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

Abstract

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

Description

[Technical Field] 【0001】 This application claims priority to U.S. Provisional Patent Application No. 63 / 004,717, filed on 3 April 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology] 【0002】 This disclosure provides compounds that can modulate alpha-1 antitrypsin (AAT) activity, and methods for treating alpha-1 antitrypsin deficiency (AATD) by administering one or more such compounds. 【0003】 AATD is a genetic disorder characterized by low circulating levels of AAT. While treatments exist for AATD, there is currently no cure. AAT is primarily produced and secreted into the bloodstream by hepatocytes, but is also produced by lung epithelial cells and other cell types, including certain leukocytes. 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 lungs from protease-induced damage, especially during periods of inflammation. 【0004】 The most commonly associated mutation in AATD involves a lysine substitution (E342K) for glutamate in the SERPINA1 gene, which encodes the AAT protein. This mutation, known as the Z mutation or Z allele, results in misfolding of the translated protein, and therefore the protein is not secreted into the bloodstream but can polymerize within the producing cell. As a result, homozygous circulating AAT levels in individuals with the Z allele (PiZZ) are significantly reduced, with only about 15% of the mutant Z-AAT protein correctly folding and being secreted from cells. Further findings regarding the Z mutation indicate that secreted Z-AAT has reduced activity compared to the wild-type protein, being 40%–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 in hepatocytes leads to gain-of-function cytotoxicity, causing cirrhosis or liver cancer later in life and potentially leading to neonatal liver disease in 12% of patients. While this accumulation may resolve spontaneously, it can be fatal in a small number of children. Deficiency of circulating AAT leads to 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, typically appearing in middle age and resulting in a reduced quality of life and shortened lifespan (average age 68) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016;11:1663-9). This effect is more pronounced in smoking PiZZ individuals, resulting in a further shortened lifespan (58 years) (Piitulainen and Tanash, COPD 2015;12(1):36-41). PiZZ individuals constitute the majority of people with clinically relevant AATD lung disease. Therefore, there is a need for further and effective treatment of AATD. A milder form of AATD is associated with the SZ genotype, in which the Z allele is combined with the S allele. The S allele is associated with somewhat reduced levels of circulating AAT but does not cause cytotoxicity in liver cells. The result is clinically significant lung disease but no liver disease. (Fregonese and Stolk, Orphanet J Rare Dis. 2008;33:16). Similar to the ZZ genotype, a deficiency in circulating AAT in subjects with the SZ genotype results in unregulated protease activity that degrades lung tissue over time, potentially leading to emphysema, especially in smokers. [Prior art documents] [Non-patent literature] 【0006】 [Non-Patent Document 1] Tanash et al.Int J Chron Obstruct Pulm Dis.2016;11:1663-9 [Non-Patent Document 2] Piitulainen and Tanash, COPD 2015;12(1):36-41 [Non-Patent Document 3] Fregonese and Stolk,Orphanet J Rare Dis.2008;33:16 [Overview of the Initiative] [Means for solving the problem] 【0007】 The current standard of care for individuals with AAT deficiency who have or show signs of developing significant lung or liver disease is augmentation therapy or replacement therapy. Augmentation therapy involves administering human AAT protein concentrate purified from pooled donor plasma to augment the deleted AAT. While plasma protein infusions have been shown to improve survival rates or slow the rate of emphysema progression, augmentation therapy is often insufficient under challenging conditions, such as during active lung infections. Similarly, protein replacement therapy shows promise in delaying disease progression, but augmentation does not restore normal physiological regulation of AAT in patients, and its efficacy has been difficult to demonstrate. In addition, augmentation therapy requires weekly hospital visits for treatment, and it cannot address liver disease driven by the toxic gain-of-function of the Z allele. Therefore, novel and more effective treatments for AATD remain needed. [Modes for carrying out the invention] 【0008】 One aspect of the present disclosure provides compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe)), and tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives, which can be used for the treatment of AATD. For example, a compound of formula (I), a tautomer thereof, a deuterated derivative of these compounds or tautomers, or a pharmaceutically acceptable salt of any of the foregoing can be represented as follows, [Chemical formula] In the formula, [Chemical formula] is, for each of the two occurrences, a single bond or a double bond, provided that one is a single bond and the other is a double bond, V a , d , p , b , , q , c and V 2 are each independently N or -CR 2 where, W 1 and W 2 are each independently N or C, provided that one of W 1 and W 2 is N and the other is C, U is hydrogen, -OH, -CH3, -NH2, or halogen, X is absent or a bond, -(CR a R b ) p -, or -SO2-, Y is absent or a bond, -(CR c R d ) q-, -C(=O)-, or -SO2-, R a and R b Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. R c and R d Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. Ring A is C3-C 12 Carbocyclyl, 3-12 member heterocyclyl, C6 or C 10 An aryl or a 5-10 member heteroaryl, provided that W 1 N is W 2 If C, then ring A is not 1,5,6,7-tetrahydro-4H-indole-4-onyl or its tautomer, Ring B is C4-C 12 Cycloalkyl, C6 or C 10 It is an aryl, a 5-10 membered heteroaryl, or benzyl. Z is [ka] And in the formula, Ring C is C3-C 12 Cycloalkyl, 3-12 membered heterocyclyl, C6 or C 10 It is an aryl or a 5-10 member heteroaryl, However, if the C ring is phenyl, then the phenyl is R 4 Substituted with, however, if ring C is phenyl, Y must not be -SO2-, However, if ring B is benzyl, ring C must not be pyridinyl or indolyl. R E , R F , and R GEach of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(=O)R s , -C(=O)OR s -C(=O)NR p R q ,-CR p (=N)OR s , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -OR s -OC(=O)R s , or -OC(=O)NR p R q And, R E , R F , and R G Any one of the above C1-C6 alkyl or C2-C6 alkenyl is cyano, -C(=O)R s , -C(=O)OR s -C(=O)NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s 、 -OR s -OC(=O)R s , -OC(=O)OR s -OC(=O)NR p Rq, -S (=O) r R s , and -S(=O) r NR p It is optionally replaced by 1 to 3 groups selected from Rq, R p , R q, and R r Each of these is independently a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3-6 member heterocycline. R p , R q , and R r Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R p , R q , and R r Any one of the above C3-C6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1-3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O(C1-C2 alkyl), -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R s Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. R s The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R sThe above C3-C6 cycloalkyl, the above phenyl, or the above 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2, R 1 is halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or -O-(C3-C6 cycloalkyl), R 2 is, for each occurrence, independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, R 2 The above C1-C6 alkyl, the above C2-C6 alkenyl, or the above C3-C6 cycloalkyl is cyano, -C(=O)R k -C(=O)OR k -C(=O)NR h R i -NR h R i -NR h C(=O)R k -NR h C(=O)OR k -NR h C(=O)NR i R j -NR h S(=O) s R k 、 -OR k -OC(=O)R k -OC(=O)OR k -OC(=O)NR h R i -S(=O) s R k, and S(=O) s NR h R i It is optionally replaced by 1 to 3 bases selected from, R h , R i , and R j Each of these occurrences is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. R h , R i , and R j Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R h , R i , and R j Any one of the above C3-C6 cycloalkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. -OR k R must not be -OH, kThe above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k The above C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 3 and R 4 For each of these occurrences, independently, they are halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) t R y 、 -OR y-OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y -S(=O) t NR v R w -S(=O) t NR v C(=O)R y ,-P(=O)R z R z , phenyl, or a 5- or 6-membered heteroaryl, R 3 and R 4 Any one of the above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) r R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y , and -S(=O) t NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R xEach of these occurrences is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocycline, or a 5- or 6-membered heteroaryl group. R v , R w , and R x Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R v , R w , and R x Any one of the above C3-C6 cycloalkyls, the above 5- or 6-membered heterocyclil, or the above 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R y Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a 5- or 6-membered heterocycline group, or a 5- or 6-membered heteroaryl group. R yThe above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R y The above C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R z Each of these occurrences is independently C1-C2 alkyl, -OH, or -O(C1-C2 alkyl). k is an integer selected from 1, 2, and 3. m and n are each independently integers selected from 0, 1, 2, and 3. p, r, s, and t are each independently integers selected from 1 and 2. q is an integer selected from 1, 2, and 3. 【0009】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, U is -OH, -CH3, -NH2, or a halogen, and all other variables are as defined in formula (I). 【0010】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables are as defined by formula (I). 【0011】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, U is -OH, -CH3, -NH2, or a halogen, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables are as defined in formula (I). 【0012】 Compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (for example, compounds of (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe)) are modulators of AAT activity. In some embodiments, compounds of formulas (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives have an EC of 2.0 μM or less when tested by an AAT functional assay. 50In some embodiments, compounds of formulas (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives have an EC of less than 0.5 μM when tested by an AAT functional assay. 50 It holds. 【0013】 In some embodiments, compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (for example, compounds of formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives exhibit an IC50 or less IC50 when tested by a Z-AAT elastase activity assay. 50It has the following characteristics. In some embodiments, compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (for example, compounds of formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives exhibit an IC50 of less than 2.0 μM when tested by a Z-AAT elastase activity assay. 50 It holds. 【0014】 In some embodiments, compounds of formulas (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives have an EC of 2.0 μM or less when tested by an AAT functional assay. 50 It possesses an IC50 of 5.0 μM or less when tested by the Z-AAT elastase activity assay. 50In some embodiments, compounds of formulas (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives have an EC of less than 0.5 μM when tested by an AAT functional assay. 50 It possesses an IC50 of 5.0 μM or less when tested by the Z-AAT elastase activity assay. 50 It has the following characteristics. In some embodiments, compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (for example, compounds of formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives have an EC of 2.0 μM or less when tested by AAT functional assay. 50 It possesses an IC50 of less than 2.0 μM when tested by the Z-AAT elastase activity assay. 50In some embodiments, compounds of formulas (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives have an EC of less than 0.5 μM when tested by an AAT functional assay. 50 It possesses an IC50 of less than 2.0 μM when tested by the Z-AAT elastase activity assay. 50 It holds. 【0015】 In some embodiments, compounds of formulas (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives are provided for use in the treatment of AATD. In some embodiments, the compounds are compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (for example, compounds 1-457, for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), compounds 1-45 7. Compounds 458-532, compounds P1-P225, compounds B1-B25, and tautomers of compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., tautomers of compounds 1-457), deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, are selected for use in the treatment of AATD. In one embodiment, the compound of formula (I) is selected from compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, are selected for use in the treatment of AATD. 【0016】 In some embodiments, the present disclosure provides pharmaceutical compositions comprising compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe)), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and at least one compound selected from pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition may comprise compounds selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional pharmaceutically active ingredient and / or at least one carrier. These compositions may further comprise at least one additional pharmaceutically active ingredient and at least one carrier. These compositions may further contain at least one additional pharmaceutically active ingredient or at least one carrier. 【0017】 In some embodiments, the present disclosure provides pharmaceutical compositions comprising compounds of formula (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), (Xa)~(Xf), (XIa)~(Xe), and (XIIa)~(XIIe) (e.g., compounds of formula (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe)), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and at least one compound selected from pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the pharmaceutical composition may comprise compounds selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W32 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional pharmaceutically active ingredient and / or at least one carrier. 【0018】 Another aspect of this disclosure relates to compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (e.g., formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(V The present invention provides a method for treating AATD, comprising administering to a subject in need a pharmaceutical composition comprising at least one compound selected from compounds IIe) and (IXa) to (IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and any of the pharmaceutically acceptable salts described herein, or at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, the method involves 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the subject requiring treatment is histologically diagnosed with a ZZ mutation. In some embodiments, the subject requiring treatment harbors an SZ mutation. 【0019】 In some embodiments, the therapeutic method comprises administering at least one additional activator to a subject requiring it, either in the same pharmaceutical composition as at least one compound selected from the compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (e.g., the compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as a separate composition. In some embodiments, the method involves administering compounds selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with at least one additional activator, either in the same pharmaceutical composition or in a separate composition. In some embodiments, the subject requiring treatment harbors a ZZ mutation. In some embodiments, the subject requiring treatment harbors an SZ mutation. 【0020】 In some embodiments, the treatment method involves compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (for example, formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and The administration of at least one additional activator to a subject requiring it, either in the same pharmaceutical composition as at least one compound selected from the compounds (IXa) to (IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as a separate composition, wherein the additional activator is alpha-1 antitrypsin protein (AAT) from the plasma of a healthy human donor. In some embodiments, the method comprises 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with at least one additional activator, either in the same pharmaceutical composition or in a separate composition, wherein the additional activator is alpha-1 antitrypsin protein (AAT) from the plasma of a healthy human donor. 【0021】 In some embodiments, the treatment method involves compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (for example, formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe) The present invention comprises administering at least one additional activator to a subject requiring it, either in the same pharmaceutical composition as at least one compound selected from the compounds (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as a separate composition, wherein the additional activator is recombinant AAT. In some embodiments, the method involves 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, together with at least one additional activator, either in the same pharmaceutical composition or in a separate composition, wherein the additional activator is recombinant AAT. 