disclosure.A. Compounds of Formula I

[0220] The compounds of the disclosure may be made according to standard chemical practices or as described herein. Throughout the following synthetic schemes and in the descriptions for preparing compounds of Formulae (I), (Ila)-(IIf), (Illa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (Vla)-(VIe), (Vlla)-(VIIe), and (IXa)-(IXe), Compounds 1-457, Compounds 458-532, Compounds B1-B25, Compounds W1-W32, Compounds P1-P225, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used:AbbreviationsBrettPhos Pd G4 = dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2- yl)phenyl]phenyl]phosphane;methanesulfonic acid;N-methyl-2-phenylaniline;palladiumDIPEA = N,N-Diisopropylethylamine or N-ethyl-N-isopropyl-propan-2-amineDMA = dimethyl acetamideDMAP = dimethylamino pyridineDME = dimethoxyethaneDMF = dimethylformamideDMSO = dimethyl sulfoxideEtOH = ethanolEtOAc = ethyl acetateHATU = [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium (Phosphorus Hexafluoride Ion)MeOH = methanolMP-TMT scavenger resin = a macroporous polystyrene-bound trimercaptotriazine, a resin bound equivalent of 2,4,6-trimercaptotriazine (TMT).MTBE = Methyl / er / -butyl ether NMM = N-methyl morpholine NMP = N-methyl pyrrolidinePd(dppf)2Cl2 = [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)PdCb = palladium(II) dichloridePdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride SFC = super critical fluid chromatographySPhos Pd G3 = (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-l,E- biphenyl)]palladium(II) methanesulfonate TBAF = Tetrabutylammonium fluoride / BuXPhos Pd G1 = Chloro[2-(di- / er / -butylphosphino)-2',4',6'-triisopropyl-l,l'-biphenyl][2-(2- aminoethyl)phenyl)]palladium(II) or / -BuXPhos palladium(II) phenethylamine chloride / BuXPhos Pd G3 = [(2-Di- / er / -butylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)-2-(2'-amino- 1,1 '-biphenyl)] palladium(II) methanesulfonate / BuXPhos Pd G4 = ditert-butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane;dichloromethane;methanesulfonate;N-methyl-2-phenyl- aniline palladium (II)TEA = triethylamineTFA = trifluoroacetic acid THF = tetrahydrofuranXPhos Pd G1 = (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2- aminoethyl)phenyl)]palladium(II) chloride or (XPhos) palladium(II) phenethylamine chloride

[0221] In some embodiments, processes for preparing compounds of Formula (I), tautomers thereof, deuterated derivatives of those compounds and tautomers, or pharmaceutically acceptable salts of any of the foregoing, comprise reacting a compound of Formula (I), tautomer, deuterated derivative, or pharmaceutically acceptable salt with a deprotection reagent as depicted in Schemes 1 through 11 below (wherein all variables are as defined for Formula (I) above):Scheme 1

[0222] Scheme 1 shows methods for the preparation of a compound of formula 1-2. PG1is an alcohol protecting group such as Benzyl (Bn), Methoxymethyl (MOM), or Methyl (Me). In some examples, where PG1is a benzyl group, a compound of formula 1-2 may be prepared by hydrogenolysis of a compound of formula 1-1 using a palladium on carbon catalyst, under an atmosphere of hydrogen. The reaction may be performed at elevated pressure. A solvent such as MeOH, EtOH or EtOAc may be used. Where PG1is a group such as MOM, a compound of formula (I) may be prepared by treatment with an acid such as HC1. In examples where PG1is a methyl group, the group may be removed by treatment with AlCb in the presence of octanethiol. In some examples, a reagent such as BBn may be used. Any other standard method suitable for the removal of an alcohol protecting group may be used to prepare a compound of formula 1-2 from compounds of formula 1-1.Scheme 22-3

[0223] Scheme 2 shows methods for the preparation of compounds of formula 2-5. Q1is a halogen such as Br , I or Cl. Compounds of formula 2-3 are boronic acids or esters with R20any suitable alkyl group (such a Me, Et), or hydrogen. All other variables are as defined above. Compounds of formula 2-1 may be transformed into compounds of formula 2-2 using any suitable method for the halogenation of an aromatic ring. For example, N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS) in a solvent such as dichloromethane may be used. A compound of formula 2-4 may be prepared from 2-2 and 2-3 using standard Suzuki coupling conditions. In some examples, Suzuki coupling conditions may involve a catalyst such as Pd(dppf)Cl2 and a base such as Na2CCh. In some examples, a catalyst such as Pd2(dba)3 in the presence of a ligand such as XPhos may be used. A solvent such as DMF or DME may be used. The reaction is performed in the presence of additional heat (e.g. 90 °C). A compound of formula 2-5 may be prepared from 2-4 using any suitable method for the removal of an alcohol protecting group.Scheme 3

[0224] Processes for the preparation of compounds of Formula 3-4 are shown in Scheme 3. PG2is any suitable carboxylic acid protecting group. For example, PG2may be Me, Et, Benzyl or tert-Butyl. All other variables are defined as above. Compounds of formula 3-2 may be prepared from compounds of formula 3-1 using any suitable method for Suzuki coupling. For example, Pd(dppf)Cl2 in the presence of Na2CCb may be used. Compounds of formula 3-3 may be prepared from compounds of formula 3-2 using any suitable method for the removal of a carboxylic acid protecting group. For example, where PG2is a methyl ester, hydrolysis with a base such as LiOH or NaOH, in a solvent such as THF and water may be used. Where PG2is a group such as tert-Butyl, treatment with an acid such as TFA or HC1 affords compounds of formula 3-3. In some examples, where PG1and PG2are both benzyl groups, a compound of formula 3-4 may be prepared directly from a compound of formula 3-2 by hydrogenation.Scheme 4

[0225] Scheme 4 shows processes for the preparation of compounds of formula 4-4. All variables are defined as above. Compounds of formula 4-2 may be prepared by reductive alkylation between an indole of formula 2-1 and a ketone of formula 4-1. In some examples, reductive alkylation may be performed in the presence of a reagent such as triethyl silane and an acid (such as trifluoroacetic acid or methanesulfonic acid). The reaction may be performed in a solvent such as dichloromethane.Scheme 5

[0226] Scheme 5 depicts methods for the preparation of compounds of formula 5-4. All variables are defined as above. Compound of formula 5-2 may be prepared from ketones or aldehydes of formula 5-1 and indoles of formula 2-1 using any suitable conditions for performing a reductive alkylation reaction. In some examples, the reaction may be performed in the presence of triethyl silane and trifluoroacetic acid. A solvent such as dichloromethane may be used. The reaction may be performed in the presence of added heat (e.g. at 40 °C).Scheme 6

[0227] Scheme 6 shows processes for the preparation of indoles of formula 2-1. Q2and Q3are halogens such as Br, Cl or I. E1is hydrogen or SiMe3. For example, in some processes Q2is iodine and Q3is bromine. In some examples, compounds of formula 6-3 may be prepared from compound of formula 6-1 and alkynes of formula 6-2 using any suitable conditions for performing a Sonagashira coupling. In some examples, a catalyst such a Pd(PPh3)2Cl2 in the presence of Cul may be used. A base such as triethylamine or diisopropylethylamine may be used. The reaction may be performed in a solvent such as DMF in the presence of added heat. In some examples, where E1is SiMe3, the reaction may be performed in the presence of TBAF. Compounds of formula 6-5 may be prepared from compounds of formula 6-3 by transition metal catalyzed amination with an amine of formula 6-4. Amination may be performed in the presence of a palladium catalyst such as tBuXPhos Pd G3, tBu XPhos Pd G, or any other suitable catalyst for performing Buchwald aminations. A base such as NaOtBu may be used. The reaction may be performed in a solvent such as xylene. The reaction may be performed at room temperature, or in the presence of added heat. In some examples, cyclization to compounds of formula 2-1 occurs spontaneously in the amination reaction. In some examples, compounds of formula 2-1 from 6-5 are prepared by treatment with PdCh in a solvent such as MeCN. The reaction may be performed with added heat (e.g. at 50 °C).Scheme 77-2

[0228] Scheme 7 shows an alternative process for the preparation of a compound of formula 6-5. Q4is a halogen such as Br or I. R21is a hydrogen or a suitable alkyl group such as ethyl or methyl. An aniline of formula 7-1 may be arylated with a boronic acid or ester 7-2 using any suitable conditions for N-arylation to give a compound of formula 7-3. In some examples, a CU(OAC)2 catalyst may be used. The reaction may be performed in the presence of a base such as K2CO3. A solvent such as DMSO may be used. A compound of formula 6-5 may be prepared by Sonagashira coupling of compounds of formula 7-3 with alkynes of formula 7-4 to afford compounds of Formula 6-5.Scheme 8

[0229] Scheme 8 depicts processes for the preparation of compounds of formula 8-7 from a dihaloaryl of general formula 8-1. Q5is a halogen such as Cl, Br, or I. In some embodiments, group A is an aromatic or heteroaromatic ring. Amination of compound of formula 8-1 with an amine of formula 8-2 affords compounds of formula 8-3. Any suitable method for amination of an aryl halide with an amine may be used. For example, the reaction may be performed in the presence of a catalyst such as Pd(OAc)2 in the presence of a ligand such as dppf. In some examples, the reaction may be performed in the presence of tBuXPhos Pd Gl.The reaction may be performed in the presence of a base such as NaOtBu. Indoles of formula 8-5 may be prepared by reaction of compounds of formula 8-3 with disubstituted alkynes of formula 8-4 in the presence of a suitable palladium catalyst. For example, catalysts such as Pd(tBu3P)2 orJackiePhos Pd G3 may be used. In some alternative embodiments, Pd(OAc)2 may be used. The reaction is performed in the presence of a suitable ligand. For example, dicyclohexyl methylamine (cHx)2NMe may be used. The reaction may be performed in a solvent such as 1,4- dioxane, and in the presence of added heat (e.g.. 60 °C).Scheme 9

[0230] Any suitable conditions for Sonagashira coupling of a compound of formula 9-1 with an alkyne of formula 9-2, as shown in Scheme 9, may be used in the preparation of compounds of formula 9-3. PG4is any suitable ester protecting group (e.g. benzyl, methyl, tert-butyl), Allother variables are defined as above. Compounds of formula 9-5 may be prepared from compounds of formula 9-3 and amines of formula 9-4, using any suitable method for amination of aryl halides. In some embodiments, the reaction is performed in the presence of a tBuXPhos Pd G3 catalyst and NaOtBu. A solvent such as m-xylene may be used. Any suitable halogenating reagent may be used to prepare compounds of formula 9-6 from indoles of formula 9-5. For example, N-iodosuccinimide or N-bromosuccinimide may be used. In some embodiments, compounds of formula 9-8 may 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 may be used. Compounds of formula 9-10 may be prepared from compounds of formula 9-8 using standard methods for ester and alcohol protecting group removal, as appropriate for the protecting groups used in that embodiment.Scheme 10

[0231] Scheme 10 refers to processes for the preparation of compounds of formula 10-7. Q8is a halogen such as Br, I, or Cl. PG4is a standard amine protecting group (e.g. Bn, Boc, CBz). PG5is an ester protecting group such as Me, Et, or tert-Butyl. A compound of formula 10-3 may be prepared from a compound of formula 10-1 and an amine of formula 10-2 by Buchwald amination. In some embodiments, a catalyst such as Pd(OAc)2 with a ligand such as dppf may be used. The reaction may be performed in the presence of a base such as sodium tert-butoxide. A compound of formula 10-5 may be prepared from 10-3 and an alkyne of formula 10-4 using any suitable conditions for Larock indole cyclization. For example, catalysts such as Pd(tBu3P)2 or JackiePhos Pd G3 may be used. In some alternative embodiments, Pd(OAc)2 may be used. The reaction is performed in the presence of a suitable ligand. For example, dicyclohexylmethylamine (oTRfNMe may be used. The reaction may be performed in a solvent such as 1,4- dioxane, and in the presence of added heat (e.g. 60 °C). A compound of formula 10-6 may be prepared from 10-5 using any suitable method for the removal of an ester protecting group. For example, where PG5is methyl, a base such as LiOH or NaOH may be used. Any suitable method for the removal of a nitrogen protecting group may be used for the preparation of compound 10-7 from 10-6. For example, where PG4is a benzyl group hydrogenation using a palladium on carbon catalyst under an atmosphere of hydrogen may be used. In some embodiments, the reaction may be performed in a solvent such as THF.Scheme 1111-2

[0232] Scheme 11 refers to an alternative method of preparation of compounds of formula 11- 3. Ring B is an alkyl or alkoxy group. Reductive amination reaction between amines of formula 11-1 with a ketone or aldehyde of formula 11-2 affords compounds of formula 11-3. In some examples, the reductive amination may be performed using a reagent such as sodium triacetoxyborohydride. A solvent such as AcOH may be used. The reaction may be performed at room temperature.EXAMPLES

[0233] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.Example 1. Synthesis of Compounds

[0234] All the specific and generic compounds, the methods for making those compounds, and the intermediates disclosed for making those compounds, are considered to be part of the disclosure disclosed herein.A. Synthesis of Starting Materials