【0022】 Furthermore, compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (for example, formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe The present invention also provides a method for modulating AAT, comprising administering to a subject requiring it a pharmaceutical composition comprising (IXa) to (IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition comprising this at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. In some embodiments, a method for adjusting the above AAT includes administering a pharmaceutical composition comprising: compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457); tautomers of these compounds; deuterated derivatives of these compounds and tautomers; and at least one compound selected from any pharmaceutically acceptable salt of the foregoing; or at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. 【0023】 Another aspect of the present disclosure provides compounds B1-B25 and W1-W32 that can be used in the treatment of AATD, as well as tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of these compounds, tautomers, or deuterated derivatives. 【0024】 In some embodiments, the present disclosure provides pharmaceutical compositions comprising compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and at least one compound selected from pharmaceutically acceptable salts of any of the foregoing. These compositions may further comprise at least one additional pharmaceutically active ingredient and / or at least one carrier. 【0025】 Another aspect of the present disclosure provides a method for treating AATD, comprising administering to a subject in need of it a pharmaceutical composition comprising at least one compound selected from compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or at least one such compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt. 【0026】 In some embodiments, the therapeutic method comprises administering at least one additional activator to a subject in need, either in the same pharmaceutical composition as at least one compound selected from compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or as a separate composition. In some embodiments, the subject in need of treatment harbors a ZZ mutation. In some embodiments, the subject in need of treatment harbors an SZ mutation. 【0027】 In some embodiments, the therapeutic method comprises administering to a subject in need at least one additional activator, either in the same pharmaceutical composition as, or as a separate composition from, at least one compound selected from the compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the additional activator being alpha-1 antitrypsin protein (AAT) from the plasma of a healthy human donor. 【0028】 In some embodiments, the therapeutic method comprises administering at least one additional activator to a subject requiring it, either in the same pharmaceutical composition as, or as a separate composition from, at least one compound selected from compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein the additional activator is recombinant AAT. 【0029】 The present invention also provides a method for adjusting AAT, which involves administering a pharmaceutical composition to a subject requiring it, comprising at least one compound selected from compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, or at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof. 【0030】 The present invention also provides compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) for therapeutic use (for example, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe)), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, compounds are provided for therapeutic use, selected from compounds 1-457, compounds 458-531, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 【0031】 The present invention also provides pharmaceutical compositions for therapeutic use, comprising compounds of formulas (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc), (VIa)-(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (for example, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, pharmaceutical compositions are provided for therapeutic use, comprising compounds selected from compounds 1-457, compounds 458-531, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 【0032】 Also provided are compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32) for therapeutic use, as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, compounds selected from compounds B1 to B25 and compounds W1 to W32, as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided. 【0033】 Also provided are pharmaceutical compositions for therapeutic use comprising compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, pharmaceutical compositions are provided comprising compounds selected from compounds B1 to B25 and compounds W1 to W32, as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 【0034】 I. Definition As used herein, the term "AAT" means alpha-1 antitrypsin or its variants, including but not limited to AAT gene mutations such as Z mutations. As used herein, "Z-AAT" means an AAT variant having a Z mutation. 【0035】 As used herein, “mutation” may refer to a mutation in the SERPINA1 gene (the gene encoding AAT) or an alteration in the gene sequence of the AAT protein. “SERPINA1 gene mutation” refers to a mutation in the SERPINA1 gene, and “AAT protein mutation” refers to a mutation that results in an alteration in the amino acid sequence of the AAT protein. Genetic defects or mutations, or changes in nucleotides within a gene, generally result in mutations 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 in each allele. 【0037】 As used herein, a patient with the PiZZ genotype is a patient who is homozygous for the Z mutation in the AAT protein. 【0038】 As used herein, the term "AATD" refers to alpha-1 antitrypsin deficiency, a genetic disorder characterized by low circulating levels of AAT. 【0039】 The term “compound,” when referring to the compounds of this disclosure, means an assembly of molecules having the same chemical structure unless otherwise indicated as an assembly of stereoisomers (e.g., an assembly of racemic compounds, an assembly of cis / trans stereoisomers, or an assembly of (E) and (Z) stereoisomers), except that isotopic variation may exist between the constituent atoms of the molecules. Therefore, it will be apparent to those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom may also contain a smaller amount of isotopic substitutions having hydrogen atoms in one or more of the designated deuterium positions in its structure. The relative amount of such isotopic substitutions in the compounds of this disclosure will depend on several factors, including the isotopic purity of the reagents used to prepare the compounds and the efficiency of isotopic incorporation in the various synthetic steps used to prepare the compounds. However, as stated above, the relative amount of such isotopic substitutions overall will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotope substitutions is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound overall. 【0040】 The compounds of this disclosure may be optionally substituted with one or more substituents. It should be understood that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Generally, the term “substituted,” whether preceded by the term “optionally,” refers to the substitution of a hydrogen radical in a given structure with the radical of a particular substituent. Unless otherwise indicated, an “optionally substituted” group may have substituents at each substitutedable position of the group, and if two or more positions in any given structure are substituted with two or more substituents selected from a particular group, the substituents may be the same or different at all positions. The substituent combinations envisioned by this disclosure result in the formation of stable or chemically feasible compounds. 【0041】 The term "isotope-substituted compound" refers to a species whose chemical structure differs from a particular compound in this disclosure solely in terms of its isotopic composition. In addition, unless otherwise specified, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, by substitution of hydrogen with deuterium or tritium, or 13 C or 14 Apart from the substitution of carbon by C, compounds having this structure are within the scope of this disclosure. 【0042】 Unless otherwise specified, the structures shown herein also include all isomeric forms of the structures, such as geometric (or conformational) isomers, including racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds disclosed herein are within the scope of this disclosure. Unless otherwise specified, all tautomers of the compounds disclosed herein are within the scope of this disclosure. 【0043】 As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily exchanged by the movement of atoms or groups within the molecule. 【0044】 "Stereoisomers" refer to both enantiomers and diastereomers. 【0045】 As used herein, “deuterated derivative” refers to a compound having the same chemical structure as the reference compound, but in which one or more hydrogen atoms are replaced by deuterium atoms ("D"). It will be recognized that some variation in the natural isotopic abundance occurs in the synthesized compound depending on the origin of the chemicals used in the synthesis. Despite this variation, the concentrations of naturally occurring stable hydrogen isotopes are small and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein. Therefore, unless otherwise specified, when referring to a “deuterated derivative” of a compound in this disclosure, at least one hydrogen is replaced by deuterium to a degree considerably higher than its natural isotopic abundance (typically about 0.015%). In some embodiments, the deuterated derivatives of the present disclosure have an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation in each designated deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation) for each deuterium atom. 【0046】 As used herein, the term “isotope enrichment factor” means the ratio of the isotopic abundance to the natural abundance of a particular isotope. 【0047】 As used herein, the term “alkyl” means a linear (i.e., linear or unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or may contain one or more saturated units, but is not fully aromatic. Unless otherwise specified, alkyl groups contain 1 to 12 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 10 aliphatic carbon atoms. In other embodiments, alkyl groups contain 1 to 8 aliphatic carbon atoms. In yet another embodiment, alkyl groups contain 1 to 6 alkyl carbon atoms, in yet another embodiment, alkyl groups contain 1 to 4 alkyl carbon atoms, and in yet another embodiment, alkyl groups contain 1 to 3 alkyl carbon atoms and 1 to 2 alkyl carbon atoms. 【0048】 As used herein, the term "heteroalkyl" means an aliphatic group in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroalkyl groups may be substituted or unsubstituted, and branched or unbranched substituted. 【0049】 As used herein, the term “alkenyl” means a linear (i.e., linear or unbranched), branched, substituted or unsubstituted hydrocarbon chain containing one or more carbon-carbon double bonds. 【0050】 The terms "cycloalkyl," "cyclic alkyl," "carbocykrill," or "carbocyclic" refer to condensed, spirocyclic, or cross-linked monocyclic C atoms. 3~9 Hydrocarbons, or condensed, spirocyclic, or bridging bicyclic or tricyclic carbons that are fully saturated or may contain one or more saturated units but are not fully aromatic. 8-14This refers to hydrocarbons, where any individual ring in the aforementioned bicyclic ring system has 3 to 9 members. Typically, cycloalkyls are completely saturated, while carbocyclyls may contain one or more unsaturated units but are not aromatic. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 12 carbon atoms. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 8 carbon atoms. In some embodiments, the cycloalkyl or carbocyclic group contains 3 to 6 carbon atoms. 【0051】 As used herein, the terms “heterocyclic,” “heterocyclyl,” or “heterocyclic formula” mean a condensed, spirocyclic, or bridging non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are heteroatoms. In some embodiments, the “heterocyclic,” “heterocyclyl,” or “heterocyclic formula” group has 3 to 14 ring members, with one or more ring members being heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, or silicon, and each ring in the system contains 3 to 9 ring members. In some embodiments, the 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" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen, or a substituteable nitrogen in a heterocycle, e.g., N(3,4-dihydro-2H-pyrrolyl), NH(in the case of pyrrolidinyl), or NR) + This means one or more of the following (including the case of N-substituted pyrrolidinyl): 【0053】 As used herein, the term “alkoxy” means an alkyl group as already defined, wherein one carbon atom of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is bonded between two carbon atoms. “Cyclic alkoxy” means a monocyclic, condensed, spirocyclic, bicyclic, bridging bicyclic, tricyclic, or bridging tricyclic hydrocarbon containing at least one alkoxy group but 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" mean, depending on the context, an alkyl or alkoxy that is substituted with one or more halogen atoms. The term "halogen" 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 perhaloalkyls, such as -CF2CF3. 【0055】 As used herein, the "=O" group refers to an oxo group. 【0056】 As used herein, the "cyano" or "nitrile" group refers to -C≡N. 【0057】 As used herein, the "hydroxy" group refers to the -OH group. 【0058】 As used herein, "aromatic group" or "aromatic ring" refers to a chemical group containing a conjugated planar ring system having a delocalized pi electron orbital consisting of [4n+2]p orbital electrons, where n is an integer between 0 and 6. Non-limiting 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, with at least one ring in the system being aromatic and each ring containing 3 to 7 ring members. In some embodiments, the aryl group contains 6 or 10 carbon atoms. A non-limiting example of an aryl group is the phenyl ring. 【0060】 The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 10 ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the system contains 3 to 7 ring members. In some embodiments, heteroaryls contain 6 or 10 ring atoms. 【0061】 Examples of protecting groups useful for nitrogen-containing groups such as amine groups include, for example, t-butylcarbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethylcarbamate (Fmoc), benzylcarbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods for adding (a process generally referred to as "protecting") and removing (a process generally referred to as "deprotecting") such amine protecting groups are well known in the art and are available, for example, in PJ Kocienski, Protecting Groups, Thieme, 1994, and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which are incorporated herein by reference in their entirety. 【0062】 Examples of suitable solvents that may be used in this disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (SiO), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP). 【0063】 Examples of suitable bases that may be used in this disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N,TEA), diisopropylethylamine (i-Pr2EtN;DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe;NaOCH3). 【0064】 This disclosure includes pharmaceutically acceptable salts of the compounds disclosed. Salts of the compounds are formed between an acid and a basic group of the compound, such as an amino acid functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group. 【0065】 As used herein, the term “pharmaceutically acceptable” means a component that, within the bounds of sound medical judgment, is suitable for use in contact with human and other mammalian tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. “pharmaceutically acceptable salt” means any non-toxic salt that can directly or indirectly provide the compounds of this disclosure to a recipient upon administration. Suitable pharmaceutically acceptable salts are disclosed, for example, in SMBerge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. 【0066】 Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Therefore, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, capries, acrylates, formates, isobutyrates, caprinates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butyn-1,4-dicarboxylates, and hexyn-1,6-dicarboxylates. These include carboxylates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfons, xylenesulfons, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfons, propanesulfons, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed from inorganic acids such as hydrochloric acid and hydrobromic acid, and those formed from organic acids such as maleic acid. 【0067】 pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1-4This includes alkyl) 4 salts. This disclosure also assumes quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Preferred non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, phosphates, nitrates, lower alkyl sulfons and aryl sulfons. Other preferred non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts. 【0068】 The terms "patient" and "subject" are used interchangeably and refer to animals, including humans. 【0069】 The terms “effective dose,” “effective amount,” “therapeutic effective dose,” and “therapeutic effective dose” are used interchangeably herein and refer to the amount of compound administered that produces the desired effect (e.g., improvement of AATD or symptoms of AATD, reduction of the severity of AATD or symptoms of AATD, and / or reduction of the onset or incidence of AATD or symptoms of AATD). The exact amount of the effective dose depends on the therapeutic purpose and can be determined by those skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). 【0070】 As used herein, the terms “treatment” and its related terms (e.g., “to treat,” “to treat”) mean improvement of AATD or its symptoms in a subject, delay of the onset of AATD or its symptoms in a subject, or reduction of the severity of AATD or its symptoms in a subject. As used herein, “treatment” and its related terms include, but are not limited to, improvement of liver and / or spleen function, reduction of macular degeneration, improvement of lung function, reduction of lung disease and / or lung exacerbation (e.g., emphysema), reduction of skin disease (e.g., necrotizing panniculitis), increased growth in children, improved appetite, and reduced fatigue. Improvement or reduction of the severity of any of these symptoms can be readily assessed according to methods and techniques known or subsequently developed in the art. 【0071】 The terms “about” and “approximately,” when used in relation to the dose, volume, or weight percentage of an ingredient in a composition or dosage form, include a specific dose, volume, or weight percentage value, or range of doses, volumes, or weight percentages, that a person skilled in the art would recognize as providing the same pharmacological effect as that obtained by a particular dose, volume, or weight percentage. Typically, the term “about” refers to a variation of up to 10%, up to 5%, or up to 2% of the stated value. 【0072】 Compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (for example, compounds of formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe)), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and any one or more pharmaceutically acceptable salts of any of the foregoing may be administered once daily, twice daily, or three times daily for the treatment of AATD. In some embodiments, any one or more compounds are selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the above. In some embodiments, at least one compound selected from compounds of formula (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formula (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the above, is administered once daily.In some embodiments, compounds 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 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, at least one compound selected from compounds of formula (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formula (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the above, is administered twice daily. In some embodiments, compounds 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 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered twice daily.In some embodiments, at least one compound selected from compounds of formula (I), (IIa) to (IIg), (IIIa) to (IIIc), (IVa) to (IVb), (Va) to (Vc), (VIa) to (VIg), (VIIa) to (VIIg), (IXa) to (IXe), and (Xa) to (Xf) (for example, compounds of formula (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe)), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the above is administered three times daily. In some embodiments, compounds 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 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered three times daily. 【0073】 Compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (for example, compounds of formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe)), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and any one or more pharmaceutically acceptable salts of any of the foregoing may be administered in combination with AAT augmentation therapy or AAT replacement therapy for the treatment of AATD. In some embodiments, any one or more compounds are selected from compounds 1-457, compounds 458-532, compounds P1-P225, compounds B1-B25, and compounds W1-W4, W6-W23, W25, W26, W28, W30, and W31 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing. 【0074】 Any one or more of the compounds B1-B25 and W1-W32, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and any pharmaceutically acceptable salts of any of the foregoing may be administered once daily, twice daily, or three times daily for the treatment of AATD. In some embodiments, at least one compound selected from the compounds of formulas (XIa)-(XIe) and (XIIa)-(XIIe) (e.g., compounds B1-B25 and compounds W1-W32), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and any pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one compound selected from compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily. In some embodiments, at least one compound selected from compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered three times daily. 【0075】 Any one or more of the compounds B1-B25 and W1-W32, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and any 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) derived from the plasma of a healthy human donor to augment (increase) alpha-1 antitrypsin levels circulating in the blood. “AAT replacement therapy” refers to the administration of recombinant AAT. 【0077】 In some embodiments, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) in amounts of 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 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, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the foregoing are administered once, twice, or three times daily. In some embodiments, compounds 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 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) are administered once, twice, or three times a day in doses of 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, or 400 mg to 600 mg. 【0078】 In some embodiments, compounds selected from compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the above, in doses of 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, 400 mg to 2,500 mg, or 400 mg to 600 mg, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and pharmaceutically acceptable salts of any of the above, are administered once, twice, or three times daily. In some embodiments, compounds selected from compounds of formulas (XIa) to (XIe) and (XIIa) to (XIIe) (e.g., compounds B1 to B25 and compounds W1 to W32), in doses of 10 mg to 1,500 mg, 100 mg to 1,800 mg, 100 mg to 500 mg, 200 mg to 600 mg, 200 mg to 800 mg, 400 mg to 2,000 mg, or 400 mg to 600 mg, are administered once, twice, or three times a day. 【0079】 Those skilled in the art will recognize that, when a quantity of a compound is disclosed, the corresponding quantity of a pharmaceutically acceptable salt form of the compound is equivalent to the concentration of the free base of that compound. Note that the disclosed quantities of compounds, tautomers, deuterated derivatives, and pharmaceutically acceptable salts are based on the free base form of the reference compound. For example, “10 mg of the compound of formula (I) and at least one compound selected from its pharmaceutically acceptable salts” includes 10 mg of the compound of formula (I) and the concentration of a pharmaceutically acceptable salt of the compound of formula (I) equivalent to 10 mg of the compound of formula (I). 【0080】 As used herein, the term “ambient conditions” means room temperature, open air conditions, and uncontrolled humidity conditions. 【0081】 Treatment methods (for example, one or more compounds (for example, compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)-(VIIg), (IXa)-(IXe), and (Xa)-(Xf) (for example, compounds of formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe)), and tautomers of these compounds) References herein to therapeutic methods (e.g., methods for treating AATD) using these compounds and their deuterated derivatives, as well as pharmaceutically acceptable salts thereof) include: - For example, one or more compounds of formulas (I), (IIa)~(IIg), (IIIa)~(IIIc), (IVa)~(IVb), (Va)~(Vc), (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) for use in methods for treating AATD (e.g., compounds of formulas (I), (IIa)~(IIf Compounds of (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds) and / or - for example, one or more compounds (e.g., compounds of formula (I), (IIa)-(IIg), (IIIa)-(IIIc), (IVa)-(IVb), (Va)-(Vc) in the manufacture of a pharmaceutical product for treating AATD) It should be understood that this should also be interpreted as a reference to the use of (VIa)~(VIg), (VIIa)~(VIIg), (IXa)~(IXe), and (Xa)~(Xf) (for example, the compounds of formula (I), (IIa)-(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)-(VIe), (VIIa)~(VIIe), and (IXa)~(IXe), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of these compounds). 【0082】 Exemplary Embodiment 1: Non-limiting embodiments of this disclosure include: 1. Compounds represented by the following structural formulas, [ka] The tautomer, the compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, wherein the formula is: [ka] For each of the two occurrences, it is either a single bond or a double bond, provided that one is a single bond and the other is a double bond. V 1 and V 2 Each of these can be N or -CR independently. 2 And, W 1 and W 2 Each is independently N or C, except W 1 and W 2 One of them is N, and the other is C. U is -OH, -CH3, -NH2, or a halogen. X does not exist, or is combined with -(CR a R b ) p -, or -SO2-, Y does not exist or is combined with -(CR c R d ) q -, -C(=O)-, or -SO2-, R a and R b Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. R c and R dEach of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. Ring A is C3-C 12 Carbocyclyl, 3-12 member heterocyclyl, C6 or C 10 An aryl or a 5-10 member heteroaryl, provided that W 1 N is W 2 If C, then ring A is not 1,5,6,7-tetrahydro-4H-indole-4-onyl or its tautomer, Ring B is C4-C 12 Cycloalkyl, C6 or C 10 It is an aryl, a 5-10 membered heteroaryl, or benzyl. Z is [ka] And in the formula, Ring C is C3-C 12 Cycloalkyl, 3-12 membered heterocyclyl, C6 or C 10 It is an aryl or a 5-10 member heteroaryl, However, if the C ring is phenyl, then the phenyl is R 4 Substituted with, however, if ring C is phenyl, Y must not be -SO2-, However, if ring B is benzyl, ring C must not be pyridinyl or indolyl. R E , R F , and R G Each of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(=O)R s , -C(=O)OR s -C(=O)NR p R q ,-CR p (=N)OR s , -NR p C(=O)R s , -NRp C(=O)OR s , -NR p C(=O)NR q R r , -OR s -OC(=O)R s , or -OC(=O)NR p R q And, R E , R F , and R G Any one of the above C1-C6 alkyl or C2-C6 alkenyl is cyano, -C(=O)R s , -C(=O)OR s -C(=O)NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s 、 -OR s -OC(=O)R s , -OC(=O)OR s -OC(=O)NR p R q -S(=O) r R s , and -S(=O) r NR p R q It is optionally replaced by 1 to 3 bases selected from, R p , R q , and R r Each of these is independently a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3-6 member heterocycline. R p , R q , and R rAny one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R p , R q , and R r Any one of the above C3-C6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1-3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O(C1-C2 alkyl), -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R s Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. R s The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R s The above C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 1These are halogens, cyanos, C1-C3 alkyls, C1-C3 haloalkyls, C1-C3 alkoxys, C1-C3 haloalkoxys, or -O-(C3-C6 cycloalkyls). R 2 For each of these appearances, independently, hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NR h R i , phenyl, or a 5- or 6-membered heteroaryl, R 2 The above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R k , -C(=O)OR k -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) s R k 、 -OR k -OC(=O)R k , -OC(=O)OR k -OC(=O)NR h R i -S(=O) s R k , and S(=O) s NR h R i It is optionally replaced by 1 to 3 bases selected from, R h , R i , and R j Each of these occurrences is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. R h , R i , and Rj Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R h , R i , and R j Any one of the above C3-C6 cycloalkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. -OR k It must not be -OH, R k The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R kThe above C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 3 and R 4 For each of these occurrences, independently, they are halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) t R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y -S(=O) t NR v R w -S(=O) t NR v C(=O)R y ,-P(=O)R zR z , phenyl, or a 5- or 6-membered heteroaryl, R 3 and R 4 Any one of the above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) r R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y , and -S(=O) t NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x Each of these occurrences is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocycline, or a 5- or 6-membered heteroaryl group. R v , R w , and R xAny one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R v , R w , and R x Any one of the above C3-C6 cycloalkyls, the above 5- or 6-membered heterocyclil, or the above 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R y Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a 5- or 6-membered heterocycline group, or a 5- or 6-membered heteroaryl group. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R yThe above C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R z Each of these occurrences is independently C1-C2 alkyl, -OH, or -O(C1-C2 alkyl). k is an integer selected from 1, 2, and 3. m and na are each independently integers selected from 0, 1, 2, and 3. A compound, its tautomer, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, wherein p, q, r, s, and t are each independently integers selected from 1 and 2. 2. It is represented by one of the following structural formulas, [ka] During the ceremony, U is -OH, -CH3, -NH2, F, or Cl. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1, wherein all other variables not specifically defined in this embodiment are as defined in Embodiment 1. 3. Represented by one of the following structural formulas, [ka] During the ceremony, U is -OH, -CH3, -NH2, F, or Cl. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1, wherein all other variables not specifically defined in this embodiment are as defined in Embodiment 1. 4. It is represented by one of the following structural formulas, [ka] During the ceremony, U is -OH or -NH2, Ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6-9 member heterocyclyl, a phenyl, or a 5-9 member heteroaryl. Ring B is R 1 Substituted with, and ring B is a C4-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, or benzyl, Z, R 4 If ring C is optionally substituted, ring C is a C4-C8 cycloalkyl, a 4- to 8-membered heterocyclyl, a phenyl, or a 5 or 6-membered heteroaryl. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1 or Embodiment 2, wherein all other variables not specifically defined in this embodiment are as defined in Embodiment 1 or Embodiment 2. 5. Represented by one of the following structural formulas, [ka] During the ceremony, Ring B is R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, and 4, wherein ring B is substituted with and ring B is cyclohexyl, phenyl, pyridinyl, or benzyl, and all other variables not specifically defined in this embodiment are as defined in any one of Embodiments 1, 2, and 4. 6. It is represented by the following structural formula, [ka] During the ceremony, R 1 However, these are halogens, cyanos, C1-C2 alkyls, C1-C2 haloalkyls, or C1-C2 alkoxys. k is an integer selected from 1 and 2. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1, 2, 4, and 5, wherein all other variables not specifically defined in this embodiment are as defined in any one of Embodiments 1, 2, 4, and 5. 7.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 6, wherein the compound is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 8. At least one R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 7, wherein F is present, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 9.X does not exist or is combined with -(CR a R b )-, or -SO2-, R a and R b A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 8, wherein each appearance is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 10. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 9, wherein X is absent or bonded, -CH2-, or -SO2-, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 11. Y does not exist, or is combined, -(CR c R d ) q -, -C(=O)-, or -SO2-, R c and R d A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 10, wherein each appearance is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 12. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 11, wherein Y is absent or bonded, -CH2-, -CHCH3-, -C(CH3)2-, -C(=O)-, or -SO2-, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 13. Ring A is R 3 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 12, wherein ring A is optionally substituted with a C3-C7 carbocyrill, a 6-9 member heterocyclyl containing 1-3 oxygen atoms, a phenyl, or a 5-9 member heteroaryl containing 1-3 heteroatoms selected from O and N, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 14. Ring A is R 3A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 13, wherein ring A is optionally substituted with a C3-C7 carbocyrill, a 6- to 9-membered heterocyclyl containing one or two oxygen atoms, a phenyl, or a 5- to 9-membered heteroaryl containing one or two nitrogen atoms or one or two oxygen atoms, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 15. Ring A is R 3 It is optionally substituted by and ring A is [ka] Selected from, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 14, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 16. Ring A is R 3 It is optionally substituted by and ring A is [ka] Selected from, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 15, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 17. Z is a ring C, and ring C is R 4 The C ring is optionally substituted, and the C ring is a 4-8 member heterocyclyl; phenyl; or a 5 member heteroaryl; containing one or two heteroatoms selected from C4-C8 cycloalkyl, O, N, and S. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 16, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 18. Z is a ring C, and ring C is R 4 It is optionally substituted by and ring C is [ka] Selected from, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 17, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 19. Z is a ring C, and ring C is (R 4 ) o It is optionally substituted by and ring C is [ka] Selected from, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 18, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 20.R E , R F , and R G Each of these independently comprises hydrogen, halogen, cyano(-C≡N), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and -C(=O)OR. s -C(=O)NR p R q ,-CR p (=N)OR s , or -OR s And, R E , R F , and R G Any one of the above C1-C4 alkyl groups is cyano, -C(=O)R s , -C(=O)OR s -C(=O)NR p R q , -OR s -OC(=O)R s , -OC(=O)OR s -OC(=O)NR p Rq , and -S(=O)2R s It is optionally replaced by 1 to 3 bases selected from, R p and R q However, each appearance is independently of hydrogen, C1-C2 alkyl, C3-C5 cycloalkyl, or a 5- or 6-membered heterocycline. R p and R q Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH. R p and R q The above C3-C5 cycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH. R s However, for each appearance, independently, it is hydrogen, C1-C2 alkyl, or a 5- or 6-membered heteroaryl, R s The above C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. R s The above 5 or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 19, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 21.R E , R F , and R G Each of these independently comprises hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, and -C(=O)NR. p R q ,-CR p (=N)OR s , or -OR s And, R E , R F , and RG Any one of the above C1-C2 alkyl groups is cyano, -C(=O)NR p R q , -OR s -OC(=O)NR p R q , and -S(=O)2R s It is optionally replaced by 1 to 3 bases selected from, R p and R q However, each appearance is independently hydrogen, C1-C2 alkyl, cyclopentyl, or tetrahydrofuranyl. R p and R q Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 halogen groups selected from F and Cl. R s However, each appearance is independently hydrogen, C1-C2 alkyl, pyridinyl, or pyrimidinyl. R s The above C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups selected from F and Cl. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 20, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 22.R E , R F , and R Gare each independently hydrogen, F, -OH, -CH(OH)CH3, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CF3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -C2H5, -(CH2)2OH, -CH2OCH3, -CH2OC2H5 , -(CH2)2OCH3, -CH2OCHF2, -(CH2)2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O)C(=O A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 21, wherein the compound is N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridine-2-yl), or -CH2(O)(pyrimidine-2-yl), and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 23.R E , R F , and R G Each of these is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, or -CH2OCH3. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 22, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 24. Represented by one of the following structural formulas, [ka] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 23, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 25. Represented by one of the following structural formulas, [ka] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 24, wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 26. Represented by one of the following structural formulas, [ka] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 25, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 27. Represented by one of the following structural formulas, [ka] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 26, wherein n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 28.R 2 However, for each of these appearances, 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, and -NR appear. h R i , or C3-C6 cycloalkyl, R h and R i A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of any one of Embodiments 1 to 27, wherein each appearance is independently hydrogen or a C1-C4 alkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 29.R2 However, for each of these appearances, 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, and -NR appear. h R i , or C3-C5 cycloalkyl, R h and R i A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 28, wherein each appearance is independently hydrogen or C1-C4 alkyl, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 30.R 2 However, for each of the occurrences, independently, hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C2 haloalkyl, -NR h R i , or C3-C4 cycloalkyl, R h and R i However, for each appearance, each is independently hydrogen or -CH3. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 29, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 31.R 2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 30, wherein, for each appearance, independently, the elements are hydrogen, F, Cl, cyano, -CH3, -CHF2, -CF3, -NH2, or cyclopropyl, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 32.R 3 However, for each of their appearances, independently, halogen, cyano, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)Ry , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The above C1-C4 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x However, for each appearance, each is independently hydrogen or C1-C2 alkyl, and R v , R w , and R x Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. R y However, each appearance is independently hydrogen, C1-C4 alkyl, or a 5- or 6-membered heterocycline. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=O)OH. R y The above 5 or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=O)OH. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 31, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 33.R 3 However, for each of their appearances, independently, halogen, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The above C1-C4 alkyl groups are cyano, -OR y and -C(=O)OR y It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x However, for each appearance, each is independently hydrogen or C1-C4 alkyl, and R v , R w , and R x Any one of the above C1-C4 alkyl groups is optionally substituted with -OH, R y However, each of the occurrences is independently hydrogen, C1-C2 alkyl, or a 6-membered heterocycline. R y The above C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. Ry The above 6-member heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. R z However, for each occurrence, independently, it is -CH3, -OH, or -OCH3. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 32, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 34.R 3 However, for each of their appearances, independently, halogen, cyano, =O, C1-C2 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The above C1-C2 alkyl groups are -OH and -C(=O)OR y It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x However, for each appearance, each is independently hydrogen or C1-C2 alkyl, and R v , R w , and R x Any one of the above C1-C2 alkyl groups is optionally substituted with -OH, R yHowever, each appearance is independently hydrogen, C1-C2 alkyl, or tetrahydro-2H-pyranyl. R y The above C1-C2 alkyl group is optionally substituted with -C(=O)OH, R y The above tetrahydro-2H-pyranyl is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. R z However, for each occurrence, it is independently -CH3 or -OH. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 33, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 35.R 3 However, for each appearance, independently, F, Cl, cyano, -OH, =O, -CH3, -OCH3, -CF3, -CH3CN, -C(CH3)2CH2OH, -CH2COOH, -CH2OCH3, -C(=O)CHCH3OH, -COOH, -C(=O)O(2-tetrahydro-2H-pyranyl), -C(=O)NH2, -C(=O)NH(CH2)2OH, -C(=O)NHOH, -C(=O)NHS(=O)2CH3, -NH2, -NHCH3, -OCH2COOH, NHS(=O)2CH3, -S(=O)2 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 34, wherein the compound is CH3, -S(=O)2NH2, -S(=O)2NHC(=O)CH3, or -P(=O)(CH3)2, and the 2-tetrahydro-2H-pyranyl of the above -C(=O)O(2-tetrahydro-2H-pyranyl) is substituted with 1 to 3 groups selected from -OH and -C(=O)OH, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 36.R 4 However, regarding the appearance of each, independently, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)R y , -C(=O)OR y , -ORy , or -S(=O)2R y And, R 4 The above C1-C6 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NR v R w It is optionally replaced by 1 to 3 bases selected from, R v and R w However, each appearance is independently hydrogen or C1-C4 alkyl. R y However, each of their appearances is independently hydrogen and C1-C4 alkyl. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 35, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 37.R 4 However, regarding the appearance of each, independently, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y , -OR y , or -S(=O)2R y And, R 4 The above C1-C4 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NR v R w It is optionally replaced by 1 to 3 bases selected from, R v and R w However, each appearance is independently hydrogen or C1-C4 alkyl. R y However, each appearance is independently hydrogen or C1-C2 alkyl. Ry Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2. o is an integer selected from 0, 1, and 2. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 36, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 38.R 4 However, regarding the appearance of each, independently, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=O)R y , -C(=O)OR y , -OR y , or -S(=O)2R y And, R 4 The above C1-C2 alkyl group is optionally substituted with cyano, -OH, or -OCH3. R y However, each appearance is independently hydrogen or C1-C2 alkyl. R y The above C1-C2 alkyl group is optionally substituted with -OCH3, o is an integer selected from 0 and 1. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 37, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 39.R 4 However, each occurrence is independently cyano, -OH, -OCH3, -CH3, -C2H5, -CF3, -CH2CN, -CH2OH, -CH2OCH3, -COOH, -C(=O)CH3, -C(=O)OCH3, -C(=O)CH2OCH3, -S(=O)2CH3, S(=O)2C2H5, or S(=O)2CF3. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 38, wherein all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 40. Compounds selected from compounds 1 to 457, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of the above compounds, tautomers, and deuterated derivatives. 41. A pharmaceutical composition comprising at least one compound described in any one of Embodiments 1 to 40, a tautomer thereof, a deuterated derivative of the compound or tautomer thereof, or a pharmaceutically acceptable salt thereof. 42. A method for treating alpha-1 antitrypsin (AAT) deficiency, comprising administering to a patient in need of such treatment at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 40, or a therapeutically effective amount of the pharmaceutical composition described in Embodiment 41. 43. A method for modulating alpha-1 antitrypsin (AAT) activity, comprising the step of contacting the AAT with a therapeutically effective amount of at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 40, or a therapeutically effective amount of the pharmaceutical composition described in Embodiment 41. 44. The method according to Embodiment 42 or Embodiment 43, wherein a therapeutically effective amount of at least one of the above compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts is administered in combination with AAT augmentation therapy and / or AAT replacement therapy. 【0083】 To avoid misunderstanding, it should be added that the features described in relation to formula (I') can also be combined with the features described in relation to formulas (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe). 【0084】 Exemplary Embodiment 2: Non-limiting embodiments / terms of this disclosure include: 1. Compounds represented by the following structural formulas, [ka] The tautomer, the compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt thereof, wherein the formula is: [ka] For each of the two occurrences, it is either a single bond or a double bond, provided that one is a single bond and the other is a double bond. V 1 and V 2 Each of these can be N or -CR independently. 2 And, W 1 and W 2 Each is independently N or C, except W 1 and W 2 One of them is N, and the other is C. U is hydrogen, -OH, -CH3, -NH2, or a halogen. X does not exist, or is combined with -(CR a R b ) p -, or -SO2-, Y does not exist or is combined with -(CR c R d ) q -, -C(=O)-, or -SO2-, R a and R b Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. R c and R d Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. Ring A is C3-C 12 Carbocyclyl, 3-12 member heterocyclyl, C6 or C 10 An aryl or a 5-10 member heteroaryl, provided that W 1 N is W 2 If C, then ring A is not 1,5,6,7-tetrahydro-4H-indole-4-onyl or its tautomer, Ring B is C4-C 12 Cycloalkyl, C6 or C 10 It is an aryl, a 5-10 membered heteroaryl, or benzyl. Z is [ka] And in the formula, Ring C is C3-C 12 Cycloalkyl, 3-12 membered heterocyclyl, C6 or C 10 It is an aryl or a 5-10 member heteroaryl, However, if the C ring is phenyl, then the phenyl is R 4 Substituted with, however, if ring C is phenyl, Y must not be -SO2-, However, if ring B is benzyl, ring C must not be pyridinyl or indolyl. R E , R F , and R G Each of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(=O)R s , -C(=O)OR s -C(=O)NR p R q ,-CR p (=N)OR s , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -ORs -OC(=O)R s , or -OC(=O)NR p R q And, R E , R F , and R G Any one of the above C1-C6 alkyl or C2-C6 alkenyl is cyano, -C(=O)R s , -C(=O)OR s -C(=O)NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s 、 -OR s -OC(=O)R s , -OC(=O)OR s -OC(=O)NR p R q -S(=O) r R s , and -S(=O) r NR p R q It is optionally replaced by 1 to 3 bases selected from, R p , R q , and R r Each of these is independently a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3-6 member heterocycline. R p , R q , and R r Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R p , R q , and R rAny one of the above C3-C6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1-3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O(C1-C2 alkyl), -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R s Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. R s The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R s The above C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 1 These are halogens, cyanos, C1-C3 alkyls, C1-C3 haloalkyls, C1-C3 alkoxys, C1-C3 haloalkoxys, or -O-(C3-C6 cycloalkyls). R 2 For each of these appearances, independently, hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -NRh R i , phenyl, or a 5- or 6-membered heteroaryl, R 2 The above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R k , -C(=O)OR k -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) s R k 、 -OR k -OC(=O)R k , -OC(=O)OR k -OC(=O)NR h R i -S(=O) s R k , and S(=O) s NR h R i It is optionally replaced by 1 to 3 bases selected from, R h , R i , and R j Each of these occurrences is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. R h , R i , and R jAny one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R h , R i , and R j Any one of the above C3-C6 cycloalkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. -OR k It must not be -OH, R k The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R kThe above C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 3 and R 4 For each of these occurrences, independently, they are halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) t R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y -S(=O) t NR v R w -S(=O) t NR v C(=O)R y ,-P(=O)R zR z , phenyl, or a 5- or 6-membered heteroaryl, R 3 and R 4 Any one of the above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) r R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y , and -S(=O) t NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x Each of these occurrences is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocycline, or a 5- or 6-membered heteroaryl group. R v , R w , and R xAny one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R v , R w , and R x Any one of the above C3-C6 cycloalkyls, the above 5- or 6-membered heterocyclil, or the above 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R y Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a 5- or 6-membered heterocycline group, or a 5- or 6-membered heteroaryl group. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R yThe above C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R z Each of these occurrences is independently C1-C2 alkyl, -OH, or -O(C1-C2 alkyl). k is an integer selected from 1, 2, and 3. m and na are each independently integers selected from 0, 1, 2, and 3. p, r, s, and t are each independently integers selected from 1 and 2. q is an integer selected from 1, 2, and 3, and the compound, its tautomer, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt thereof. 2. It is represented by one of the following structural formulas, [ka] During the ceremony, U is -OH, -CH3, -NH2, F, or Cl. The compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described in Clause 1, wherein all other variables not specifically defined in this Clause are as defined in Embodiment 1. 