[0235] Preparations of S1-S22 describe synthetic routes to intermediates used in the synthesis of Compound 1-457.Preparation of SIStep 1. Synthesis of l-benzyloxy-3-bromo-2-iodo-benzene ( C2 )

[0236] A solution of 3-bromo-2-iodo-phenol Cl (129 g, 431.6 mmol) in acetone (1.5 L) was stirred for 5 minutes. K2CO3 (75 g, 542.7 mmol), Nal (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 x 100 mL). The combined filtrates were concentrated in vacuo. The residue was dissolved in dichloromethane (1.5 L), washed with water (2 x 100 mL) and brine (100 mL). The organic phase was dried over MgSCri, filtered and concentrated in vacuo. Purification by silica gel chromatography (0- 50% ethyl acetate in heptane) afforded the product as a white solid (162 g, 96%). ¾ NMR (300 MHz, Chloroform- ) d 7.54 - 7.46 (m, 2H), 7.40 (ddd, J = 7.9, 7.0, 1.1Hz, 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).Step 2. Synthesis of 4-[2-(2-henzyloxy-6-hromo-phenyl)ethynyl]tetrahydropyran (C3)

[0237] l-benzyloxy-3-bromo-2-iodo-benzene 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 solution in THF) and water (20 mL, 1.1 mol). The mixture was purged with N2 for 10 minutes, and Cul (11 g, 57.8 mmol) was added. After purging with N2, for a further 10 minutes, PdCl2(PPh3)2 (22 g, 31.3 mmol) was added. The mixture was heated at 65 °C, After 6.5 hours, the heat was removed and the mixture stirred at room temperature overnight. Water (1 L) and saturated MLCl (500 mL) were added, the mixture was stirred for 10 minutes, then split into two equal portions. Each portion was extracted with EtOAc (1.5 L), and the organic extract was washed successively with 1 M aq HC1 (1 L), brine (1 L), then dried (MgSCL) filtered and concentrated. The two portions were combined, dissolved in dichloromethane (300 mL). Silica gel chromatography (1.6 kg silica gel. Gradient: 0-40% EtOAc in heptane) afforded the product as an amber oil (151 g, 79%). 'H NMR (300 MHz, Chloroform- ) d 7.33 - 7.25 (m, 2H), 7.25 - 7.10 (m, 3H), 7.03 (dd, J = 8.1,I.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 =II.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).Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4- ylethynyl) aniline (C4)

[0238] 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 minutes. NaOtBu (200 g,2.08 mol) was added, then N2 bubbling was continued for 15 minutes. 3,4-difluoroaniline (84 mL) was added, and N2 purging was continued for 15 minutes. tBuXPhos Pd G3 (15 g, 18.9 mmol) was added, then N2 purging was continued for another 10 minutes. The mixture was allowed to stir, and after 90 minutes the internal temperature has risen from 21 °C to 29 °C.After a further 2.5 hours, internal temperature dropped to 24 °C. The mixture was then heated to 50 °C for 45 minutes. Additional tBuXPhos Pd G3 (2.0 g, 2.52 mmol) was added and the mixture stirred a further 2 hours at 50 °C. The reaction mixture was poured onto ice-water (6 L), then 2-MeTHF (3 L) was added. Following agitation, layers were separated. The organic layer was washed successively with water (4 L), 1 M aq HC1 (3 L), saturated aqueous NaHCCh (3 L), and brine (3 L). The organic layer was then dried (MgSCri) filtered and concentrated in vacuo. Purification by silica gel chromatography (3 kg silica gel. Gradient: 0-40% EtOAc in heptane)afforded the product 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4- ylethynyl)aniline C4 in a 2: 1 mixture with the cyclized product C5 (277 g, 94%) as a brown oil. The mixture was carried to the subsequent step without further purification.Step 4. Synthesis of 4-henzyloxy-l -(3, 4-difluorophenyl)-2-tetrahydropyran-4-yl-indole ( C5 )

[0239] A solution of 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4- ylethynyl)aniline (277 g, 660.4 mmol) (mixture of ~2:1 aniline C4: indole C5) in MeCN (1.9 L) was purged with nitrogen for 15 minutes. PdCb (3.5 g, 19.7 mmol) was added, reaction was placed under a positive pressure of N2, then heated to 50 °C for 1 hour. The heat was removed, and the reaction mixture was stirred overnight. After 16 hours, the resulting suspension was filtered, and the solid collected, washing with heptane (400 mL), and drying under suction to afford -150 g of an off-white solid. The filtrate was concentrated, to give -100 g of product as a dark oil which was purified by silica gel chromatography (1.6 kg silica gel column, Gradient: 0- 40% EtOAc in heptane) (Note: compound does precipitate out on column resulting in product loss) to afford additional product (-90 g) as an off-white solid. This portion of the product from column chromatography was combined with product isolated from 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, then filtered, and the collected solid was washed with heptane (300 mL). The product was dried under vacuum to afford the product (224.6 g) as slightly off-white crystals. The filtrate yielded an additional 8.0 g off-white crystals, which were combined with the first crop to afford the product 4-benzyloxy-l-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole (232.6 g, 84%). 'H NMR (300 MHz, Chloroform- ) d 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 (282 MHz, Chloroform- d) d -134.09 (d, J = 21.5 Hz), -136.75 (d, J = 21.7 Hz). LCMS m / z 419.9 [M+l]+.Step 5. Synthesis of 4-henzyIoxy- 1 -( 3, 4-t / ifhioropheny / )-3-iodo-2-tetrahydropyran-4-y / -indo / e (SI)

[0240] To a solution of 4-benzyloxy-l-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole C5 (159 g, 379.1 mmol) in CH2CI2 (2.5 L) cooled to 0 °C (ice / water bath), was added 1- iodopyrrolidine-2,5-dione (96 g, 413.9 mmol) in three portions over 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 aqueous Na2S2Ch (600 mL). The organic layer was separated, washed successively with saturated aqueous NaHCCh (-600 mL) and brine (-600 mL each). Theorganic layer was dried (MgSCri), filtered and concentrated. The residue was treated with EtOAc (-200 mL), heated to reflux for 15 minutes, to afford a suspension. Suspension was treated with heptane (-1 L), the resulting suspension was slowly allowed to room temperature over 14 hours (overnight), then filtered. The collected solid was washed with heptane (100 mL), then dried under vacuum oven at 45 °C for 2 hours to afford the product as a tan solid (180 g, 86%). 'H NMR (300 MHz, DMSO- e) d 7.81 - 7.54 (m, 4H), 7.49 - 7.37 (m, 2H), 7.37 - 7.26 (m, 2H),6.99 (t, J = 8.1 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 6.43 (d, J = 8.2 Hz, 1H), 5.26 (s, 2H), 3.86 (dd, J = 11.5, 4.1 Hz, 2H), 3.21 (ddd, J = 12.0, 9.8, 5.1 Hz, 2H), 3.06 - 2.84 (m, 1H), 2.19 (dt, J = 12.7, 4.7 Hz, 2H), 1.56 (s, 2H).19F NMR (282 MHz, DMSO- e) d -135.42, -135.50, -136.83, - 136.91. LCMS m / z 545.21 [M+l]+.Preparation of S2

[0241] KOtBu (8.68 g, 11 A mmol) was added to a solution of 3 -amino-2 -bromo-6-fluoro- phenol C6 (15.6 g, 75.8 mmol), chloromethylbenzene (9.6 g, 75.8 mmol) in DMF (120 mL).The reaction was stirred at room temperature overnight. The reaction was concentrated, diluted with EtOAc and washed with water. The organic layer was dried and concentrated. The crude was purified on silica gel (Gradient: 10-40% EtOAc in hexane) to afford the product. 3- benzyloxy-2-bromo-4-fluoro-aniline (17.8 g, 75%) LCMS m / z 295.94 [M+H]+.Step 2. Synthesis of 3-benzyloxy-4-fluoro-2-iodo-aniline (C8)

[0242] 3-benzyloxy-2-bromo-4-fluoro-aniline (7.36 g, 24.9 mmol), Nal (15 g, 100.1 mmol), N,N'-dimethylethane- 1,2-diamine (780 mg, 8.9 mmol) and Cul (980 mg, 5.146 mmol) were mixed into 1,4-dioxane (60 mL) and the reaction was stirred in a sealed vessel and heated at 140 degrees for overnight. The reaction was cooled to room temperature and diluted with EtOAc (100 ml) and filtered through a plug of Celite®. The filtrate was washed with water, brine and dried over Na2S04. The solvent was removed and the crude was purified on silica gel (220 g column, 10-90% EtOAc in hexane) to afford desired product. 3-benzyloxy-4-fluoro-2-iodo- aniline (7.5 g, 84%) LCMS m / z 344.17 [M+H]+.Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-iodo-aniline (C9)

[0243] 3-benzyloxy-4-fluoro-2-iodo-aniline (2.68 g, 7.810 mmol), (3,4- difhiorophenyl)boronic acid (1.82 g, 11.53 mmol), K2C03 (3.2 g, 23.15 mmol) and diacetoxycopper (1.68 g, 9.25 mmol) were mixed into DMSO (20 mL) and the reaction was stirred at room temperature for overnight. The reaction was diluted with EtOAc and filtered through a plug of Celite®. The filtrate was washed with water. The organic layer was dried and concentrated. The crude was purified on silica gel (120 g column, 10-40% EtOAc in hexane) to afford desired product. 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-iodo-aniline (1.8 g, 41%). LCMS m / z calc. 455.87 [M+H]+.Step 4. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-(2-tetrahydropyran-4- ylethynyl) aniline (CIO)

[0244] 3-benzyloxy-N-(3,4-difhiorophenyl)-4-fluoro-2-iodo-aniline (1.8 g, 3.56 mmol), 4- ethynyltetrahydropyran (600 mg, 5.45 mmol), PdCh(PPh3)2 (400 g, 569.9 mmol) and Cul (110 mg, 0.58 mmol) were mixed into 1,4-dioxane (10 mL), Et3N (10 mL) and the reaction was degassed with nitrogen for 30 seconds. The reaction was stirred at room temperature overnight. The reaction was concentrated and diluted with EtOAc and washed with water. The organic layer was dried and concentrated. The crude was purified on silica gel (4 g column, 10-40% Hex: EtOAc) to afford 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+l]+.Step 5. Synthesis of 4-benzyloxy-l-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl-indole(Cll)

[0245] 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-(2-tetrahydropyran-4- ylethynyl)aniline (1.6 g, 3.658 mmol) was dissolved into MeCN (20 mL) and PdCh (120 mg, 0.68 mmol) was added. The reaction was heated at 45 degrees for overnight. The reaction was cooled to room temperature and filtered through a plug of Celite® . The crude was diluted with EtOAc and washed with water. The organic layer was dried and concentrated. Purification by silica gel chromatography (40 g column, 10-90% EtOAc in hexane) afforded the product. 4- benzyloxy-l-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl-indole (1.4 g, 77%). 'H NMR (400 MHz, DMSO- e) d 7.76 (ddd, J = 11.2, 7.2, 2.6 Hz, 1H), 7.68 (dt, J = 10.6, 8.9 Hz, 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, 8.8 Hz, 1H), 6.65 (ddd, J = 8.8, 3.5, 0.8 Hz, 1H), 6.60 (d, J = 0.8 Hz, 1H), 5.29 (s, 2H). LCMS m / z 438.06 [M+l]+Step 6. Synthesis of 4-benzyloxy-l -(3, 4-difluorophenyl)-5-fluoro-3-iodo-2-tetrahydr opyran-4-yl- indole (S2)

[0246] A solution of 4-benzyloxy-l-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl- indole (730 mg, 1.33 mmol) in dichloromethane (10 mL) and l-iodopyrrolidine-2,5-dione (345 mg, 1.533 mmol) was stirred at room temperature for overnight. The reaction was concentrated and diluted with EtOAc and washed with water. The organic layer was dried and concentrated. The crude was purified on silica gel (4 g column, 10-40% Hex: EtOAc) to afford desired product. 4-benzyloxy-l-(3,4-difluorophenyl)-5-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (720 mg, 81%). ¾ NMR (400 MHz, DMSO-d) d 7.80 (ddd, J = 11.1, 7.3, 2.6 Hz, 1H), 7.71 (dt, J = 10.6, 8.9 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.50 - 7.32 (m, 4H), 7.06 (dd, J = 11.5, 8.9 Hz, 1H), 6.61 (dd, J = 8.9, 3.7 Hz, 1H), 5.13 (s, 2H), 3.87 (dd, J = 11.5, 4.2 Hz, 2H), 3.22 (tdd, J = 12.0, 7.2, 2.0 Hz, 2H), 2.93 (tt, J = 12.4, 3.6 Hz, 1H), 2.21 (tq, J = 16.6, 5.7, 4.4 Hz, 2H), 1.58 (t, J = 10.1 Hz, 2H). LCMS m / z 563.08 [M+H]+.Preparation of S3Step 1. Synthesis of l-benzyloxy-3-bromo-5-fluoro-2-iodo-benzene (C13)

[0247] A mixture of 3-bromo-5-fluoro-2-iodo-phenol C12 (50 g, 157.8 mmol), bromomethylbenzene (27.8 g, 162.5 mmol), Nal (4 g, 26.7 mmol) and K2CO3 (45 g, 325.6 mmol) in acetone (500 mL) was stirred at room temperature overnight. The reaction mixture was then filtered over Celite® and the filtrate was concentrated to dryness, Purification by silica gel chromatography (Gradient: 0-40% CH2CI2 in heptane) afforded the product as a white solid. 1- benzyloxy-3-bromo-5-fluoro-2-iodo-benzene (55 g, 81%). LCMS m / z 406.56 [M+l]+.Step 2. Synthesis of 4-[2-(2-benzyloxy-6-bromo-4-fluoro-phenyl)ethynyl]tetrahydropyran (C14)

[0248] A solution of l-benzyloxy-3-bromo-5-fluoro-2-iodo-benzene C13 (19 g, 46.7 mmol), PdCl2(PPh3)2 (1.98 g, 2.8 mmol) and Cul (890 mg, 4.673 mmol) in anhydrous DMF (150 mL)was degassed for 10 minutes. Trimethyl(2-tetrahydropyran-4-ylethynyl)silane (9.78 g, 53.64 mmol) and diethylamine (7.22 mL, 69.8 mmol) were then added, followed by TBAF (54 mL of 1 M, 54.00 mmol in THF). The reaction mixture was stirred overnight at 65 °C. Upon 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 in heptane) afforded the product as a light yellow solid. 4-[2-(2-benzyloxy-6-bromo-4- fluoro-phenyl)ethynyl]tetrahydropyran (11.3 g, 62%). 'H NMR (400 MHz, Chloroform-r / ) d 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).Step 3. Synthesis of 3-henzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(2-tetrahydropyran-4- ylethynyl) aniline (Cl 5)

[0249] A 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) (light brown solution) was purged with nitrogen for 10 minutes, then NaOtBu (1.5 g, 15.61 mmol) and tBuXPhos Pd G3 (200 mg, 0.25 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was cooled to room temperature, then ice water (20 mL) and EtOAc (50 mL) were added. The organic layer was separated, washed with brine, dried and concentrated. Purification by silica gel chromatography (Gradient: 0 - 30% EtOAc in hexane) afforded the product as a light yellow solid. 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(2- tetrahydropyran-4-ylethynyl)aniline (2.2 g, 97%). 'H NMR (400 MHz, Chloroform-r / ) d 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 (dd, J = 11.0, 2.3 Hz, 1H), 6.21 (dd, J = 10.5, 2.3 Hz, 1H), 5.13 (s, 2H), 3.94 (ddd, J = 11.6, 6.2, 3.5 Hz, 2H), 3.56 (ddd, J = 11.4, 8.0, 3.1 Hz, 2H), 3.01 (tt, J = 8.2, 4.1 Hz, 1H), 2.03 - 1.89 (m, 2H), 1.78 (dtd, J = 13.3, 8.1, 3.5 Hz, 2H). LC-MS m / z 438.3 [M+l]+.Step 4. Synthesis of 4-benzyloxy-l -(3, 4-difluorophenyl)-6-fluoro-2-tetrahydropyran-4-yl-indole (C16)

[0250] 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) (light brown solution) was added PdCh (600 mg, 3.4 mmol). The reaction was heated at 60 °C for 12 hours. The solution were concentrated to dryness and purified by silica gel chromatography (Gradient: 0-25%EtOAc in heptane) to give a white solid. 4-benzyloxy-l -(3, 4-difluorophenyl)-6-fluoro-2- tetrahydropyran-4-yl-indole (13.6 g, 94%) LCMS m / z 438.3 [M+l]+.Step 5. Synthesis of 4-benzyloxy-l-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-tetrahydropyran-4-yl- indole (S3)

[0251] To a solution of 4-benzyloxy-l-(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) was added N-iodosuccinimide (26.4 g, 117.3 mmol). The ice-water bath was slowly allowed to warm to room temperature and the reaction allowed to stir for 18 hours. The reaction mixture was washed successively with 1 M aq sodium thiosulfate, saturated aqueous NaHCCh, and brine (800 mL each), then dried (MgSCri), filtered and concentrated. The residue was treated with EtOAc (100 mL), and the resulting suspension was spun on a rotary evaporator at 75 °C for 1 hour. The suspension was treated with heptane (100 mL), then allowed to stand at room temperature for 2 hours. The resulting crystals were isolated via filtration, washing with heptane (100 mL), and then dried under suction to afford the product as an off-white solid. 4-benzyloxy- l-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (54.6 g, 91%). 'H NMR (300 MHz, DMSO- e) d 7.82 - 7.56 (m, 4H), 7.49 - 7.38 (m, 2H), 7.38 - 7.26 (m, 2H), 6.70 (dd,J = 12.0, 2.1 Hz, 1H), 6.24 (dd, J = 9.4, 2.1 Hz, 1H), 5.28 (s, 2H), 3.85 (dd, J = 11.4, 4.1 Hz,2H), 3.20 (tdd, J = 11.7, 5.4, 2.0 Hz, 2H), 2.91 (ddd, J = 12.5, 8.8, 3.7 Hz, 1H), 2.16 (dq, J =17.6, 7.2, 6.2 Hz, 2H), 1.65 - 1.44 (m, 2H).19F NMR (282 MHz, DMSO-d) d -116.95, -135.20 (d, J = 22.9 Hz), -136.62 (d, J = 22.9 Hz). LCMS m / z 563.12 [M+l]+.Preparation of S44-benzyloxy-l-(3, 4-difluorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-l, 1 -dimethyl-ethyl) indole (S4)Step 1. Synthesis of 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-l-ol (Cl 7)

[0252] A solution of l-benzyloxy-3-bromo-5-fluoro-2-iodo-benzene C13 (5 g, 12.3 mmol), 2,2-dimethylbut-3-yn-l-ol (1.8 g, 18.3 mmol) in 1,4-dioxane (40 mL) and Et3N (40 mL) was purged with nitrogen for 10 minutes, then added Cul (157 mg, 0.82 mmol) and PdCh(PPh3)2 (500 mg, 0.71 mmol) were added. The resulting reaction mixture was warmed to 50 °C, and stirred overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and partitioned between sat. aqueous NLLCl solution (~50 mL) and ethyl acetate (-150 mL). Upon stirring for 10 minutes, the organic layer was separated, was washed with 1 N HC1 solution (2 x 50 mL), water (30 mL), brine (30 mL), dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Gradient: 0-70% ethyl acetate in heptane) to afford the product as a clear yellow viscous oil. 4- (2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-l-ol (4.23 g, 90%).1HNMR (400 MHz, Chloroform - ) d 7.49 (dtd, J = 6.9, 1.4, 0.7 Hz, 2H), 7.46 - 7.32 (m, 3H), 6.98 (dd, J= 8.0, 2.4 Hz, 1H), 6.65 (dd, J = 10.2, 2.4 Hz, 1H), 5.12 (s, 2H), 3.49 (d, J = 7.1 Hz, 2H), 1.34 (s, 6H). LCMS m / z 377.01 [M+l]+.Step 2. Synthesis of l-benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3-dimethyl-but-l- ynyl)benzene (Cl 8)

[0253] A mixture of 4-(2-benzyloxy-6-bromo-4-fluoro-phenyl)-2,2-dimethyl-but-3-yn-l-ol C17 (3.65 g, 9.5 mmol) and iodomethane (1.5 mL, 24.1 mmol) in THF (50 mL) under nitrogen, was cooled to 0 °C. NaH (600 mg, 15.0 mmol) was added and the resulting reaction mixture was stirred and allowed to warm to room temperature. The mixture was poured into water (50 mL), partitioned between sat. aqueous MLCl solution (~50 mL) and ethyl acetate (-150 mL), then stirred for 10 minutes. The organic layer was separated, washed successively with 1 N HC1 solution (2 x 50 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over MgSCL, filtered and concentrated under reduced pressure to afford the product as a dark oil, which turned into brown solid under vacuum. l-benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3- dimethyl-but- 1 -ynyl)benzene (3.8 g, 100%). ¾NMR (400 MHz, CD3CN) d 7.51 (dtd, J = 6.9, 1.4, 0.7 Hz, 2H), 7.46 - 7.32 (m, 3H), 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 6.87 (dd, J = 10.8, 2.4 Hz, 1H), 5.13 (s, 2H), 3.32 (s, 3H), 3.31 (s, 2H), 1.27 (s, 6H). LCMS m / z 390.96 [M+l]+.Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(4-methoxy-3,3-dimethyl-but- l-ynyl)aniline (C19)

[0254] To a solution of l-benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3-dimethyl-but-l- ynyl)benzene C18 (667 mg, 1.71 mmol) and 3,4-difluoroaniline (330 mg, 2.56 mmol) in degassed Xylene (12 mL) added NaOtBu (500 mg, 5.20 mmol) followed by 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 EtOAc (3 x 10 mL). The combined organics were concentrated to dryness and purified via silica gel chromatography eluting (Gradient: 0-25% EtOAc in heptane) to afford the product as a brown oil. 3-benzyloxy-N-(3,4-difluorophenyl)-5- fluoro-2-(4-methoxy-3,3-dimethyl-but-l-ynyl)aniline (667 mg, 89%). ¾ NMR (400 MHz, Chloroform - ) d 7.53 (d, J = 7.3 Hz, 2H), 7.42 (dd, J = 8.1, 6.8 Hz, 3H), 7.39 - 7.33 (m, 1H),7.16 (dt, J = 10.4, 8.9 Hz, 1H), 7.07 (ddd, J = 11.8, 6.9, 2.6 Hz, 1H), 7.01 - 6.89 (m, 2H), 6.46 (dt, J = 11.1, 1.7 Hz, 1H), 6.18 (dt, J = 10.7, 1.5 Hz, 1H), 5.14 (s, 2H), 3.41 (d, J = 1.0 Hz, 3H), 3.37 (d, J = 1.1 Hz, 2H), 1.43 - 1.33 (m, 6H). LCMS m / z 440.42 [M+l]+.Step 5. Synthesis of 4-benzyloxy-l-(3,4-difluorophenyl)-6-fluoro-2-(2-methoxy-l,l-dimethyl- ethyl)indole (C20)

[0255] To a solution of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(4-methoxy-3,3- dimethyl-but-l-ynyl)aniline C19 (515 mg, 1.17 mmol) in MeCN (5 mL) was added PdCh (21mg, 0.12 mmol). 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 in heptane) to give a white solid. 4-benzyloxy-l-(3,4-difluorophenyl)- 6-fluoro-2-(2-m ethoxy- l,l-dimethyl-ethyl)indole (483 mg, 94%).1H NMR (400 MHz, Chloroform - ) d 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+l]+.Step 6. Synthesis of 4-benzyloxy-l-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-l ,1- dime thyl-e thy l) indole (S4)

[0256] 4-benzyloxy-l-(3,4-difluorophenyl)-6-fluoro-2-(2-methoxy-l,l-dimethyl-ethyl)indole C20 (357 mg, 0.81 mmol) in dichloromethane (5 mL) was added A-iodosuccinimide (190 mg, 0.84 mmol) at room temperature and stirred for 1 hour. The mixture was concentrated to dryness and purified by silica gel chromatography (Gradient: 0 - 25% EtOAc in Hexanes) to afford the product as a white solid. 4-benzyloxy-l-(3,4-difhiorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-l,l- dimethyl-ethyl)indole (432 mg, 93%). LCMS m / z 565.3 [M+l]+.Preparation of S54-benzyloxy-l-( 3, 4-difluorophenyl)-3-iodo-2-(2-methoxy-l, 1 -dimethyl-ethyl) indole (S5)Step 1. Synthesis of 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-l-ol (C21)

[0257] A 3 L 3 -neck RB flask with overhead stirrer, temperature probe, reflux condenser and nitrogen inlet was charged with l-benzyloxy-3-bromo-2-iodo-benzene C2 (160 g, 411.3 mmol) and 2,2-dimethylbut-3-yn-l-ol (51 g, 519.6 mmol) in 1,4-dioxane (1.1 L), and stirred for 5 minutes. N-isopropylpropan-2-amine (370 mL, 2.64 mol) was then added. The reaction mixture was purged with nitrogen for ~15 minutes, then iodocopper (3.7 g, 19.4 mmol) and PdCk (12.5 g, 17.8 mmol) were added. The resulting reaction mixture was warmed to 50 °C, and stirred for 3 hours. The reaction mixture was cooled to room temperature, poured into water (300 mL). Sat. aqueous NLLCl solution (-400 mL), followed by ethyl acetate (-2 L) were added, and the mixture stirred for 15 minutes. The organic layer was separated, washed with 1 N HC1 solution (2 x 200 mL), brine (200 mL), then dried over MgSCri, filtered and concentrated under reduced pressure.