3. Represented by one of the following structural formulas, [ka] During the ceremony, U is -OH, -CH3, -NH2, F, or Cl. The compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described in Clause 1, wherein all other variables not specifically defined in this embodiment are as defined in Embodiment 1. 4. It is represented by one of the following structural formulas, [ka] During the ceremony, U is -OH or -NH2, Ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6-9 member heterocyclyl, a phenyl, or a 5-9 member heteroaryl. Ring B is R 1 Substituted with, and ring B is a C4-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, or benzyl, Z, R 4 If ring C is optionally substituted, ring C is a C4-C8 cycloalkyl, a 4- to 8-membered heterocyclyl, a phenyl, or a 5 or 6-membered heteroaryl. All other variables not specifically defined in this clause are as defined in Clause 1 or Clause 2, for any compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in Clause 1 or Clause 2. 5. Represented by one of the following structural formulas, [ka] During the ceremony, Ring B is R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1, 2, and 4, wherein ring B is substituted with and ring B is cyclohexyl, phenyl, pyridinyl, or benzyl, and all other variables not specifically defined in this Clause are as defined in any one of Clauses 1, 2, and 4. 6. It is represented by the following structural formula, [ka] During the ceremony, R 1 However, these are halogens, cyanos, C1-C2 alkyls, C1-C2 haloalkyls, or C1-C2 alkoxys. k is an integer selected from 1 and 2. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1, 2, 4, and 5, wherein all other variables not specifically defined in this Clause are as defined in any one of Clauses 1, 2, 4, and 5. 7.R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 6, wherein the compound is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 8. At least one R 1 A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 7, wherein F is present, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 9.X does not exist or is combined with -(CR a R b )-, or -SO2-, R a and R b However, each occurrence is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, such as any compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 8. 10. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 9, wherein X is absent or is a bond, -CH2-, or -SO2-, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 11. Y is absent or is a bond, -(CR c R d ) q -, -C(=O)-, or -SO2-, and R c and R d are each independently, for each occurrence, hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of clauses 1 to 10. 12. q is an integer selected from 1 and 2, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of clauses 1 to 11. 13. Y is absent or is a bond, -CH2-, -CHCH3-, -C(CH3)2-, -C(=O)-, or -SO2-, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of clauses 1 to 12. 14. Ring A is optionally substituted with R 3 and Ring A is C3-C7 carbocyclic, 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 in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of clauses 1 to 13. 15. Ring A is optionally substituted with R 3Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described in any one of Clauses 1 to 14, wherein ring A is optionally substituted with a C3-C7 carbocyrill, a 6- to 9-membered heterocyclyl containing one or two oxygen atoms, a phenyl, or a 5- to 9-membered heteroaryl containing one or two nitrogen atoms or one or two oxygen atoms, and all other variables not specifically defined in this Clause are as defined in any one of the preceding Clauses. 16. Ring A is R 3 It is optionally substituted by and ring A is [ka] Selected from, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 15, wherein all other variables not specifically defined in this Clause are as defined in any one of the preceding Clauses. 17. Ring A is R 3 It is optionally substituted by and ring A is [ka] Selected from, A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 16, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 18. Z is a ring C, and ring C is R 4 The C ring is optionally substituted, and the C ring is a 4-8 member heterocyclyl; phenyl; or a 5 member heteroaryl; containing one or two heteroatoms selected from C4-C8 cycloalkyl, O, N, and S. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 17, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 19. Z is a ring C, and ring C is R4 is optionally replaced, and ring C is [Chemical formula] selected from a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of clauses 1 to 18, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 20. Z is ring C, and ring C is (R 4 ) o is optionally replaced, and ring C is [Chemical formula] selected from a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of clauses 1 to 19, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 21. R E , R F , and R G are each independently hydrogen, halogen, cyano (-C≡N), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)OR s , -C(=O)NR p R q , -CR p (=N)OR s , or -OR s , and R E , R F , and R G any one of the above C1-C4 alkyls is cyano, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , and -S(=O)2R sIt is optionally replaced by 1 to 3 bases selected from, R p and R q However, each appearance is independently of hydrogen, C1-C2 alkyl, C3-C5 cycloalkyl, or a 5- or 6-membered heterocycline. R p and R q Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH. R p and R q The above C3-C5 cycloalkyl or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH. R s However, for each appearance, independently, it is hydrogen, C1-C2 alkyl, or a 5- or 6-membered heteroaryl, R s The above C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. R s The above 5 or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 20, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 22.R E , R F , and R G Each of these independently comprises hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, and -C(=O)NR. p R q ,-CR p (=N)OR s , or -OR s And, R E , R F , and R G Any one of the above C1-C2 alkyl groups is cyano, -C(=O)NRp R q , -OR s -OC(=O)NR p R q , and -S(=O)2R s It is optionally replaced by 1 to 3 bases selected from, R p and R q However, each appearance is independently hydrogen, C1-C2 alkyl, cyclopentyl, or tetrahydrofuranyl. R p and R q Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 halogen groups selected from F and Cl. R s However, each appearance is independently hydrogen, C1-C2 alkyl, pyridinyl, or pyrimidinyl. R s The above C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups selected from F and Cl. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 21, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 23.R E , R F , and R Gare each independently hydrogen, F, -OH, -CH(OH)CH3, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CF3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -C2H5, -(CH2)2OH, -CH2OCH3, -CH2OC2H 5, -(CH2)2OCH3, -CH2OCHF2, -(CH2)2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O)C Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described in any one of Clauses 1 to 22, which are (=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridine-2-yl), or -CH2(O)(pyrimidine-2-yl), where all other variables not specifically defined in this Clause are as defined in any one of the preceding Clauses. 24.R E , R F , and R G Each of these is independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, or -CH2OCH3. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 23, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 25. Represented by one of the following structural formulas, [ka] A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 24, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 26. Represented by one of the following structural formulas, [ka] In the formula, n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 25. 27. Represented by one of the following structural formulas, 【Chemical formula】 All other variables not specifically defined in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 26. 28. Represented by one of the following structural formulas, 【Chemical formula】 In the formula, n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 27. 29. R 2 is, for each occurrence, 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, -NR h R i , or C3-C6 cycloalkyl, and R h and R i are, for each occurrence, each independently hydrogen or C1-C4 alkyl, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 28. 30. R 2However, for each of these appearances, 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, and -NR appear. h R i , or C3-C5 cycloalkyl, R h and R i However, each occurrence is independently hydrogen or a C1-C4 alkyl, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, such as any compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 29. 31.R 2 However, for each of the occurrences, independently, hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C2 haloalkyl, -NR h R i , or C3-C4 cycloalkyl, R h and R i However, for each appearance, each is independently hydrogen or -CH3. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 30, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 32.R 2 However, for each occurrence, independently, is hydrogen, F, Cl, cyano, -CH3, -CHF2, -CF3, -NH2, or cyclopropyl, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 31. 33.R 3 However, for each of their appearances, independently, halogen, cyano, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)R y , -C(=O)OR y-C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The above C1-C4 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x However, for each appearance, each is independently hydrogen or C1-C2 alkyl, and R v , R w , and R x Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. R y However, each appearance is independently hydrogen, C1-C4 alkyl, or a 5- or 6-membered heterocycline. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=O)OH. R y The above 5 or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=O)OH. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 32, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 34.R 3 However, for each of their appearances, independently, halogen, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The above C1-C4 alkyl groups are cyano, -OR y and -C(=O)OR y It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x However, for each appearance, each is independently hydrogen or C1-C4 alkyl, and R v , R w , and R x Any one of the above C1-C4 alkyl groups is optionally substituted with -OH, R y However, each of the occurrences is independently hydrogen, C1-C2 alkyl, or a 6-membered heterocycline. R y The above C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. R yThe above 6-member heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. R z However, for each occurrence, independently, it is -CH3, -OH, or -OCH3. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 33, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 35.R 3 However, for each of their appearances, independently, halogen, cyano, =O, C1-C2 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The above C1-C2 alkyl groups are -OH and -C(=O)OR y It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x However, for each appearance, each is independently hydrogen or C1-C2 alkyl, and R v , R w , and R x Any one of the above C1-C2 alkyl groups is optionally substituted with -OH, R yHowever, each appearance is independently hydrogen, C1-C2 alkyl, or tetrahydro-2H-pyranyl. R y The above C1-C2 alkyl group is optionally substituted with -C(=O)OH, R y The above tetrahydro-2H-pyranyl is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. R z However, for each occurrence, it is independently -CH3 or -OH. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 34, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 36.R 3 However, for each appearance, independently, F, Cl, cyano, -OH, =O, -CH3, -OCH3, -CF3, -CH3CN, -C(CH3)2CH2OH, -CH2COOH, -CH2OCH3, -C(=O)CHCH3OH, -COOH, -C(=O)O(2-tetrahydro-2H-pyranyl), -C(=O)NH2, -C(=O)NH(CH2)2OH, -C(=O)NHOH, -C(=O)NHS(=O)2CH3, -NH2, -NHCH3, -OCH2COOH, NHS(=O)2CH3, -S(= A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 35, wherein the -C(=O)O(2-tetrahydro-2H-pyranyl) is -C(=O)O(2-tetrahydro-2H-pyranyl) is substituted with 1 to 3 groups selected from -OH and -C(=O)OH, and all other variables not specifically defined in this Clause are as defined in any one of the preceding Clauses. 37.R 4 However, regarding the appearance of each, independently, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)R y , -C(=O)OR y , -OR y, or -S(=O)2R y And, R 4 The above C1-C6 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NR v R w It is optionally replaced by 1 to 3 bases selected from, R v and R w However, each appearance is independently hydrogen or C1-C4 alkyl. R y However, each of their appearances is independently hydrogen and C1-C4 alkyl. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 36, wherein all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 38.R 4 However, regarding the appearance of each, independently, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y , -OR y , or -S(=O)2R y And, R 4 The above C1-C4 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NR v R w It is optionally replaced by 1 to 3 bases selected from, R v and R w However, each appearance is independently hydrogen or C1-C4 alkyl. R y However, each appearance is independently hydrogen or C1-C2 alkyl. R yAny one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2. o is an integer selected from 0, 1, and 2. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 37, wherein all other variables not specifically defined in this Clause are as defined in any one of the preceding Clauses. 39.R 4 However, regarding the appearance of each, independently, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=O)R y , -C(=O)OR y , -OR y , or -S(=O)2R y And, R 4 The above C1-C2 alkyl group is optionally substituted with cyano, -OH, or -OCH3. R y However, each appearance is independently hydrogen or C1-C2 alkyl. R y The above C1-C2 alkyl group is optionally substituted with -OCH3, o is an integer selected from 0 and 1. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Clauses 1 to 38, wherein all other variables not specifically defined in this Clause are as defined in any one of the preceding Clauses. 40.R 4 However, for each occurrence, independently, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described in any one of the preceding clauses 1 to 39 are cyano, -OH, -OCH3, -CH3, -C2H5, -CF3, -CH2CN, -CH2OH, -CH2OCH3, -COOH, -C(=O)CH3, -C(=O)OCH3, -C(=O)CH2OCH3, -S(=O)2CH3, S(=O)2C2H5, or S(=O)2CF3, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 41. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 40, wherein U is -OH, -CH3, -NH2, or halogen, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 42. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 40, wherein U is -OH and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 43. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 40, wherein U is a halogen, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 44. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 40, wherein U is fluoro and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 45. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the preceding clauses 1 to 40, wherein U is hydrogen, and all other variables not specifically defined in this clause are as defined in any one of the preceding clauses. 46. ​​Compounds selected from compounds 1-457, compounds 458-532, compounds B1-B25, compounds W1-W32, and compounds P1-P225, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of the above compounds, tautomers, and deuterated derivatives. 47. Compounds selected from compounds 1 to 457, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of the above compounds, tautomers, and deuterated derivatives. 48. Compounds selected from compounds 458-532, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of the above compounds, tautomers, and deuterated derivatives. 49. Compounds selected from compounds B1-B25 and compounds W1-W32, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of the above compounds, tautomers, and deuterated derivatives. 50. Compounds selected from compounds P1 to P225, their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of the above compounds, tautomers, and deuterated derivatives. 51. A pharmaceutical composition comprising at least one compound described in any one of clauses 1 to 50, a tautomer thereof, a deuterated derivative of the compound or tautomer thereof, or a pharmaceutically acceptable salt thereof. 52. A method for treating alpha-1 antitrypsin (AAT) deficiency, comprising administering to a patient in need of such treatment at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of clauses 1 to 50, or a therapeutically effective amount of a pharmaceutical composition described in clause 51. 53. A method for modulating alpha-1 antitrypsin (AAT) activity, comprising the step of contacting the AAT with at least one compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of the clauses 1 to 50, or a pharmaceutically acceptable composition described in the clause 51, in a therapeutically effective amount. 54. The method according to Clause 52 or Clause 53, wherein a therapeutically effective amount of at least one of the above compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts is administered in combination with AAT augmentation therapy and / or AAT replacement therapy. 【0085】 II. Compounds and Compositions In some embodiments, the compounds of the present disclosure are compounds of formula (I), [ka] A tautomer thereof, a deuterated derivative thereof or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein in the formula, [ka] For each of the two occurrences, it is either a single bond or a double bond, provided that one is a single bond and the other is a double bond. V 1 and V 2 Each of these can be N or -CR independently. 2 And, W 1 and W 2 Each is independently N or C, except W 1 and W 2 One of them is N, and the other is C. U is hydrogen, -OH, -CH3, -NH2, or a halogen. X does not exist, or is combined with -(CR a R b ) p -, or -SO2-, Y does not exist or is combined with -(CR c R d ) q -, -C(=O)-, or -SO2-, R a and R b Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. R c and R d Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. Ring A is C3-C 12 Carbocyclyl, 3-12 member heterocyclyl, C6 or C 10 An aryl or a 5-10 member heteroaryl, provided that W 1 N is W 2 If C, then ring A is not 1,5,6,7-tetrahydro-4H-indole-4-onyl or its tautomer, Ring B is C4-C12 Cycloalkyl, C6 or C 10 It is an aryl, a 5-10 membered heteroaryl, or benzyl. Z is [ka] And in the formula, Ring C is C3-C 12 Cycloalkyl, 3-12 membered heterocyclyl, C6 or C 10 It is an aryl or a 5-10 member heteroaryl, However, if the C ring is phenyl, then the phenyl is R 4 Substituted with, however, if ring C is phenyl, Y must not be -SO2-, However, if ring B is benzyl, ring C must not be pyridinyl or indolyl. R E , R F , and R G Each of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(=O)R s , -C(=O)OR s -C(=O)NR p R q ,-CR p (=N)OR s , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -OR s -OC(=O)R s , or -OC(=O)NR p R q And, R E , R F , and R G Any one of the above C1-C6 alkyl or C2-C6 alkenyl is cyano, -C(=O)R s , -C(=O)OR s-C(=O)NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s 、 -OR s -OC(=O)R s , -OC(=O)OR s -OC(=O)NR p R q -S(=O) r R s , and -S(=O) r NR p R q It is optionally replaced by 1 to 3 bases selected from, R p , R q , and R r Each of these is independently a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3-6 member heterocycline. R p , R q , and R r Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R p , R q , and R r Any one of the above C3-C6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1-3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O(C1-C2 alkyl), -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R sEach of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. R s The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R s The above C3-C6 cycloalkyl, above phenyl, or above 5 or 6 members are optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 1 These are halogens, cyanos, C1-C3 alkyls, C1-C3 haloalkyls, C1-C3 alkoxys, C1-C3 haloalkoxys, or -O-(C3-C6 cycloalkyls), for example, -O-(cyclopropyl) or -O-(cyclobutyl). R 2 Each of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl. R 2 The above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R k , -C(=O)OR k -C(=O)NR h R i , -NR h Ri , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) s R k 、 -OR k -OC(=O)R k , -OC(=O)OR k -OC(=O)NR h R i -S(=O) s R k , and S(=O) s NR h R i It is optionally replaced by 1 to 3 bases selected from, R h , R i , and R j Each of these occurrences is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. R h , R i , and R j Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R h , R i , and R jAny one of the above C3-C6 cycloalkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. -OR k It must not be -OH, R k The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k The above C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 3 and R 4 For each of these occurrences, independently, they are halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)Ry , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) t R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y -S(=O) t NR v R w -S(=O) t NR v C(=O)R y ,-P(=O)R z R z , phenyl, or a 5- or 6-membered heteroaryl, R 3 and R 4 Any one of the above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w Rx , -NR v S(=O) r R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y , and -S(=O) t NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x Each of these occurrences is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocycline, or a 5- or 6-membered heteroaryl group. R v , R w , and R x Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R v , R w , and R xAny one of the above C3-C6 cycloalkyls, the above 5- or 6-membered heterocyclil, or the above 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R y Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a 5- or 6-membered heterocycline group, or a 5- or 6-membered heteroaryl group. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R y The above C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R z Each of these occurrences is independently C1-C2 alkyl, -OH, or -O(C1-C2 alkyl). k is an integer selected from 1, 2, and 3. m and n are each independently integers selected from 0, 1, 2, and 3. p, r, s, and t are each independently integers selected from 1 and 2. q is an integer selected from 1, 2, and 3, and the compound, its tautomer, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt of any of the foregoing. 【0086】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, U is -OH, -CH3, -NH2, or halogen, and all other variables are as defined in formula (I). 【0087】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the present disclosure, U is hydrogen, and all other variables are as defined in formula (I). 【0088】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, U is -OH, and all other variables are as defined in formula (I). 【0089】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, U is a halogen, and all other variables are as defined in formula (I). 【0090】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, U is fluoro, and all other variables are as defined in formula (I). 【0091】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables are as defined by formula (I). 【0092】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, U is -OH, -CH3, -NH2, or a halogen, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables are as defined in formula (I). 【0093】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, V 2 However, -CR 2 And R 2 However, it is a halogen, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0094】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, V 2 However, -CR 2 And R 2 However, it is fluoro, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0095】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, V 1 However, -CR 2 And R 2 However, it is a halogen, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0096】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, V 1However, -CR 2 And R 2 However, it is fluoro, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0097】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (IIa) or formula (IIb), [ka] During the ceremony, U is -OH, -CH3, -NH2, F, or Cl. All other variables not specifically defined in this paragraph are as defined in equation (I). 【0098】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables not specifically defined in this paragraph are as defined in the prior embodiments. 【0099】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (IIc), formula (IId), formula (IIe), or formula (IIf), [ka] During the ceremony, U is -OH, -CH3, -NH2, F, or Cl. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0100】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables not specifically defined in this paragraph are as defined in the prior embodiments. 【0101】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (IIg), [ka] In the formula, all other variables not specifically defined in this paragraph are as defined in formula (I). 【0102】 For example, in some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0103】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (IIIa) or formula (IIIb), [ka] During the ceremony, U is -OH or -NH2, Ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6-9 member heterocyclyl, a phenyl, or a 5-9 member heteroaryl. Ring B is R 1 Substituted with, and ring B is a C4-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, or benzyl, Z, R 4If ring C is optionally substituted, ring C is a C4-C8 cycloalkyl, a 4- to 8-membered heterocyclyl, a phenyl, or a 5 or 6-membered heteroaryl. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0104】 For example, in some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0105】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (IIIc), [ka] During the ceremony, Ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6-9 member heterocyclyl, a phenyl, or a 5-9 member heteroaryl. Ring B is R 1 Substituted with, and ring B is a C4-C6 cycloalkyl, phenyl, 5-6 member heteroaryl, or benzyl, Z, R 4 If ring C is optionally substituted, ring C is a C4-C8 cycloalkyl, a 4- to 8-membered heterocyclyl, a phenyl, or a 5 or 6-membered heteroaryl. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0106】 For example, in some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0107】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with C3-carbocykrill, C4-carbocykrill, or C7-carbocykrill, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0108】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with phenyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0109】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is optionally R 3 The ring A is substituted with a pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0110】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring B is R 1 It is substituted with and ring B is phenyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0111】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (IVa) or formula (IVb), [ka] During the ceremony, Ring B is R 1 Substituted with, and ring B is cyclohexyl, phenyl, pyridinyl, or benzyl, Ring B is R 1 Substituted with, and ring B is cyclohexyl, phenyl, or benzyl. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0112】 For example, in some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0113】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (Va) or formula (Vb), [ka] During the ceremony, R 1 However, these are halogens, cyanos, C1-C2 alkyls, C1-C2 haloalkyls, or C1-C2 alkoxys. k is an integer selected from 1 and 2. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0114】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0115】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (Vc), [ka] During the ceremony, R 1 However, these are halogens, cyanos, C1-C2 alkyls, C1-C2 haloalkyls, or C1-C2 alkoxys. k is an integer selected from 1 and 2. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0116】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, p, q, r, s, and t are each independently integers selected from 1 and 2, and all other variables not specifically defined in this paragraph are as defined in the prior embodiments. 【0117】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 1 is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0118】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure contain at least one R 1However, F is the case, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0119】 In some embodiments, in the compounds, deuterated derivatives, pharmaceutically acceptable salts, or tautomers of the Disclosure, X is either absent or bonded to -(CR a R b )-, or -SO2-, R a and R b However, each occurrence is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0120】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, X is either absent or bonded, -CH2-, or -SO2-, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0121】 In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Y is absent or bonded to -(CR c R d ) q -, -C(=O)-, or -SO2-, R c and R d However, each occurrence is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0122】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, Y is either absent or a bond, -CH2-, -CHCH3-, -C(CH3)2-, -C(=O)-, or -SO2-, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0123】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6-9 member heterocycline containing 1-3 oxygen atoms, a phenyl, or a 5-9 member heteroaryl containing 1-3 heteroatoms selected from O and N, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0124】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6- to 9-membered heterocycline containing one or two oxygen atoms, a phenyl, or a 5- to 9-membered heteroaryl containing one or two nitrogen atoms or one or two oxygen atoms, and all other variables not specifically defined in this embodiment are as defined in any one of the prior embodiments. 【0125】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 It is optionally substituted by and ring A is [ka] Selected from, All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0126】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 It is optionally substituted by and ring A is [ka] Selected from, All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0127】 In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is a ring C, and ring C is R 4 It is optionally substituted by and ring C is [ka] Selected from, All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0128】 In some embodiments, in a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the present disclosure, Z is a ring C, and ring C is R 4 It is optionally substituted by and ring C is [ka] Selected from, All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0129】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R E , R F , and R G Each of these independently comprises hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and -C(=O)OR. s-C(=O)NR p R q ,-CR p (=N)OR s , or -OR s And, R E , R F , and R G Any one of the above C1-C4 alkyl groups is cyano, -C(=O)R s , -C(=O)OR s -C(=O)NR p R q , -OR s -OC(=O)R s , -OC(=O)OR s -OC(=O)NR p R q , and -S(=O)2R s It is optionally replaced by 1 to 3 bases selected from, R p and R q However, for each appearance, each independently is hydrogen or a C1-C2 alkyl, C3-C5 cycloalkyl, or a 5- or 6-membered heterocycline, R p and R q Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH. R p and R q Any one of the above C3-C5 cycloalkyl or 5 or 6-membered heteroaryl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH. R s However, each appearance is independently hydrogen, a C1-C2 alkyl group, or a 5- or 6-membered heteroaryl group. R s The above C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. R s The above 5 or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0130】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R E , R F , and R G Each of these independently comprises hydrogen, F, Cl, C1-C2 alkyl, C1-C2 haloalkyl, and -C(=O)NR. p R q ,-CR p (=N)OR s , or -OR s And, R E , R F , and R G Any one of the above C1-C2 alkyl groups is cyano, -C(=O)NR p R q , -OR s -OC(=O)NR p R q , and -S(=O)2R s It is optionally replaced by 1 to 3 bases selected from, R p and R q However, each appearance is independently hydrogen, C1-C2 alkyl, cyclopentyl, or tetrahydrofuranyl. R p and R q Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 halogen groups selected from F and Cl. R s However, each appearance is independently hydrogen, C1-C2 alkyl, pyridinyl, or pyrimidinyl. R s The above C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups selected from F and Cl. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0131】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R E , R F , and R G Each of these independently consists of hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, (CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C(= O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridine-2-yl), -CH2(O)(pyrimidine-2-yl), and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0132】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R E , R F , and R G These are independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0133】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (VIa), formula (VIb), formula (VIc), formula (VId), or formula (VIe), [ka] In the formulas, all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. In some embodiments, o is an integer selected from 0, 1, and 2. 【0134】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (VIf) or formula (VIg), [ka] In the formulas, all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. In some embodiments, o is an integer selected from 0, 1, and 2. 【0135】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F , and R G Each of these independently consists of hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, (CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C(= O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridine-2-yl), -CH2(O)(pyrimidine-2-yl), and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0136】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, RF and R G These are independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0137】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F and R G These are independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0138】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (VIIa), formula (VIIb), formula (VIIc), formula (VIId), or formula (VIIe), [ka] In the formula, n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. In some embodiments, o is an integer selected from 0, 1, and 2. 【0139】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (VIIf) or formula (VIIg), [ka] In the formula, n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. In some embodiments, o is an integer selected from 0, 1, and 2. 