[0258] Purified by silica gel chromatography (Gradient: 0-50% ethyl acetate in heptane) afforded the product as a yellow solid. 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn- l-ol (130 g, 88%). ¾ NMR (400 MHz, Chloroform- ) d 7.48 (ddt, J = 7.4, 1.5, 0.7 Hz, 2H),7.44 - 7.37 (m, 2H), 7.36 - 7.29 (m, 1H), 7.19 (dd, J = 8.1, 1.0 Hz, 1H), 7.08 (t, J = 8.2 Hz, 1H), 6.86 (dd, J = 8.3, 1.0 Hz, 1H), 5.13 (s, 2H), 3.48 (d, J = 7.2 Hz, 2H), 2.12 (t, J = 7.2 Hz, 1H),1.33 (s, 6H). LCMS m / z 359.02 [M+l]+.Step 2. Synthesis of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl- dimethyl-silane (C22)

[0259] A 3 L 3 -neck RB flask with overhead stirrer, temperature probe, reflux condenser and nitrogen inlet was charged with 4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-yn-l-ol C21 (130 g, 361.9 mmol) in DMF (850 mL). The mixture was stirred for 5 minutes at ambient temperature and then imidazole (64 g, 940.1 mmol) and TBSC1 (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 AHC1 (2 x 200 mL), and brine (200 mL), then dried over MgSCri, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Column: 1.5 kg Isco. Gradient, 0-50% ethyl acetate in heptane) afforded the product as a clear, light yellow color oil. [4-(2-benzyloxy-6-bromo- phenyl)-2,2-dimethyl-but-3-ynoxy]-tert-butyl-dimethyl-silane (164 g, 96%). 'H NMR (400 MHz, Chloroform - ) d 7.55 - 7.44 (m, 2H), 7.42 - 7.35 (m, 2H), 7.35 - 7.28 (m, 1H), 7.19 (dd, J = 8.1, 1.0 Hz, 1H), 7.04 (t, J = 8.2 Hz, 1H), 6.83 (dd, J = 8.4, 1.0 Hz, 1H), 5.12 (s, 2H), 3.59 (s, 2H), 1.31 (s, 6H), 0.90 (s, 9H), 0.05 (s, 6H).Step 3. Synthesis of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-l-ynyl]-N- ( 3, 4-difluorophenyl)aniline ( C23)

[0260] To a solution of [4-(2-benzyloxy-6-bromo-phenyl)-2,2-dimethyl-but-3-ynoxy]-tert- butyl-dimethyl-silane C22 (11 g, 23.2 mmol) and 3,4-difluoroaniline (3.27 g, 25.33 mmol) in xylene (60 mL) under nitrogen was added NaOtBu (6 g, 62.4 mmol) followed by tBuXPhos Pd G3 (315 mg, 0.40 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and sat aq. MLCl and extracted with EtOAc (x 2). The combined organics were concentrated to dryness and purified by silica gel chromatography (Column: 220g Silica. Gradient: 0-50% EtOAc in heptane) to afford the product as a yellow oil. 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-l-ynyl]-N-(3,4- difluorophenyl)aniline (11.6 g, 96%). 'H NMR (400 MHz, Chloroform-r / ) d 7.49 (ddt, J = 7.4, 1.3, 0.7 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.31 - 7.25 (m, 1H), 7.10 - 6.96 (m, 3H), 6.86 - 6.80 (m,1H), 6.70 (dd, J = 8.3, 0.8 Hz, 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+l]+.Step 4. Synthesis of 2- [4-henzyloxy-l -(3, 4-difluorophenyl)indol-2-yl] -2-methyl-propan- l-ol (C24)

[0261] A solution of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-but-l- 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 heated to 60 °C overnight. The reaction was concentrated under reduced pressure and then purified by silica gel chromatography (Gradient: 0-75% EtOAc in heptane) to afford a white solid. 2-[4-benzyloxy-l-(3,4-difluorophenyl)indol-2-yl]-2-methyl-propan-l-ol (8.2 g, 91%). ¾NMR (400 MHz, Chloroform- ) d 7.55 (dt, J = 6.3, 1.4 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.41 - 7.31 (m, 2H), 7.31 - 7.24 (m, 3H), 7.22 - 7.15 (m, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 0.8 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.33 (d, J = 8.2 Hz, 1H), 5.26 (s, 2H), 3.53 (dd, J = 6.0, 1.6 Hz, 2H), 1.28 (s, 3H), 1.27 (s, 3H). LCMS m / z 408.37 [M+l]+.Step 5. Synthesis of 4-benzyloxy-l-(3,4-difluorophenyl)-2-(2-methoxy-l , 1 -dimethyl-ethyl) indole (C25)

[0262] At 0 °C, 2-[4-benzyloxy-l-(3,4-difluorophenyl)indol-2-yl]-2-methyl-propan-l-ol C24 (500 mg, 1.23 mmol) and Mel (120 pL, 1.928 mmol) in THF (5 mL) was added NaH (60 mg of 60% w / w, 1.5 mmol) in one portion and allowed to warm to room temperature. After 1 hour, the reaction was complete. Water (5 mL) and sat NH4C1 (5 mL) were added to the reaction mixture followed by extraction with EtOAc (3 x 5 mL). Combined organic fractions were washed with brine (1 x 2 mL), dried over MgS04 and concentrated 4-benzyloxy-l-(3,4-difluorophenyl)-2-(2- methoxy-l,l-dimethyl-ethyl)indole (509 mg, 99%). ¾NMR (400 MHz, Chloroform- ) d 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 calc. 421.18533, found 422.37 [M+H]+.Step 6. 4-benzyloxy-I-(3,4-difluorophenyl)-3-iodo-2-(2-methoxy-I , I-di methyl-ethyl) indole (S5)

[0263] 4-benzyloxy-l-(3,4-difluorophenyl)-2-(2-methoxy-l,l-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. Purification by silica gel chromatography (Gradient: 0-20% EtOAc in hexanes) provided the product as white solid. 4-benzyloxy- 1 -(3 ,4-difluorophenyl)-3 -iodo-2-(2-m ethoxy- 1 , 1 -dimethyl-ethyl)indole (675 mg, 98%) ¾ NMR (400 MHz, Chloroform- ) d 7.65 (ddt, J = 7.4, 1.3, 0.7 Hz, 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, 1.6 Hz, 1H), 6.97 (dd, J = 8.3, 7.9 Hz, 1H), 6.63 (dd, J = 7.9, 0.8 Hz, 1H), 6.28 (dd, J = 8.3, 0.7 Hz, 1H), 5.26 (s, 2H), 3.79 (d, J = 9.1 Hz, 1H), 3.71 (d, J = 9.1 Hz, 1H), 1.59 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H). LCMS m / z 547.28 [M+H]+.Preparation of S6Step 1. Synthesis of l-bromo-2-iodo-3-(methoxymethoxy)benzene (C27)

[0264] To a solution of 3-bromo-2-iodo-phenol C26 (5.2 g, 17.40 mmol) and DIPEA (4.5 mL, 25.8 mmol) in dichloromethane (50 mL) at 0 °C was added dropwise chloro(methoxy)methane (1.6 mL, 21.1 mmol) in dichloromethane (10 mL). The reaction was allowed to warm to room temperature and stirred for 2 hours. Aqueous MLCl (20 mL) and water (10 mL) were added, and stirred 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. l-bromo-2-iodo-3-(methoxymethoxy)benzene (6.1 g, 100%). ¾NMR (400 MHz, Chloroform- ) d 7.34 (dd, J = 8.0, 1.3 Hz, 1H), 7.18 (t, J = 8.1 Hz, 1H), 6.99 (dd, J = 8.3, 1.3 Hz, 1H), 5.26 (s, 2H), 3.53 (s, 3H). LCMS m / z 342.22 [M+H]+.Step 2. Synthesis of 4-[2-[2-hromo-6-(methoxymethoxy)phenyl]ethynyl]tetrahydropyran (C28)

[0265] Water (250 pL, 13.9 mmol) was added to a solution of l-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 minutes. CsF (2 g, 13.17 mmol), PdCl2(PPh3)2 (245 mg, 0.35 mmol) and Cul (115 mg, 0.60 mmol) were added and the reaction heated to 90 °C overnight. The mixture was cooled, and the triethylamine was removed under vacuum. Ice- water (100 mL) was added and the mixture extracted with ether (3 x 100 mL). The organic layer was washed with water (200 mL), then brine (200 mL), and concentrated. Purification by silica gel chromatography (Gradient: 0-30% ethyl acetate in heptane) afforded the product as a light yellow oil. 4-[2-[2-bromo-6-(methoxymethoxy)phenyl]-ethynyl]tetrahydropyran (1.43 g, 75%). ¾NMR (400 MHz, Chloroform- ) d 7.24 (dd, J = 7.2, 1.8 Hz, 1H), 7.11 - 7.01 (m, 2H), 5.23 (s, 2H), 4.02 (ddd, J = 11.5, 7.0, 3.4 Hz, 2H), 3.62 (ddd, J = 11.1, 7.2, 3.3 Hz, 2H), 3.51 (s, 3H), 3.01 (tt, J = 7.7, 4.2 Hz, 1H), 2.01 - 1.91 (m, 2H), 1.87 - 1.77 (m, 2H). LCMS m / z 325.09 [M+H]+.Step 3. N-(3-chloro-4-fluoro-phenyl)-3-(methoxymethoxy)-2-(2-tetrahydropyran-4- ylethynyl) aniline (C29) and l-(3-chloro-4-fluoro-phenyl)-4-(methoxymethoxy)-2- tetrahydropyran-4-yl-indole ( C30)

[0266] A solution of 4-[2-[2-bromo-6-(methoxymethoxy)phenyl]ethynyl]tetrahydro-pyran C28 (1.5 g, 4.61 mmol), 3-chloro-4-fluoroaniline (940 mg, 6.46 mmol) in xylene (30 mL) was degassed for 5 minutes. Sodium t-Butoxide (1.33 g, 13.8 mmol) was added and the solution was degassed for another 5 minutes. / BuXPhos Pd G3 (529.6 mg, 0.66 mmol) was added and the reaction stirred at room temperature for 3 hours. Ice water (50 mL) and EtOAc (50 mL) were added. Upon stirring for 5 minutes, the aqueous layer was isolated and washed with EtOAc (20 mL). The combined organic layers were washed with brine, dried over MgS04 and concentrated. Purification by silica gel chromatography (Gradient: 0-40% EtOAc in heptane) gave products C29 and C30. N-(3-chloro-4-fluoro-phenyl)-3-(methoxymethoxy)-2-(2- tetrahydropyran-4-ylethynyl)aniline C29 (1.39 g, 75%). 'H NMR (400 MHz, Chloroform -r / ) d 7.25 (dd, J = 6.3, 2.7 Hz, 1H), 7.11 (t, J = 8.5 Hz, 2H), 7.05 (ddd, J = 8.9, 4.2, 2.7 Hz, 1H), 6.78 (dd, J = 8.3, 0.8 Hz, 1H), 6.63 (dd, J = 8.3, 0.8 Hz, 1H), 6.36 (s, 1H), 5.27 (s, 2H), 4.00 (ddd, J =11.6, 6.0, 3.6 Hz, 2H), 3.62 (ddd, J = 11.5, 8.3, 3.0 Hz, 2H), 3.55 (s, 3H), 3.02 (tt, J = 8.3, 4.1 Hz, 1H), 2.05 - 1.94 (m, 2H), 1.82 (dtd, J = 13.4, 8.3, 3.6 Hz, 2H). LCMS m / z 390.27 [M+H]+.

[0267] l-(3-chloro-4-fluoro-phenyl)-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole C30 (0.37 g, 19%). ¾ NMR (400 MHz, Chloroform- ) d 7.21 (dd, J = 6.3, 2.7 Hz, 1H), 7.14 - 7.01 (m, 4H), 6.97 (ddt, J = 8.9, 4.0, 2.2 Hz, 1H), 6.79 (dd, J = 8.3, 0.8 Hz, 1H), 6.68 (ddd, J = 8.7, 4.1, 2.6 Hz, 1H), 6.58 (dd, J = 8.3, 0.9 Hz, 1H), 6.34 (s, 1H), 5.79 (d, J = 2.7 Hz, 1H), 5.26 (s, 2H), 4.00 (ddd, J = 11.6, 6.0, 3.6 Hz, 2H), 3.61 (ddd, J = 11.5, 8.2, 3.1 Hz, 2H), 3.55 (s, 3H), 3.02 (tt, J = 8.3, 4.1 Hz, 1H), 2.06 - 1.93 (m, 2H), 1.89 - 1.77 (m, 2H).Step 4. Synthesis of l-(3-chloro-4-fluoro-phenyl)-3-iodo-4-(methoxymethoxy)-2- tetrahydropyran-4-yl-indole (S6)

[0268] To a solution of l-(3-chloro-4-fluoro-phenyl)-4-(methoxymethoxy)-2- tetrahydropyran-4-yl-indole C30 in dichloromethane (20 mL) was added N-iodosuccinimide (755 mg, 3.36 mmol). The reaction mixture was stirred for 30 minutes. The mixture was then diluted with water, and the organic layer was concentrated to dryness. Purification by silica gel chromatography (Gradient: 0-25% EtOAc in heptane) yielded the product as a white solid which was used in the next step. l-(3-chloro-4-fluoro-phenyl)-3-iodo-4-(methoxymethoxy)-2- tetrahydropyran-4-yl-indole (1.38 g, 83%) 'H NMR (400 MHz, Chloroform-r / ) d 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, 0.7 Hz, 1H), 5.36 (s, 2H), 4.02 (dd, J = 11.5, 4.6 Hz, 2H), 3.63 (d, J = 3.9 Hz, 3H), 3.39 (tdd, J = 11.9, 5.6, 2.0 Hz, 2H), 3.11 (tt, J = 12.5, 3.6 Hz, 1H), 2.55 - 2.17 (m, 2H), 1.60 (s, 2H). LCMS m / z 515.32 [M+H]+.Preparation of S7Step 1. Synthesis of 4-[2-(2-hromo-4-fluoro-6-methoxy-phenyl)ethynyl]tetrahydropyran (C34)

[0269] A 5 L 3 -neck RB flask with overhead stirrer, temperature probe, and nitrogen inlet was charged with l-bromo-5-fluoro-2-iodo-3-methoxy-benzene C33 (264 g, 797.8 mmol) and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (250 g, 1.3 mol) in 1,4-dioxane (1.5 L). The mixture was stirred for 5 minutes, and then iPrNLh (650 mL, 4.64 mol) was added, followed by Cul (6 g, 31.5 mmol), PdCl2(PPli3)2 (22 g, 31.3 mmol) and TBAF hydrate (300 g, 950.8 mmol). The reaction mixture was warmed to 60 °C for 12 hours. The reaction mixture was cooled to room temperature, poured onto a mixture of water (~1L), sat. aqueous NLLCl solution (~2 L) and ethyl acetate (~3 L), then stirred for 10 minutes. The organic phase was separated, washed successively with a 1 AHC1 solution (2 x 500 mL), brine (500 mL). The organic phase was dried over MgSCL, filtered and concentrated under reduced pressure. Purification by silica gelchromatography (Gradient: 0- 30% ethyl acetate in heptane) afforded the product as a yellow solid (151 g, 60% yield).

[0270] Mixed fractions were purified by an additional silica gel chromatography column (Gradient: 0-50% ethyl acetate in heptane) to afford additional product (50 g, 20% yield). Purified product batches were combined (151 g + 50 g) and dried under vacuum to afford 4-[2- (2-bromo-4-fluoro-6-methoxy-phenyl)ethynyl]tetrahydropyran (200 g, 80%) as a yellow solid. ¾NMR (400 MHz, DMSO-i / eChloroform- ) d 6.95 (dd, J = 8.0, 2.4 Hz, 1H), 6.57 (dd, J =10.4, 2.4 Hz, 1H), 4.01 (ddd, J = 11.6, 6.9, 3.4 Hz, 2H), 3.86 (s, 3H), 3.61 (ddd, J = 11.2, 7.3, 3.3 Hz, 2H), 3.00 (dq, J = 7.7, 3.8 Hz, 1H), 2.03 - 1.90 (m, 2H), 1.81 (dtd, J = 13.1, 7.4, 3.1 Hz, 2H).19F NMR (376 MHz, Chloroform-i / ) d -108.45. LCMS m / z 314.97 [M+l]+.Step 2. Synthesis of 5-fluoro-N-(4-fluoro-3-methyl-phenyl)-3-methoxy-2-(2-tetrahydro-pyran-4- ylethynyl) aniline (C35)

[0271] To a solution of 4-[2-(2-bromo-4-fluoro-6-methoxy-phenyl)ethynyl]tetra-hydropyran C34 (92 g, 293.8 mmol), 4-fluoro-3 -methyl-aniline (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 minutes. tBuXPhos Pd G3 (7.01 g, 8.83 mmol) was added, and the mixture heated to 60 °C for 3 hours. The mixture was cooled, then sat. NH4CI (1 L) and HC1 (64 mL of 6 M, 384.0 mmol) was added and the mixture was allowed to stir overnight. The mixture was extracted with EtOAc (x 2) and the organic layer was concentrated. Purification by silica gel chromatography (Gradient: 0-90% EtOAc in heptanes) to afford the product as a black oil 5-fluoro-N-(4-fluoro- 3-methyl-phenyl)-3-methoxy-2-(2-tetrahydropyran-4-ylethynyl)aniline (98 g, 93%).1H NMR (300 MHz, Chloroform - ) d 6.87 - 6.76 (m, 3H), 6.24 (s, 1H), 6.13 (dd, J = 11.2, 2.3 Hz, 1H), 5.90 (dd, J = 10.7, 2.3 Hz, 1H), 3.80 (ddd, J = 11.6, 5.6, 3.6 Hz, 2H), 3.68 (s, 3H), 3.40 (ddd, J =11.5, 8.4, 3.0 Hz, 2H), 2.82 (tt, J = 8.4, 4.1 Hz, 1H), 2.11 (d, J = 1.8 Hz, 3H), 1.86 - 1.73 (m,2H), 1.71 - 1.54 (m, 2H). LCMS m / z 358.22 [M+l]+.Step 3. Synthesis of 6-fluoro-l-(4-fluoro-3-methyl-phenyl)-4-methoxy-2-tetrahydropyran-4-yl- indole (C36)

[0272] 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) was added PdCb (2.08 g, 11.7 mmol). The mixture was heated to 60 °C for overnight. The mixture was then concentrated to dryness and MBTE (300 mL) was added. Upon stirring for 10 minutes, the mixture was filtered to afford solid product (40 g). The black filtrate was purified by silica gel chromatography (Gradient: 0-60% EtOAc in dichloromethane) to afford an additional 33g of product. The two product batches were combined to afford a single batch of product. 6-fluoro-l-(4-fluoro-3-methyl-phenyl)-4-methoxy-2-tetrahydropyran-4-yl-indole (73 g, 70%). ¾ NMR (300 MHz, Chloroform - ) d 7.15 (td, J = 8.2, 7.6, 4.2 Hz, 3H), 6.49 (s, 1H), 6.42 - 6.24 (m, 2H), 3.97 (s, 5H), 3.35 (td, J = 11.6, 2.7 Hz, 2H), 2.76 (ddd, J = 15.4, 11.2, 4.4 Hz, 1H), 2.38 (d, J = 1.8 Hz, 3H), 1.90 - 1.64 (m, 4H). LCMS m / z 358.12 [M+l]+.Step 4. Synthesis of 6-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-4-ol (C37)

[0273] A I L 3 -neck RB flask was charged 6-fluoro-l-(4-fluoro-3-methyl-phenyl)-4- methoxy-2-tetrahydropyran-4-yl-indole C36 (15.1 g, 42.3 mmol) in dichloromethane (250 mL), stirred for 5 minutes and then cooled to 0 °C with an ice / water bath. AlCb (20.4 g, 153.0 mmol) was added, stirred for 10 minutes, and then octane- 1 -thiol (31 mL, 178.6 mmol) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then poured into ice / water (-120 mL). 2 N HC1 (-120 mL) and ethyl acetate (400 mL) were added, and the mixture stirred for -20 minutes. The organic phase was separated, washed with brine (-300 mL), dried over Na2SC>4, filtered and then concentrated under reduced pressure. The residue was triturated with -10% MTBE in heptane (-400 mL), dried under vacuum to afford the product as a tan solid. 6-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-4-ol (13.2 g, 91%). ¾ NMR (300 MHz, DMSO-4) d 9.98 (s, 1H), 7.35 (t, J = 8.8 Hz, 2H), 7.27 (ddd, J =8.2, 4.6, 2.7 Hz, 1H), 6.45 (s, 1H), 6.26 (dd, J = 11.5, 2.1 Hz, 1H), 6.10 (dd, J = 9.8, 1.6 Hz, 1H), 3.82 (d, J = 10.9 Hz, 2H), 3.22 (td, J = 11.2, 3.2 Hz, 3H), 2.76 (dt, J = 10.3, 5.4 Hz, 1H), 2.32 (d, J = 1.6 Hz, 4H), 1.74 - 1.49 (m, 2H). LCMS m / z 344.14 [M+l]+.Step 5. Synthesis of 4-henzyloxy-6-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl- indole (C38)

[0274] A solution of 6-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indol-4- ol C37 (15 g, 43.69 mmol) in THF (163 mL) and DMF (32 mL) was stirred for 5 minutes, until a clear, light brown colored solution formed. CS2CO3 (29.1 g, 89.3 mmol) and benzyl bromide (6.3 mL, 53.0 mmol) was added and the resulting reaction mixture (white suspension) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (130 mL), stirred for 10 minutes, and then the resulting white suspension was filtered through a medium fritted funnel, washing with ethyl acetate (50 mL). The combined filtrate was washed with water (-200 mL), brine (-200 mL), dried over MgSCri, filtered and concentrated under reduced pressure. The residue was triturated with 10% MTBE in heptane (-300 mL), and dried under vacuum to afford the product as a white solid. 4-benzyloxy-6-fluoro-l-(4-fluoro-3-methyl- phenyl)-2-tetrahydropyran-4-yl-indole (16.1 g, 85%). 'H NMR (300 MHz, Chloroform -r / ) d 7.57 - 7.49 (m, 2H), 7.49 - 7.33 (m, 3H), 7.24 - 7.08 (m, 3H), 6.55 (s, 1H), 6.43 (dd, J = 11.6,2.0 Hz, 1H), 6.32 (dd, J = 9.5, 1.9 Hz, 1H), 5.22 (s, 2H), 4.03 - 3.91 (m, 2H), 3.35 (td, J = 11.6, 2.7 Hz, 2H), 2.83 - 2.69 (m, 1H), 2.38 (d, J = 1.9 Hz, 3H), 1.90 - 1.64 (m, 4H). LCMS m / z 434.15 [M+l]+.Step 6. Synthesis of 4-benzyloxy-6-fluoro-l-(4-fluoro-3-methyl-phenyl)-3-iodo-2- tetrahydropyran-4-yl-indole (S7)

[0275] A solution of 4-benzyloxy-6-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran- 4-yl-indole C38 (64.5 g, 148.8 mmol) in dichloromethane (1 L) was stirred for 5 minutes to afford a clear, colorless solution. The reaction mixture was cooled to 0 °C with an ice / water bath, then l-iodopyrrolidine-2,5-dione (36.3 g, 156.5 mmol) was added in three portions over 15 minutes. The resulting reaction mixture was stirred from 0 °C to room temperature over 1 hour. The reaction was then washed with an aqueous mixture of lAfNaiSiCh solution (-300 mL), saturated NaHCCb (150 mL), then brine (-300 mL). The mixture was dried over MgSCL, filtered, and concentrated under reduced pressure. The residue was concentrated to afford the product as a white solid. 4-benzyloxy-6-fluoro-l-(4-fluoro-3-methyl-phenyl)-3-iodo-2- tetrahydropyran-4-yl-indole (83 g, 100%). 'H NMR (300 MHz, Chloroform -r / ) d 7.64 (d, J = 7.0 Hz, 2H), 7.50 - 7.32 (m, 3H), 7.19 (t, J = 8.7 Hz, 1H), 7.09 (td, J = 8.5, 3.7 Hz, 2H), 6.43 (dd, J = 11.6, 2.0 Hz, 1H), 6.13 (dd, J = 9.2, 2.1 Hz, 1H), 5.23 (s, 2H), 3.99 (dd, J = 11.5, 4.1 Hz, 2H), 3.36 (td, J = 11.9, 1.9 Hz, 2H), 3.09 (tt, J = 12.5, 3.5 Hz, 1H), 2.38 (d, J = 1.9 Hz, 3H), 2.26 (ddt, J = 16.9, 12.7, 6.4 Hz, 2H), 1.53 (m, 2H). LCMS m / z 559.99 [M+l]+.Preparation of S84-benzyloxy-5-fluoro-I-(4-fluoro-3-methyl-phenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (S8)Step 1. Synthesis of 3-benzyloxy-4-fluoro-N-(4-fluoro-3-methyl-phenyl)-2-iodo-aniline (C39)

[0276] 3-benzyloxy-4-fluoro-2-iodo-aniline C8 (7.1 g, 20.7 mmol), (4-fluoro-3-methyl- phenyl)boronic acid (6.4 g, 41.6 mmol), copper (II) acetate (5.6 g, 30.8 mmol) and K2CO3 (6.0 g, 43.4 mmol) were suspended in DMSO (100 mL) and the reaction was stirred at room temperature for 1 week. The reaction was combined with another batch of this reaction run on 3- benzyloxy-4-fluoro-2-iodo-aniline (1.6 g, 4.66 mmol) for workup and purification. The combined reactions were diluted with EtOAc, and filtered through a plug of Celite®. The filtrate was washed with water, brine, and then the organic layer was concentrated to dryness. Purification by silica gel chromatography (Eluent: EtOAc in heptane) afforded the product as a dark brown oil which was used in the subsequent step without further purification. 3-benzyloxy- 4-fluoro-N-(4-fluoro-3-methyl-phenyl)-2-iodo-aniline (5.76 g, 62%). LCMS m / z 452.0 [M+l]+. Step 2 & 3. Synthesis of 4-benzyloxy-5-fluoro- 1 -(4-fluoro-3-methyl-phenyl)-2-tetrahydr opyran- 4-yl-indole (C40) and A-benzyloxy-5-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4- yl-indole (C41)