【0140】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6- to 9-membered heterocycline, a phenyl, or a 5- to 9-membered heteroaryl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0141】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with C3-carbocykrill, C4-carbocykrill, or C7-carbocykrill, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0142】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with phenyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0143】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is optionally R 3 The ring A is substituted with a pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0144】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F , and R GEach of these independently consists of hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, (CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C(= O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridine-2-yl), -CH2(O)(pyrimidine-2-yl), and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0145】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F and R G These are independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0146】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F and R G These are independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0147】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (VIIIa), formula (VIIIb), formula (VIIIc), formula (VIIId), or formula (VIIIe), [ka] In the formula, all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0148】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (IXa), formula (IXb), formula (IXc), formula (IXd), or formula (IXe), [ka] In the formula, n is an integer selected from 0, 1, and 2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0149】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 2 However, for each of these appearances, 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, and -NR appear. h R i , or C3-C6 cycloalkyl, R h and R i However, for each occurrence, each is independently hydrogen or C1-C4 alkyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0150】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 2However, for each of the occurrences, independently, hydrogen, halogen, cyano, C1-C4 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), C1-C4 haloalkyl, -NR h R i , or C3-C5 cycloalkyl, R h and R i However, for each occurrence, each is independently hydrogen or C1-C2 alkyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0151】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 2 However, for each appearance, independently, hydrogen, halogen, cyano, C1-C2 alkyl (optionally substituted with 1 to 3 groups selected from cyano, -OH, -OCH3, and -NH2), -NR h R i , or C3-C4 cycloalkyl, R h and R i However, for each occurrence, each is independently hydrogen or -CH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0152】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 2 However, each appearance is independently hydrogen, F, Cl, cyano, -CH3, -CF3, -NH2, or cyclopropyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0153】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 3However, for each of their appearances, independently, halogen, cyano, =O, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The C1-C4 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x However, for each appearance, each is independently hydrogen or C1-C2 alkyl, and R v , R w , and R x Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, and -NH2. R y However, each appearance is independently hydrogen, C1-C4 alkyl, or a 5- or 6-membered heterocycline. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=O)OH. R yThe above 5 or 6-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, and -C(=O)OH. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0154】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 3 However, for each of their appearances, independently, halogen, cyano, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The above C1-C4 alkyl groups are cyano, -OR y and -C(=O)OR y It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R x However, for each appearance, each is independently hydrogen or C1-C4 alkyl, and R v , R w , and R x Any one of the above C1-C4 alkyl groups is optionally substituted with -OH, R yHowever, each of the occurrences is independently hydrogen, C1-C2 alkyl, or a 6-membered heterocycline. R y The above C1-C2 alkyl group is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. R y The above 6-member heterocyclyl is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. R z However, for each occurrence, independently, it is -CH3, -OH, or -OCH3. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0155】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 3 However, for each of their appearances, independently, halogen, cyano, =O, C1-C2 alkyl, C1-C2 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O)2R y , -NR v R w , -OR y -S(=O)2R y -S(=O)2NR v R w -S(=O)2NR v C(=O)R y , or -P(=O)R z R z And, R 3 The above C1-C2 alkyl groups are -OH and -C(=O)OR y It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R xHowever, for each appearance, each is independently hydrogen or C1-C2 alkyl, and R v , R w , and R x Any one of the above C1-C2 alkyl groups is optionally substituted with -OH, R y However, each appearance is independently hydrogen, C1-C2 alkyl, or tetrahydro-2H-pyranyl. R y The above C1-C2 alkyl group is optionally substituted with -C(=O)OH, R y The above tetrahydro-2H-pyranyl is optionally substituted with 1 to 3 groups selected from -OH and -C(=O)OH. R z However, for each occurrence, it is independently -CH3 or -OH. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0156】 In some embodiments, in the compound, a tautomer, a deuterated derivative, or a pharmaceutically acceptable salt of the present disclosure, R 3 However, for each of their appearances, independently, F, Cl, cyano, -OH, =O, -CH3, -OCH3, -CF3, -CH3CN, -C(CH3)2CH2OH, -CH2COOH, -CH2OCH3, -C(=O)CHCH3OH, -COOH, -C(=O)O(2-tetrahydro-2H-pyranyl), -C(=O)NH2, -C(=O)NH(CH2)2OH, -C(=O)NHOH, -C(=O)NHS(=O)2CH3, -NH2, -NHCH3, NHS The -C(=O)O(2-tetrahydro-2H-pyranyl) is (=O)2CH3, -S(=O)2NH2, -S(=O)2NHC(=O)CH3, or -P(=O)(CH3)2, where the 2-tetrahydro-2H-pyranyl in the above -C(=O)O(2-tetrahydro-2H-pyranyl) is substituted with 1 to 3 groups selected from -OH and -C(=O)OH, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0157】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 4 However, regarding the appearance of each, independently, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C(=O)R y , -C(=O)OR y , -OR y , or -S(=O)2R y And, R 4 The above C1-C6 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NR v R w It is optionally replaced by 1 to 3 bases selected from, R v and R w However, each appearance is independently hydrogen or C1-C4 alkyl. R y However, each of their appearances is independently hydrogen and C1-C4 alkyl. R y The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0158】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 4 However, regarding the appearance of each, independently, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -C(=O)R y , -C(=O)OR y , -OR y , or -S(=O)2R y And, R 4 The above C1-C4 alkyl groups are cyano, -OR y , -C(=O)OR y , and -NRv R w It is optionally replaced by 1 to 3 bases selected from, R v and R w However, each appearance is independently hydrogen or C1-C4 alkyl. R y However, each appearance is independently hydrogen or C1-C2 alkyl. R y Any one of the above C1-C2 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -OCH3, and -NH2. m is an integer selected from 0, 1, and 2. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0159】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 4 However, regarding the appearance of each, independently, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, -C(=O)R y , -C(=O)OR y , -OR y , or -S(=O)2R y And, R 4 The above C1-C2 alkyl group is optionally substituted with cyano, -OH, or -OCH3. R y However, each appearance is independently hydrogen or C1-C2 alkyl. R y The above C1-C2 alkyl group is optionally substituted with -OCH3, m is an integer selected from 0 and 1. All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0160】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 4 However, for each occurrence, independently, they are cyano, -OH, -OCH3, -CH3, -C2H5, -CH2CN, -CH2OH, -CH2OCH3, -COOH, -C(=O)CH3, -C(=O)OCH3, -C(=O)CH2OCH3, -S(=O)2CH3, S(=O)2C2H5, or S(=O)2CF3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0161】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure are represented by formula (Xa), formula (Xb), formula (Xc), formula (Xd), formula (Xe), or formula (Xf), [ka] All other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. In some embodiments, o is an integer selected from 0, 1, and 2. 【0162】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6- to 9-membered heterocycline, a phenyl, or a 5- to 9-membered heteroaryl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0163】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with C3-carbocykrill, C4-carbocykrill, or C7-carbocykrill, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0164】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with phenyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0165】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is optionally R 3 The ring A is substituted with a pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0166】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F , and R G Each of these independently consists of hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, (CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C(= O)NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridine-2-yl), -CH2(O)(pyrimidine-2-yl), and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0167】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F and R G These are independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0168】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F and R G These are independently hydrogen, -OH, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0169】 In some embodiments, the compounds of the present disclosure are compounds of formula (XIa), formula (XIb), formula (XIc), formula (XId), formula (XIe), or formula (XIf), [ka] [ka] A tautomer thereof, a deuterated derivative thereof or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein in the formula, U is hydrogen or -OH, X does not exist, or is combined with -(CR a R b ) p -, or -SO2-, R a and R b Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. R E , R F , and RG Each of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(=O)R s , -C(=O)OR s -C(=O)NR p R q ,-CR p (=N)OR s , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -OR s -OC(=O)R s , or -OC(=O)NR p R q And, R E , R F , and R G Any one of the above C1-C6 alkyl or C2-C6 alkenyl is cyano, -C(=O)R s , -C(=O)OR s -C(=O)NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s 、 -OR s -OC(=O)R s , -OC(=O)OR s -OC(=O)NR p Rq, -S (=O) r R s , and -S(=O) r NR p It is optionally replaced by 1 to 3 groups selected from Rq, R p , R q, and R r Each of these is independently a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3-6 member heterocycline. R p , R q , and R r Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R p , R q , and R r Any one of the above C3-C6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1-3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O(C1-C2 alkyl), -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R s Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. R s The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R sThe above C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 1 These are halogens, cyanos, C1-C3 alkyls, C1-C3 haloalkyls, C1-C3 alkoxys, C1-C3 haloalkoxys, or -O-(C3-C6 cycloalkyls). R 2 Each of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl. R 2 The above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R k , -C(=O)OR k -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) s R k 、 -OR k -OC(=O)R k , -OC(=O)OR k -OC(=O)NR h R i -S(=O) s R k, and S(=O) s NR h R i It is optionally replaced by 1 to 3 bases selected from, R h , R i , and R j Each of these occurrences is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. R h , R i , and R j Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R h , R i , and R j Any one of the above C3-C6 cycloalkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. -OR k R must not be -OH, kThe above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k The above C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 3 and R 4 For each of these occurrences, independently, they are halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) t R y 、 -OR y-OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y -S(=O) t NR v R w -S(=O) t NR v C(=O)R y ,-P(=O)R z R z , phenyl, or a 5- or 6-membered heteroaryl, R 3 and R 4 Any one of the above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) r R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y , and -S(=O) t NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R xEach of these occurrences is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocycline, or a 5- or 6-membered heteroaryl group. R v , R w , and R x Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R v , R w , and R x Any one of the above C3-C6 cycloalkyls, the above 5- or 6-membered heterocyclil, or the above 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R y Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a 5- or 6-membered heterocycline group, or a 5- or 6-membered heteroaryl group. R yThe above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R y The above C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R z Each of these occurrences is independently C1-C2 alkyl, -OH, or -O(C1-C2 alkyl). k is an integer selected from 1, 2, and 3. o, p, r, s, and t are each independent integers selected from 1 and 2. 【0170】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F , and R GEach of these independently consists of hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C(=O)NHCH3, -CH2(O )C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridine-2-yl), -CH2(O)(pyrimidine-2-yl), and all other variables not specifically defined in this paragraph are as defined by formulas (XIa), (XIb), (XIc), (XId), (XIe), or (XIf). 【0171】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F and R G These are independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined by equations (XIa), (XIb), (XIc), (XId), (XIe), or (XIf). 【0172】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 1 is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0173】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure contain at least one R 1 However, F is the case, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0174】 In some embodiments, in the compounds, deuterated derivatives, pharmaceutically acceptable salts, or tautomers of the Disclosure, X is either absent or bonded to -(CR a R b )-, or -SO2-, R a and R b However, each occurrence is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0175】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, X is either absent or bonded, -CH2-, or -SO2-, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0176】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 2 However, for each occurrence, independently, it is hydrogen, F, Cl, cyano, -CH3, -CF3, or -NH2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0177】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 3 C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)R y , -C(=O)ORy , -OR y -OC(=O)R y , or -OC(=O)OR y And, R 3 The above C1-C6 alkyl or C2-C6 alkenyl is cyano, -C(=O)R y , -C(=O)OR y , -OR y -OC(=O)R y , and -OC(=O)OR y It is optionally substituted with 1 to 3 groups selected from R y However, for each occurrence, it is independently hydrogen or C1-C4 alkyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0178】 In some embodiments, the compounds of the present disclosure are compounds of formula (XIIa), formula (XIIb), formula (XIIc), formula (XIId), formula (XIIe), or formula (XIIf), [ka] A tautomer thereof, a deuterated derivative thereof or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein in the formula, U is hydrogen or -OH, Y does not exist or is combined with -(CR c R d ) q -, -C(=O)-, or -SO2-, R c and R d Each of these is independently hydrogen, halogen, -OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. Ring A is C3-C 12 Carbocyclyl, 3-12 member heterocyclyl, C6 or C 10 It is an aryl or a 5-10 member heteroaryl, R E, R F , and R G Each of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -C(=O)R s , -C(=O)OR s -C(=O)NR p R q ,-CR p (=N)OR s , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -OR s -OC(=O)R s , or -OC(=O)NR p R q And, R E , R F , and R G Any one of the above C1-C6 alkyl or C2-C6 alkenyl is cyano, -C(=O)R s , -C(=O)OR s -C(=O)NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) r R s 、 -OR s -OC(=O)R s , -OC(=O)OR s -OC(=O)NR p Rq, -S (=O) r R s , and -S(=O) r NR p It is optionally replaced by 1 to 3 groups selected from Rq, Rp , R q , and R r Each of these is independently a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or a 3-6 member heterocycline. R p , R q , and R r Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, C1-C3 alkoxy, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R p , R q , and R r Any one of the above C3-C6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1-3 groups selected from halogen, cyano, -OH, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)O(C1-C2 alkyl), -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R s Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. R s The above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R sThe above C3-C6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 2 Each of these is independently hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl. R 2 The above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R k , -C(=O)OR k -C(=O)NR h R i , -NR h R i , -NR h C(=O)R k , -NR h C(=O)OR k , -NR h C(=O)NR i R j , -NR h S(=O) s R k 、 -OR k -OC(=O)R k , -OC(=O)OR k -OC(=O)NR h R i -S(=O) s R k , and S(=O) s NR h R i It is optionally replaced by 1 to 3 bases selected from, R h , Ri , and R j Each of these occurrences is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. R h , R i , and R j Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R h , R i , and R j Any one of the above C3-C6 cycloalkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. -OR k R must not be -OH, kThe above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R k The above C3-C6 cycloalkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R 3 and R 4 For each of these occurrences, independently, they are halogen, cyano, =O, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w -C(=O)NR v Ure y -C(=O)NR v S(=O) t R y , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) t R y 、 -OR y-OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y -S(=O) t NR v R w -S(=O) t NR v C(=O)R y ,-P(=O)R z R z , phenyl, or a 5- or 6-membered heteroaryl, R 3 and R 4 Any one of the above C1-C6 alkyl, C2-C6 alkenyl, or C3-C6 cycloalkyl is cyano, -C(=O)R y , -C(=O)OR y -C(=O)NR v R w , -NR v R w , -NR v C(=O)R y , -NR v C(=O)OR y , -NR v C(=O)NR w R x , -NR v S(=O) r R y 、 -OR y -OC(=O)R y , -OC(=O)OR y -OC(=O)NR v R w -S(=O) t R y , and -S(=O) t NR v R w It is optionally replaced by 1 to 3 bases selected from, R v , R w , and R xEach of these occurrences is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 5- or 6-membered heterocycline, or a 5- or 6-membered heteroaryl group. R v , R w , and R x Any one of the above C1-C4 alkyl groups is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R v , R w , and R x Any one of the above C3-C6 cycloalkyls, the above 5- or 6-membered heterocyclil, or the above 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R y Each of these is independently hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a 5- or 6-membered heterocycline group, or a 5- or 6-membered heteroaryl group. R yThe above C1-C4 alkyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2alkyl), -N(C1-C2alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2alkyl), -C(=O)NH2, -C(=O)NH(C1-C2alkyl), and -C(=O)N(C1-C2alkyl)2. R y The above C3-C6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 groups selected from halogen, cyano, -OH, -NH2, -NH(C1-C2 alkyl), -N(C1-C2 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, -C(=O)OH, -C(=O)O(C1-C2 alkyl), -C(=O)NH2, -C(=O)NH(C1-C2 alkyl), and -C(=O)N(C1-C2 alkyl)2. R z Each of these occurrences is independently C1-C2 alkyl, -OH, or -O(C1-C2 alkyl). n is an integer selected from 0, 1, 2, and 3. o, q, r, s, and t are each independent integers selected from 1 and 2. 