[0277] A mixture of 3-benzyloxy-4-fluoro-N-(4-fluoro-3-methyl-phenyl)-2-iodo-aniline C39 (5.76 g, 12.76 mmol), PdCl2(PPh3)2 (538 mg, 0.77 mmol), and Cul (243 mg, 1.28 mmol) inDMF (40 mL) was degassed for 10 minutes. Trimethyl(2-tetrahydropyran-4-ylethynyl)silane (2.68 g, 14.7 mmol) and Et2NH (1.52 mL, 14.7 mmol) were added, followed by TBAF (19.1 mL of 1 M, 19.1 mmol), and the reaction mixture was stirred overnight at 80 °C. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated to dryness and purified by silica gel chromatography (Gradient: 0-40% EtOAc in heptane) to afford the product C40. The product was dissolved in MeCN (40 mL) and PdCh (200 mg, 1.13 mmol) was then added. The reaction mixture was then stirred overnight at 65 °C. The solvent was removed in vacuo , and the resulting material was triturated in MeCN, filtered, washed with heptane. The product was dried to give 4-benzyloxy-5-fluoro-l-(4-fluoro-3-methyl-phenyl)-2- tetrahydropyran-4-yl-indole as a tan solid (2.68 g, 48%). ¾ NMR (400 MHz, Chloroform-r / ) d 7.60 - 7.54 (m, 2H), 7.44 (ddt, J = 8.0, 6.4, 1.0 Hz, 2H), 7.41 - 7.35 (m, 1H), 7.22 - 7.11 (m, 3H), 6.88 (dd, J = 11.8, 8.8 Hz, 1H), 6.59 (ddd, J = 8.8, 3.4, 0.8 Hz, 1H), 6.49 (t, J = 0.8 Hz, 1H), 5.34 (s, 2H), 3.99 (ddd, J = 11.7, 4.5, 1.9 Hz, 2H), 3.36 (td, J = 11.7, 2.4 Hz, 2H), 2.76 (tt, J = 11.5,3.9 Hz, 1H), 2.38 (d, J = 2.0 Hz, 3H), 1.85 - 1.71 (m, 4H). LCMS m / z 434.0 [M+l]+.Step 3. Synthesis of 4-henzyloxy-5-fluoro-l-(4-fluoro-3-methyl-phenyl)-3-iodo-2- tetrahydropyran-4-yl-indole (S8)

[0278] To a solution of 4-benzyloxy-5-fluoro-l-(4-fluoro-3-methyl-phenyl)-2- tetrahydropyran-4-yl-indole C40 (2.68 g, 6.18 mmol) in dichloromethane (30 mL) was added N- iodosuccinimide (1.46 g, 6.5 mmol). The reaction mixture was stirred at room temperature for 20 minutes, then washed with water and concentrated to dryness. Purification by silica gel chromatography (Gradient: 0-45% EtOAc in heptane) afforded the product as light yellow solid. 4-benzyloxy-5-fluoro-l-(4-fluoro-3-methyl-phenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (2.84 g, 82%). ¾ NMR (400 MHz, Chloroform- ) d 7.71 - 7.62 (m, 2H), 7.47 - 7.42 (m, 2H), 7.42 - 7.35 (m, 1H), 7.20 (td, J = 8.8, 1.5 Hz, 1H), 7.16 - 7.05 (m, 2H), 6.95 - 6.88 (m, 1H), 6.49 (dd, J = 8.9, 3.6 Hz, 1H), 5.26 (d, J = 2.7 Hz, 2H), 4.01 (dd, J = 11.6, 4.6 Hz, 2H), 3.38 (td, J = 11.9,2.0 Hz, 2H), 3.11 (tt, J = 12.6, 3.6 Hz, 1H), 2.38 (d, J = 2.0 Hz, 3H), 1.59 (s, 4H). LCMS m / z 559.0 [M+l]+.Preparation of S9 and SI 04-benzyloxy-5-fluoro-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole (S9) and 4- henzyloxy-l-( 4-fluoro-3-methyl-phenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (SI 0)Step 1. Synthesis of 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole (C42)

[0279] A solution of 4-[2-(2-benzyloxy-6-bromo-phenyl)ethynyl]tetrahydropyran C3 (2.85 g, 7.68 mmol) and 4-fluoro-3 -methyl-aniline (1.8 g, 14.38 mmol) in m-xylene (40 mL) was degassed for 15 minutes. NaOtBu (2.2 g, 22.89 mmol) was added, followed by tBuXPhos Pd G3 (300 mg, 0.38 mmol). The reaction mixture was stirred at room temperature for 8 hours. The mixture was diluted with ice water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were concentrated to dryness and purified by silica gel chromatography (Gradient: 0-25% EtOAc in heptane) to provide the product. 3-benzyloxy-N-(4-fluoro-3-methyl- phenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline (3.21 g, 100%). 'H NMR (400 MHz, Chloroform - ) d 7.61 - 7.51 (m, 2H), 7.51 - 7.42 (m, 2H), 7.42 - 7.34 (m, 1H), 7.16 - 6.98 (m, 4H), 6.74 (dd, J = 8.3, 0.8 Hz, 1H), 6.46 (dd, J = 8.3, 0.8 Hz, 1H), 6.41 (s, 1H), 5.19 (s, 2H),4.00 (ddd, J = 11.6, 6.2, 3.5 Hz, 2H), 3.60 (ddd, J = 11.3, 7.9, 3.1 Hz, 2H), 3.05 (tt, J = 8.1, 4.1 Hz, 1H), 2.33 (d, J = 2.0 Hz, 3H), 2.01 (ddt, J = 13.0, 6.7, 3.7 Hz, 2H), 1.84 (dtd, J = 13.3, 8.0, 3.5 Hz, 2H). LCMS m / z 416.34 [M+H]+.Step 2. Synthesis of 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole (S9)

[0280] To a solution of 3-benzyloxy-N-(4-fluoro-3-methyl-phenyl)-2-(2-tetrahydropyran-4- ylethynyl)aniline C42 (3.2 g, 7.6 mmol) in acetonitrile (40 mL) was added PdCh (70 mg, 0.4 mmol). The reaction mixture was stirred at 50 °C for 2 hours, then overnight at same temperature. The solution was concentrated to dryness and purified via silica gel chromatography (Gradient: 0-20% EtOAc in heptane) to give the product as light yellow solid. 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl-indole (2.7 g, 85%).1H NMR (400 MHz, Chloroform - ) d 7.66 - 7.55 (m, 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.41 (t, J = 7.2 Hz,1H), 7.27 - 7.16 (m, 3H), 7.07 (t, J = 8.0 Hz, 1H), 6.76 - 6.60 (m, 3H), 5.31 (s, 2H), 4.03 (ddd, J = 11.6, 4.5, 1.8 Hz, 2H), 3.41 (td, J = 11.8, 2.3 Hz, 2H), 2.86 (tt, J = 11.6, 3.9 Hz, 1H), 2.43 (d, J = 1.9 Hz, 3H), 1.97 - 1.84 (m, 2H), 1.83 - 1.78 (m, 2H). LCMS m / z 416.38 [M+H]+.Step 3. Synthesis of 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-3-iodo-2-tetrahydropyran-4-yl- indole (S10)

[0281] To a solution of 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-2-tetrahydropyran-4-yl- indole S9 (2.7 g, 6.5 mmol) in dichloromethane (30 mL) was added N-iodosuccinimide (1.5 g, 6.67 mmol). The solution was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, and then the organic layer separated and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-25% EtOAc in heptane) afforded the product as a white solid. 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-3-iodo-2-tetrahydropyran-4- yl-indole (3.5 g, 99%). ¾ NMR (400 MHz, Chloroform- ) d 7.70 - 7.63 (m, 2H), 7.47 - 7.40 (m, 2H), 7.40 - 7.33 (m, 1H), 7.19 (t, J = 8.7 Hz, 1H), 7.16 - 7.07 (m, 2H), 7.01 (td, J = 8.1, 4.1 Hz, 1H), 6.69 - 6.61 (m, 1H), 6.50 - 6.43 (m, 1H), 5.27 (s, 2H), 4.00 (dd, J = 11.5, 4.5 Hz, 2H), 3.38 (td, J = 11.9, 2.1 Hz, 2H), 3.14 (tt, J = 12.4, 3.5 Hz, 1H), 2.38 (d, J = 2.1 Hz, 3H), 2.30 (td,J = 12.3, 4.4 Hz, 2H), 1.59 - 1.50 (m, 2H). LCMS m / z 541.33 [M+H]+.Preparation of SI 1 l-(4-fluoro-3-methyl-phenyl)-2-isopropyl-4-methoxy-indole (Sll)1. NaOtBu tBuXPhos Pd G3C42 C43 S11Step 1. Synthesis of l-bromo-3-methoxy-2-(3-methylbut-l-ynyl)benzene (C43)

[0282] A mixture of 3-methylbut-l-yne (6.6 mL, 63.95 mmol), l-bromo-2-iodo-3-m ethoxy- benzene C42 (5 g, 15.98 mmol) in Et3N (30 mL) and DMF (15 mL) was purged with nitrogen for 5 minutes, Pd(PPh3)2Cl2 (1.1 g, 1.57 mmol), Cul (310 mg, 1.63 mmol) were added and the reaction mixture stirred at room temperature for 60 hours. The reaction mixture was then poured into water (200 mL), extracted with EtOAc (2 x 100 mL), washed with water, then dried over Na2SC>4. The solvent was removed under reduced pressure. Purification by silica gel chromatography (Gradient: 0-100% EtOAc in heptane), then purified by reversed-phase chromatography (Column: C18. Gradient: 0-100% MeCN in water with 0.1% trifluoroacetic acid) afforded the product l-bromo-3-methoxy-2-(3-methylbut-l-ynyl)benzene (2.6 g, 62%) as a thick oil. ¾ NMR (400 MHz, Chloroform- ) d 7.19 (d, J = 1.0 Hz, 1H), 7.09 (t, J = 8.2 Hz, 1H), 6.82 (dd, J = 8.3, 1.0 Hz, 1H), 3.89 (s, 3H), 2.92 (p, J = 6.9 Hz, 1H), 1.35 (d, J = 6.9 Hz, 6H). LCMS m / z 253.39 [M+H]+.Step 2. Synthesis of l-(4-fluoro-3-methyl-phenyl)-2-isopropyl-4-methoxy-indole (Sll)

[0283] A solution of 4-fluoro-3-methyl-aniline (1.93 g, 15.4 mmol), l-bromo-3-methoxy-2- (3-methylbut-l-ynyl)benzene C43 (2.6 g, 10.3 mmol) in t-BuOH (8 mL) and 1,4-dioxane (12 mL) was purged with nitrogen for 10 minutes. Sodium t-butoxide (1.9 g, 19.8 mmol) was added, followed by tBuXPhos Pd G3 (352 mg, 0.51 mmol) then after 5 minutes. The reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100 mL) and EtOAc (100 mL). The organic layer was separated and aq. layer was extracted with EtOAc (2x 50 mL). The combined organic layers was dried over Na2S04 and the solvent was evaporated under reduced pressure to afford the product N-(4-fluoro-3-methyl-phenyl)-3- methoxy-2-(3-methylbut-l-ynyl)aniline (2.3 g, 75%).

[0284] InBn (730 mg, 2.059 mmol) was added to a solution of N-(4-fluoro-3 -methyl- phenyl)^ -methoxy-2-(3-methylbut-l-ynyl)aniline (2.3 g) in toluene (25 mL) and the solution was heated at 110 °C for 3 hours. The solvent was removed under reduced pressure, and the residue dissolved in EtOAc (25 mL), then washed with water. The organic layer was dried and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient: 0- 40% EtOAc in heptane) afforded l-(4-fluoro-3-methyl-phenyl)-2-isopropyl-4-methoxy-indole (2 g, 65%) as yellow solid. ¾ NMR (400 MHz, Chloroform- ) d 7.20 - 7.06 (m, 2H), 7.03 (t, J = 8.0 Hz, 1H), 6.63 (dt, J = 8.3, 0.8 Hz, 1H), 6.58 - 6.47 (m, 2H), 4.01 (s, 3H), 2.94-2.91 (m, 1H), 2.37 (dd, J = 2.2, 0.7 Hz, 3H), 1.23-1.16 (m, 6H). LCMS m / z 298.52 [M+l]+.Preparation of SI 24-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (S12)Step 1. Synthesis of l-benzyloxy-3-bromo-2-(3-methylbut-l-ynyl)benzene (C44)

[0285] A solution of l-benzyloxy-3-bromo-2-iodo-benzene C2 (7 g, 17.99 mmol), PdCl2(PPh3)2 (757 mg, 1.08 mmol) and Cul (343 mg, 1.80 mmol) in anhydrous DMF (60 mL) was degassed for 10 minutes. 3-methylbut-l-yne (2.76 mL, 26.99 mmol) and diethylamine (2.79 mL, 26.97 mmol) were added and the reaction mixture was stirred overnight at 60 °C in a sealed tube. The reaction mixture was cooled to room temperature, diluted with water (60 mL) and extracted EtOAc (3 x). The organic layer was concentrated to dryness, dissolved in MTBE, and washed with water. Purification by silica gel chromatography (Gradient: 0-35% EtOAc in heptane) yielded the product with was used in the subsequent reaction without further purification. l-benzyloxy-3-bromo-2-(3-methylbut-l-ynyl)benzene (5.6 g, 95%). 'H NMR (400MHz, Chloroform - ) d 7.53 - 7.51 (m, 2H), 7.45 - 7.36 (m, 3H), 7.23 - 7.18 (m, 1H), 7.06 (t, J = 8.2 Hz, 1H), 6.86 (dd, J = 8.3, 1.0 Hz, 1H), 5.17 (s, 2H), 2.92 (hept, J = 6.9 Hz, 1H), 1.34 (d, J = 6.9 Hz, 6H).Step 2. Synthesis of 3-benzyloxy-N-(4-fluoro-3-methyl-phenyl)-2-(3-methylbut-l-ynyl)aniline (C45)

[0286] A mixture of l-benzyloxy-3-bromo-2-(3-methylbut-l-ynyl)benzene C44 (933 mg, 2.83 mmol), 4-fluoro-3 -methyl-aniline (413 mg, 3.3 mmol), NaOtBu (817 mg, 8.50 mmol) and tBuXPhos Pd G3 (113 mg, 0.14 mmol) was added to a vial. The vial was sealed and was purged with one vacuum / nitrogen cycle. 1,4-Dioxane (7.1 mL) was added and the mixture was stirred overnight at 50 °C. The reaction was evaporated to dryness and the residue was triturated with EtOAc. The reaction was filtered over a pad of Celite® and rinsed using additional EtOAc. The combined organic layers were dried over NaiSCE, filtered and concentrated providing an inseparable mixture of 3-benzyloxy-N-(4-fluoro-3-methyl-phenyl)-2-(3-methylbut-l- ynyl)aniline and 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (1058 mg,100%) which was used in the subsequent step without further purification. LCMS m / z 374.25 [M+l]+.Step 3. Synthesis of 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-2-isopropyl-indole (S12)

[0287] In a flask, to a solution of 3 -benzyl oxy-N-(4-fluoro-3-methyl-phenyl)-2-(3-methylbut- l-ynyl)aniline C45(1058 mg, 2.83 mmol) in THF (11.3 mL) was added NaOtBu (973 mg, 8.5 mmol).

[0288] The reaction was stirred at 60 °C for 30 minutes. The reaction was cooled to room temperature and was filtered through a pad of Celite®, and rinsed with additional EtOAc. The combined organic phases were evaporated and purified by silica gel chromatography (Gradient: 0-100% EtOAc in heptane) to afford the product. 4-benzyloxy-l-(4-fluoro-3-methyl-phenyl)-2- isopropyl-indole (550 mg, 49%). ¾ NMR (400 MHz, Chloroform- ) d 7.54 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.37 - 7.31 (m, 1H), 7.19 - 7.11 (m, 3H), 6.97 (t, J = 8.0 Hz, 1H), 6.64 - 6.55 (m, 3H), 5.24 (s, 2H), 2.97 - 2.83 (m, 1H), 2.34 (s, 3H), 1.22 - 1.17 (m, 6H). LCMS m / z 374.25 [M+H]+.Preparation of SI 3 and SI 44-benzyloxy-l-(4-fluorophenyl)-2-tetrahydropyran-4-yl-indole ( S13 ) and 4-benzyloxy-l-(4- fluorophenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (SI 4)Step 1. Synthesis of 3-benzyloxy-N-(4-fluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline (C46)

[0289] To a solution of 4-[2-(2-benzyloxy-6-bromo-phenyl)ethynyl]tetrahydropyran C3 (74.5 g, 200.7 mmol) and 4-fluoroaniline (23.0 mL) in m-xylene (900 mL) was added NaOtBu (58 g, 603.5 mmol) followed by tBuXPhos Pd G3 (8 g, 10.07 mmol). The reaction mixture was stirred at room temperature for 20 hours, then diluted with water (1L) and extracted with EtOAc (3 x 500 mL). The combined organics were concentrated to dryness and purified via silica gel chromatography (Gradient: 0-35% EtOAc in heptane) afforded the product as a brown oil. 3- benzyloxy-N-(4-fluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline (73 g, 89%).1HNMR (300 MHz, Chloroform - ) d 7.57 - 7.47 (m, 2H), 7.46 - 7.31 (m, 3H), 7.18 (ddt, J = 8.2, 5.7, 2.8 Hz, 2H), 7.13 - 6.98 (m, 3H), 6.74 - 6.60 (m, 1H), 6.51 - 6.31 (m, 2H), 5.16 (s, 2H), 3.96 (ddd, J = 11.6, 6.2, 3.5 Hz, 2H), 3.56 (ddd, J = 11.4, 7.9, 3.2 Hz, 2H), 3.02 (tt, J = 8.1, 4.1 Hz, 1H), 2.04 - 1.88 (m, 2H), 1.80 (dtd, J = 13.4, 8.0, 3.5 Hz, 2H). LCMS m / z 402.15 [M+H]+.Step 2. Synthesis of 4-benzyloxy-l-(4-fluorophenyl)-2-tetrahydropyran-4-yl-indole (S13)

[0290] To a solution of 3-benzyloxy-N-(4-fluorophenyl)-2-(2-tetrahydropyran-4- ylethynyl)aniline C46 (6.08 g, 15.14 mmol) in acetonitrile (50 mL) was added PdCh (269 mg,1.52 mmol). The reaction mixture was stirred at 50 °C for 2 hours (significant ppt observed after 10 min) then filtered, washed with heptane, and dried to give 4.8 g light gray solid. The filtrate was concentrated to dryness and purified via silica gel chromatography eluting with 0-30% EtOAc in heptane. Pure fractions were combined and concentrated to give an additional 280 mg of desired product. 4-benzyloxy-l-(4-fluorophenyl)-2-tetrahydropyran-4-yl-indole (5.1 g, 84%). ¾NMR (400 MHz, Chloroform- ) d 7.59 - 7.53 (m, 2H), 7.48 - 7.41 (m, 2H), 7.41 - 7.32 (m, 3H), 7.28 - 7.23 (m, 2H), 7.03 (t, J = 8.1 Hz, 1H), 6.69 - 6.60 (m, 3H), 5.27 (s, 2H), 3.99 (ddd, J = 11.6, 4.7, 1.8 Hz, 2H), 3.35 (td, J = 11.9, 2.2 Hz, 2H), 2.80 (tt, J = 11.6, 3.8 Hz, 1H), 1.85 (dtd, J = 13.5, 11.9, 4.3 Hz, 2H), 1.74 (dq, J = 13.1, 2.0 Hz, 2H). LCMS m / z 402.0 [M+H]+.Step 3. Synthesis of 4-henzyloxy-l-(4-fluorophenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (S14)

[0291] To a solution of 4-benzyloxy-l-(4-fluorophenyl)-2-tetrahydropyran-4-yl-indole S13 (2 g, 4.98 mmol) in dichloromethane (25 mL) at 0 °C was added N-iodosuccinimide (1.18 g,5.25 mmol). The reaction mixture was stirred at 0 °C for 1 hour then washed with water. The organic layer was concentrated to dryness and purified via silica gel chromatography (Gradient: 0-30% EtOAc in heptane) to afford the product as a yellow solid. 4-benzyloxy-l-(4- fluorophenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (2.4 g, 91%). 'H NMR (400 MHz, Chloroform - ) d 7.67 (ddt, J = 7.5, 1.4, 0.7 Hz, 2H), 7.47 - 7.41 (m, 2H), 7.39 - 7.33 (m, 1H), 7.30 - 7.24 (m, 4H), 7.02 (td, J = 8.1, 4.2 Hz, 1H), 6.65 (ddd, J = 7.9, 3.2, 0.7 Hz, 1H), 6.48 (ddd, J = 15.4, 8.3, 0.7 Hz, 1H), 5.28 (s, 2H), 4.05 - 3.95 (m, 2H), 3.37 (td, J = 11.9, 2.0 Hz,2H), 3...

Claims

CLAIMS1. A compound represented by the following structural formula:a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: for each of the two occurrences, is a single bond or a double bond, provided that one is a single bond and the other is a double bond;V1and V2are each independently N or -CR2;W1and W2are each independently N or C, provided that one of W1and W2is N and the other is C;U is hydrogen, -OH, -CH3, -NH2, or halogen;X is absent or a bond, -(CRaRb)p-, or -SO2-;Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, halogen, -OH, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy;Rcand Rd, for each occurrence, are each independently hydrogen, halogen, -OH, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy;Ring A is C3-C12 carbocyclyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl; provided that when W1is N and W2is C, Ring A is not 1 ,5,6,7-tetrahydro-4 / / -indol-4-onyl or a tautomer thereof;Ring B is C4-C12 cycloalkyl, Ce or C10 aryl, 5 to 10-membered heteroaryl, or benzyl;wherein:Ring C is C3-C12 cycloalkyl, 3 to 12-membered heterocyclyl, Ce or C10 aryl, or 5 to 10-membered heteroaryl; provided that when Ring C is phenyl, the phenyl is substituted with R4; provided that when Ring C is phenyl, Y cannot be -SO2-; and provided that when Ring B is benzyl, Ring C cannot be pyridinyl or indolyl;RE, Rr, and RGare each independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -CRP(=N)ORs, -NR"C(=0)Rs, -NR"C(=0)0Rs, -NRpC(=0)NRqRr,-ORs, -0C(=0)Rs, or -0C(=0)NRpRq; wherein: the C1-C6 alkyl or the C2-C6 alkenyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano,-C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq, -NRpC(=0)Rs, -NRpC(=0)0Rs, -NRpC(=0)NRqRr, -NRpS(=0)rRs, -ORs, -0C(=0)Rs, -0C(=0)0Rs, -0C(=0)NRpRq, -S(=0)rRs, and -S(=0)rNRpRq; wherein:Rp, Rq, and Rr, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3 to 6-membered heterocyclyl; wherein: the C1-C4 alkyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, Ci- C3alkoxy, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6 cycloalkyl or the 3 to 6-membered heterocyclyl of any one of Rp, Rq, and Rris optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0(Ci-C2alkyl), -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rs, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3- Ce cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C4 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2alkyl)2, C1-C3 alkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; andthe C3-C6 cycloalkyl, the phenyl, or the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;R1is halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or -0-(C3-C6cycloalkyl);R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2- Ce alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NRhR‘, phenyl, or 5 or 6-membered heteroaryl; wherein: the C1-C6 alkyl, the C2-C6 alkenyl or the C3-C6 cycloalkyl of R2is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rk,-C(=0)0Rk, -C(=0)NRhR‘, -NRhR‘, -NRhC(=0)Rk, -NRhC(=0)0Rk, -NRhC(=0)NR'Rj, -NRhS(=0)sRk-ORk, -0C(=0)Rk, -0C(=0)0Rk, -0C(=0)NRhR‘, -S(=0)sRk, and S(=0)sNRhRi; wherein:Rh, R', and R', for each occurrence, are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl; wherein: the C1-C4 alkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6 cycloalkyl of any one of Rh, R', and R' is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, - NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Rk, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3- C6 cycloalkyl, phenyl, or 5 or 6-membered heteroaryl; wherein:-ORkcannot be -OH;the C1-C4 alkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3 alkyl, C1-C3alkoxy, C1-C3 haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, - C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl of Rkis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3alkyl, Ci-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl),-C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci- C2 alkyl)2;R3and R4, for each occurrence, are each independently halogen, cyano, =0, C1-C6alkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C3-C6cycloalkyl, - C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -C(=0)NRv0Ry, -C(=0)NRvS(=0)tRy, -NRVRW, - NRvC(=0)Ry, -NRvC(=0)0Ry, -NRvC(=0)NRwRx, -NRvS(=0)tRy-ORy, -0C(=0)Ry, - 0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, -S(=0)tNRvRw, -S(=0)tNRvC(=0)Ry, - P(=0)RzRz, phenyl, or a 5 or 6-membered heteroaryl; wherein: the C1-C6alkyl, the C2-C6alkenyl, or the C3-C6cycloalkyl of any one of R3and R4is optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -NRVRW, -NRvC(=0)Ry,-NRvC(=0)0Ry, -NRVC (=0)NRwRx, - -NRvS(=0 Ry-ORy, -0C(=0)Ry, - 0C(=0)0Ry, -0C(=0)NRvRw, -S(=0)tRy, and -S(=0)tNRvRw; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen, C1-C4 alkyl, C3-C6cycloalkyl, 5 or 6-membered heterocyclyl, or 5 or 6-membered heteroaryl; wherein: the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2; and the C3-C6cycloalkyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen,cyano, -OH, -NH2, -NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3 alkyl, Ci-C3 alkoxy, C1-C3 haloalkyl, Ci-C3haloalkoxy,-C(=0)0H, -C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(Ci-C2alkyl)2;Ry, for each occurrence, is independently hydrogen, C1-C4 alkyl, C3- Ce cycloalkyl, phenyl, a 5 or 6-membered heterocyclyl, or a 5 or 6-membered heteroaryl; wherein the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(CI-C2 alkyl), - N(CI-C2alkyl)2, C1-C3alkyl, Ci-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H, -C(=0)0(Ci-C2alkyl),-C(=0)NH2, -C(=0)NH(CI-C2alkyl), and -C(=0)N(Ci-C2alkyl)2; and the C3-C6cycloalkyl, the phenyl, the 5 or 6-membered heterocyclyl, or the 5 or 6-membered heteroaryl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, NH(CI-C2 alkyl), -N(CI-C2 alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, -C(=0)0H,-C(=0)0(Ci-C2alkyl), -C(=0)NH2, -C(=0)NH(Ci-C2alkyl), and -C(=0)N(CI-C2alkyl)2;Rz, for each occurrence, is independently C1-C2 alkyl, -OH, or -0(Ci-C2alkyl); k is an integer selected from 1, 2, and 3; m and n a are each independently an integer selected from 0, 1, 2, and 3; p, r, s, and t are each independently an integer selected from 1 and 2; and q is an integer selected from 1, 2, and 3.

2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 represented by one of the following structural formulae:wherein:U is -OH, -CH3, -NH2, F, or Cl; and wherein all other variables not specifically defined herein are as defined in claim 1.

3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 represented by one of the following structural formulae:wherein:U is -OH, -CH3, -NH2, F, or Cl; and wherein all other variables not specifically defined herein are as defined in claim 1.

4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 or claim 2 represented by one of the following structural formulae:wherein:U is -OH or -NH2;Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9- membered heterocyclyl, phenyl, or 5 to 9-membered heteroaryl;Ring B is substituted with R1and Ring B is C4-C6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl, or benzyl; andwhen Z is Ring C optionally substituted with R4, Ring C is C4-C8 cycloalkyl, 4 to 8- membered heterocyclyl, phenyl, or 5 or 6-membered heteroaryl; and wherein all other variables not specifically defined herein are as defined in claim 1 or claim 2.

5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 2, and 4 represented by one of the following structural formulae:wherein:Ring B is substituted with R1and Ring B is cyclohexyl, phenyl, pyridinyl, or benzyl; and wherein all other variables not specifically defined herein are as defined in any one of claims 1, 2, and 4.

6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1, 2, 4, and 5 represented by the following structural formula:(Va) (Vb) wherein:R1is halogen, cyano, C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 alkoxy; and k is an integer selected from 1 and 2; and wherein all other variables not specifically defined herein are as defined in any one of claims 1, 2, 4, and 5.

7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein R1is cyano, F, Cl, -CFb, -CHF2, -CF3,-OCH3, or -OCH(CH3)2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein at least one R1is F; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein:X is absent or a bond, -(CRaRb)-, or -SO2-;Raand Rb, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

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

11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein:Y is absent or a bond, -(CRcRd)q-, -C(=0)-, or -SO2-;Rcand Rd, for each occurrence, are each independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 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 one of the preceding claims.

13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 12, wherein Y is absent or a bond, -CH2-, -CHCH3-, -C(CH3)2-, -C(=0)-, or -SO2-; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl containing 1 to 3 oxygen atoms, phenyl, or 5 to 9-membered heteroaryl containing 1 to 3 heteroatoms selected from O and N; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein Ring A is optionally substituted with R3and Ring A is C3-C7 carbocyclyl, 6 to 9-membered heterocyclyl containing one or two oxygen atoms, phenyl, or 5 to 9-membered heteroaryl containing one or two nitrogen atoms or one or two oxygen atoms; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein Ring A is optionally substituted with R3andand wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 16, wherein Ring A is optionally substituted with R3andand wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein Z is Ring C, Ring C is optionally substituted with R4, and Ring C is Ch-Cx cycloalkyl; 4 to 8-membered heterocyclyl containing one or two heteroatoms selected from O, N, and S; phenyl; or 5-membered heteroaryl containing one or two heteroatoms selected from O and N; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein Z is Ring C, Ring C is optionally substitutedand wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

20. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein Z is Ring C, Ring C is optionally substituted with (R4)o, and Ring C is selected fromand wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

21. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein RE, Rr, and RGare each independently hydrogen, halogen, cyano (-CºN), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=0)0Rs, - C(=0)NRpRq, -CRP(=N)ORs, or -ORs; wherein: the C1-C4 alkyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)Rs, -C(=0)0Rs, -C(=0)NRpRq,-ORs, -0C(=0)Rs, -0C(=0)0Rs, -0C(=0)NRpRq, and -S(=0)2Rs; wherein:Rpand Rq, for each occurrence, are each independently hydrogen, Ci- C2 alkyl, C3-C5 cycloalkyl, or 5 or 6-membered heterocyclyl; wherein: the C1-C2 alkyl of any one of Rpand Rqis optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; the C3-C5 cycloalkyl or the 5 or 6-membered heteroaryl of Rpand Rqis optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH;Rs, for each occurrence, is independently hydrogen, C1-C2 alkyl, or 5 or 6-membered heteroaryl; wherein the C1-C2 alkyl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; wherein:the 5 or 6-membered heteroaryl of Rsis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -ML·; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

22. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 21, wherein RE, Rr, and RGare each independently hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, -C(=0)NRPRq, -CRP(=N)ORs, or -ORs; wherein: the C1-C2 alkyl of any one of RE, RE, and RGis optionally substituted with 1 to 3 groups selected from cyano, -C(=0)NRpRq, -ORs, -0C(=0)NRpRq, and -S(=0)2Rs; wherein:Rpand Rq, for each occurrence, are each independently hydrogen, Ci- C2 alkyl, cyclopentyl, or tetrahydrofuranyl; wherein: the C1-C2 alkyl of any one of Rpand Rqis optionally substituted with 1 to 3 halogen groups selected from F and Cl;Rs, for each occurrence, is independently hydrogen,C1-C2 alkyl, pyridinyl, or pyrimidinyl; wherein: the C1-C2 alkyl of Rsis optionally substituted with 1 to 3 halogen groups selected from F and Cl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

23. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 22, wherein RE, RE, and RGare each independently hydrogen, F, -OH, -CH(OH)CH3, -C(=0)MiCH3, -C(=N)OCH3, -CH3,-CF3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -C2H5, -(CH2)20H, -CH2OCH3,-CH2OC2H5, -(CH2)20CH3, -CH2OCHF2, -(CH2)20CHF2, -CH2C(=0)ML·, -CH2C(=0)N(CH3)2, -CH2S(=0)2CH3, -(CH2)2S(=0)2CH3, -CH2(0)C(=0)MfCH3, -CH2(0)C(=0)N(CH3)C2H5,-CH2(0)C(=0)N(CH3)2, -CH2(0)C(=0)N(C2H5)2, -CH2(0)C(=0)Mi(cyclopentyl), -CH2(0)C(=0)Mi(tetrahydrofuranyl), -CH2(0)(pyridin-2-yl), or -CH2(0)(pyrimidin-2-yl); and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

24. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 23, wherein RE, Rr, and RGare each independently hydrogen, F, -CH(OH)CH3, -CHs, -CH2CN, -CH2OH, or -CH2OCH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

25. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 24 represented by one of the following structural formulae:wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

26. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 25 represented by one of the following structural formulae:(Vile); wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

27. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 26 represented by one of the following structural formulae:(Vllle); wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

28. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 27 represented by one of the following structural formulae:(IXe); wherein n is an integer selected from 0, 1, and 2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

29. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 28, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C6 alkoxy, C1-C6 haloalkyl, -NRhR', or C3-C6 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or C1-C4 alkyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

30. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 29, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C4 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C4 alkoxy, C1-C4 haloalkyl, -NRhR‘, or C3-C5 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or C1-C4 alkyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

31. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 30, wherein R2, for each occurrence, is independently hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C2 haloalkyl, -NRhR‘, or C3-C4 cycloalkyl; wherein Rhand R', for each occurrence, are each independently hydrogen or -CH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

32. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 31, wherein R2, for each occurrence, is independently hydrogen, F, Cl, cyano, -CH3, -CHF2, -CF3, -NH2, or cyclopropyl; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

33. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 32, wherein R3, for each occurrence, is independently halogen, cyano, =0, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw, -C(=0)NRv0Ry,-C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C4 alkyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)0Ry, and -NRVRW; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or Ci-C2alkyl; wherein the Ci-C2alkyl of any one of Rv, Rw, and Rxis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2; andRy, for each occurrence, is independently hydrogen, C1-C4 alkyl, or 5 or 6-memberedheterocyclyl; wherein: the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=0)0H; and the 5 or 6-memberedheterocyclyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=0)0H; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

34. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 33, wherein R3, for each occurrence, is independently halogen, cyano, =0, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw,-C(=0)NRv0Ry, -C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C4 alkyl of R3is optionally substituted with 1 to 3 groups selected from cyano, -ORyand -C(=0)0Ry; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or C1-C4 alkyl; wherein the C1-C4 alkyl of any one of Rv, Rw, and Rxis optionally substituted with -OH; andRy, for each occurrence, is independently hydrogen, Ci-C2alkyl, or 6- memberedheterocyclyl; wherein:the C1-C2 alkyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0H; and the 6-membered heterocyclyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0H;Rz, for each occurrence, is independently -CH3, -OH, or -OCH3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

35. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 34, wherein R3, for each occurrence, is independently halogen, cyano, =0, C1-C2 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -C(=0)NRvRw,-C(=0)NRv0Ry, -C(=0)NRvS(=0)2Ry, -NRVRW, - ORy, -S(=0)2Ry, -S(=0)2NRVRw, -S(=0)2NRvC(=0)Ry, or -P(=0)RzRz; wherein: the C1-C2 alkyl of R3is optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0Ry; wherein:Rv, Rw, and Rx, for each occurrence, are each independently hydrogen or C1-C2 alkyl; wherein the C1-C2 alkyl of any one of Rv, Rw, and Rxis optionally substituted with -OH; andRy, for each occurrence, is independently hydrogen, C1-C2 alkyl, or tetrahydro-2H-pyranyl; wherein: the C1-C2 alkyl of Ryis optionally substituted with -C(=0)0H; and the tetrahydro-2H-pyranyl of Ryis optionally substituted with 1 to 3 groups selected from -OH and -C(=0)0H;Rz, for each occurrence, is independently -CH3 or -OH; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

36. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 35, wherein R3, for each occurrence, is independently F, Cl, cyano, -OH, =0, -CH3, -OCH3, -CF3, -CH3CN, -C(CH3)2CH2OH, -CH2COOH, -CH2OCH3, -C(=0)CHCH30H, -COOH, -C(=0)0(2-tetrahydro-2H-pyranyl), -C(=0)NH2, -C(=0)NH(CH2)20H, -C(=0)NH0H, -C(=0)NHS(=0)2CH3, -NH2, -NHCH3,-OCH2COOH, NHS(=0)2CH3,-S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHC(=0)CH3, or-P(=0)(CH3)2; wherein the 2-tetrahydro-2H-pyranyl in -C(=0)0(2-tetrahydro-2H-pyranyl) is substituted with 1 to 3 groups selected from -OH and -C(=0)0H; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

37. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 36, wherein R4, for each occurrence, is independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl,-C(=0)Ry, -C(=0)0Ry, -ORy, or -S(=0)2Ry; wherein: the Ci-Ce alkyl of R4is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)0Ry, and -NRVRW; wherein:Rvand Rw, for each occurrence, are each independently hydrogen or C1-C4 alkyl; andRy, for each occurrence, is independently hydrogen and C1-C4 alkyl; wherein: the C1-C4 alkyl of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

38. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 37, wherein R4, for each occurrence, is independently halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=0)Ry,-C(=0)0Ry, -ORy, or -S(=0)2Ry; wherein: the C1-C4 alkyl of R4is optionally substituted with 1 to 3 groups selected from cyano, -ORy, -C(=0)0Ry, and -NRVRW; wherein:Rvand Rw, for each occurrence, are each independently hydrogen or C1-C4 alkyl;Ry, for each occurrence, is independently hydrogen or C1-C2 alkyl; wherein: the C1-C2 alkyl of any one of Ryis optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2; and wherein 0 is an integer selected from 0, 1, and 2; andwherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

39. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 38, wherein R4, for each occurrence, is independently cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=0)Ry, -C(=0)0Ry, -ORy, or - S(=0)2Ry; wherein: the C1-C2 alkyl of R4is optionally substituted with cyano, -OH, or -OCH3;Ry, for each occurrence, is independently hydrogen or C1-C2 alkyl; wherein: the C1-C2 alkyl of Ryis optionally substituted with -OCH3; wherein 0 is an integer selected from 0 and 1; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

40. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 39, wherein R4, for each occurrence, is independently cyano, -OH, -OCH3, -CH3, -C2H5, -CF3, -CH2CN, -CH2OH, -CH2OCH3, -COOH,-C(=0)CH3, -C(=0)0CH3, -C(=0)CH20CH3, -S(=0)2CH3, S(=0)2C2H5, or S(=0)2CF3; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

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

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

43. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 40, wherein U is halogen; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

44. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 40, wherein U is fluoro; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

45. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 40, wherein U is hydrogen; and wherein all other variables not specifically defined herein are as defined in any one of the preceding claims.

46. A compound selected from Compounds 1-457, Compounds 458-532, Compounds B1-B25, Compounds W1-W32, and Compounds P1-P225, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.

47. A compound selected from Compounds 1-457, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.

48. A compound selected from Compounds 458-532, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.

49. A compound selected from Compounds B1-B25 and Compounds W1-W32, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.

50. A compound selected from Compounds P1-P225, tautomers thereof, deuterated derivatives of those compounds and tautomers and pharmaceutically acceptable salts of the compounds, tautomers, and deuterated derivatives.

51. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 50, a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

52. A method of treating alpha- 1 antitrypsin (AAT) deficiency comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to50, or a therapeutically effective amount of a pharmaceutical composition according to claim51.

53. A method of modulating alpha- 1 antitrypsin (AAT) activity comprising the step of contacting said AAT with a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 50, or a therapeutically effective amount of a pharmaceutical composition according to claim 51.

54. The method of claim 52 or claim 53, wherein said therapeutically effective amount of the at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt is administered in combination with AAT augmentation therapy and / or AAT replacement therapy.