【0179】 In some embodiments, U is -OH. 【0180】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with a C3-C7 carbocyrill, a 6- to 9-membered heterocyclyl, a phenyl, or a 5- to 9-membered heteroaryl, and all other variables not specifically defined in this paragraph are as defined by formula (XIIa), formula (XIIb), formula (XIIc), formula (XIId), or formula (XIIe). 【0181】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with C3-carbocykrill, C4-carbocykrill, or C7-carbocykrill, and all other variables not specifically defined in this paragraph are as defined in formulas (XIIa), (XIIb), (XIIc), (XIId), or (XIIe). 【0182】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The following are optionally substituted, and ring A is phenyl, and all other variables not specifically defined in this paragraph are as defined in formulas (XIIa), (XIIb), (XIIc), (XIId), or (XIIe). 【0183】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, ring A is R 3 The ring A is optionally substituted with pyridine, pyrimidine, pyrazole, thiophene, or oxadiazole, and all other variables not specifically defined in this paragraph are as defined in formulas (XIIa), (XIIb), (XIIc), (XIId), or (XIIe). 【0184】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F , and R GEach of these independently consists of hydrogen, F, -OH, -CH(OH)CH3, -C2H5, -C(=O)NHCH3, -C(=N)OCH3, -CH3, -CH2F, -CH2CN, -(CH2)2CN, -CH2OH, -(CH2)2OH, -CH2OCH3, -CH2OC2H5, -(CH2)2OCH3, -CH2OCHF2, -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, -CH2S(=O)2CH3, -(CH2)2S(=O)2CH3, -CH2(O)C(=O )NHCH3, -CH2(O)C(=O)N(CH3)C2H5, -CH2(O)C(=O)N(CH3)2, -CH2(O)C(=O)N(C2H5)2, -CH2(O)C(=O)NH(cyclopentyl), -CH2(O)C(=O)NH(tetrahydrofuranyl), -CH2(O)(pyridine-2-yl), -CH2(O)(pyrimidine-2-yl), and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0185】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R F and R G These are independently hydrogen, F, -CH(OH)CH3, -CH3, -CH2CN, -CH2OH, and -CH2OCH3, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0186】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 1 is cyano, F, Cl, -CH3, -CHF2, -CF3, -OCH3, or -OCH(CH3)2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0187】 In some embodiments, the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure contain at least one R 1However, F is the case, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0188】 In some embodiments, in the compounds, deuterated derivatives, pharmaceutically acceptable salts, or tautomers of the Disclosure, X is either absent or bonded to -(CR a R b )-, or -SO2-, R a and R b However, each occurrence is independently hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkoxy, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0189】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, X is either absent or bonded, -CH2-, or -SO2-, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0190】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 2 However, for each occurrence, independently, it is hydrogen, F, Cl, cyano, -CH3, -CF3, or -NH2, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0191】 In some embodiments, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, R 3 C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)R y , -C(=O)OR y , -OR y -OC(=O)R y , or -OC(=O)OR yAnd, R 3 The above C1-C6 alkyl or C2-C6 alkenyl is cyano, -C(=O)R y , -C(=O)OR y , -OR y -OC(=O)R y , and -OC(=O)OR y It is optionally substituted with 1 to 3 groups selected from R y However, for each occurrence, it is independently hydrogen or C1-C4 alkyl, and all other variables not specifically defined in this paragraph are as defined in any one of the prior embodiments. 【0192】 In some embodiments, one compound from formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe) is selected from compounds 1 to 457 (Table A below), tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of any of the above. 【0193】 In some embodiments, one compound from formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe) is selected from compounds 458 to 532 (Table B below), tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of any of the above. 【0194】 In some embodiments, one compound from formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe) is selected from compounds P1 to P225 (Table E below), tautomers of these compounds, deuterated derivatives of these tautomers and compounds, and pharmaceutically acceptable salts of any of the above. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 2-1 Table 2-2 Table 2-3 Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 4-1 Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 【0195】 Some embodiments of the present 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 formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) or tautomers thereof. In some embodiments, the above derivative is a silicon derivative in which at least one carbon atom is substituted with silicon in a compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, P1-P225 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) or their tautomers. In some embodiments, the derivative is a boron derivative in which at least one carbon atom is substituted with boron in a compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, P1-P225 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) or their tautomers.In other embodiments, the derivative is a phosphoric acid derivative in which at least one carbon atom is substituted with phosphorus in a compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, P1-P225 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) or their tautomers. Because the general properties of silicon, boron, and phosphorus are similar to those of carbon, the substitution of carbon with silicon, boron, or phosphorus can result in compounds with similar biological activity to those containing the original carbon. 【0196】 In some embodiments, the above derivative is a silicon derivative in which one carbon atom is substituted with silicon in a compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, P1-P225 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) or their tautomers. In other embodiments, two carbon atoms are substituted with silicon. The silicon-substituted carbon atoms may be non-aromatic carbon atoms. In some embodiments, the quaternary carbon atoms of the tert-butyl moiety may be substituted with silicon. In some embodiments, the silicon derivative of the present invention may contain one or more hydrogen atoms substituted with deuterium. For example, one or more hydrogen atoms of the tert-butyl moiety, where carbon is substituted with silicon, may be substituted with deuterium. In other embodiments, silicon derivatives of compounds selected from compounds 1-457, 458-532, B1-B25, W1-W32, P1-P225 (for example, compounds 1-457, or for example, compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457) or formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe) or their tautomers may have silicon incorporated into a heterocycle. 【0197】 In some embodiments, examples of silicon derivatives of compounds 1 to 457 or compounds of formula (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe) include the following compounds: [ka] Variables not specifically defined in the formulas are defined in any one of the following formulas: (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe). 【0198】 In some embodiments, examples of boron derivatives of compounds 1 to 457 or compounds of formula (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe) include the following compounds: [ka] 【0199】 In some embodiments, examples of phosphate derivatives of compounds 1 to 457 or compounds of formula (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe) include the following compounds: [ka] Variables not specifically defined in the formulas are defined in any one of the following formulas: (I), (IIa)~(IIf), (IIIa)~(IIIb), (IVa)~(IVb), (Va)~(Vb), (VIa)~(VIe), (VIIa)~(VIIe), and (IXa)~(IXe). 【0200】 In some embodiments, examples of phosphate derivatives of formula (I) include the following compounds: [ka] Variables not specifically defined in the formula are defined as shown in formula (I). 【0201】 In some embodiments, examples of phosphate derivatives of formula (I) include the following compounds: [ka] Variables not specifically defined in the formula are defined as shown in formula (I). 【0202】 Another aspect of the present disclosure provides a pharmaceutical composition comprising compounds according to any of the formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe), compounds 1 to 457, compounds 458 to 532, compounds B1 to B25, compounds W1 to W32, compounds P1 to P225 (e.g., compounds 1 to 457, or e.g., compounds 1 to 142, 144 to 177, 179 to 399, 401 to 422, 425 to 433, and 435 to 457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and compounds selected from pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a pharmaceutical composition comprising at least one compound selected from formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), as well as 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered to a patient in need. 【0203】 The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the at least one pharmaceutically acceptable is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants. 【0204】 It will also be understood that the pharmaceutical compositions of this disclosure may be used in combination therapy, that is, the pharmaceutical compositions described herein may further contain at least one other active agent. Alternatively, a pharmaceutical composition comprising at least one compound of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), as well as tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may be administered simultaneously with, before, or after a composition containing at least one additional active agent, as a separate composition. 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 P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can be administered simultaneously with, before, or after a composition comprising at least one additional active agent, as a separate composition. 【0205】 In some embodiments, compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are combined with at least one additional active agent for simultaneous, individual, or sequential use in the treatment of AATD. In some embodiments, when used simultaneously, the compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe), tautomers of these compounds, deuterated derivatives of these compounds and their tautomers, and pharmaceutically acceptable salts of any of the foregoing are in a separate pharmaceutical composition from at least one additional active agent. In some embodiments, when used simultaneously, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe), tautomers of these compounds, deuterated derivatives of these compounds and their tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one additional active agent are present together in the same pharmaceutical composition. 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 these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 【0206】 In some embodiments, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe), their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided for use in a method of treating AATD, the method comprising co-administering the compound and an additional active agent. In some embodiments, the compound and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compound and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compound and the additional active agent are co-administered simultaneously. In some embodiments, the compound and the additional active agent are co-administered sequentially. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the above. 【0207】 In some embodiments, combinations of compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe), their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, with additional active agents are provided for use in methods of treating AATD. In some embodiments, the compounds and additional active agents are co-administered in the same pharmaceutical composition. In some embodiments, the compounds and additional active agents are co-administered in separate pharmaceutical compositions. In some embodiments, the compounds and additional active agents are co-administered simultaneously. In some embodiments, the compounds and additional active agents are co-administered sequentially. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the above. 【0208】 In some embodiments, additional active agents are provided for use in methods of treating AATD, the method comprising co-administering the additional active agent with compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compounds and the additional active agent are co-administered in the same pharmaceutical composition. In some embodiments, the compounds and the additional active agent are co-administered in separate pharmaceutical compositions. In some embodiments, the compounds and the additional active agent are co-administered simultaneously. In some embodiments, the compounds and the additional active agent are co-administered sequentially. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the above. 【0209】 In some embodiments, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe), their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing are provided for use in methods of treating AATD, and the compounds are prepared for administration in combination with additional active agents. In some embodiments, the compounds and additional activators are prepared for administration in the same pharmaceutical composition. In some embodiments, the compounds and additional activators are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compounds and additional activators are prepared for co-administration. In some embodiments, the compounds and additional activators are prepared for sequential administration. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the above. 【0210】 In some embodiments, compounds of formulas (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe), their tautomers, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with additional active agents, are provided for use in methods of treating AATD. In some embodiments, the compounds and additional active agents are prepared for administration in the same pharmaceutical composition. In some embodiments, the compounds and additional active agents are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compounds and additional active agents are prepared for co-administration. In some embodiments, the compounds and additional active agents are prepared for sequential administration. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the above. 【0211】 In some embodiments, additional activators are provided for use in methods of treating AATD, and these additional activators are prepared for administration in combination with compounds of formulas (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compounds and additional activators are prepared for administration in the same pharmaceutical composition. In some embodiments, the compounds and additional activators are prepared for administration in separate pharmaceutical compositions. In some embodiments, the compounds and additional activators are prepared for co-administration. In some embodiments, the compounds and additional activators are prepared for sequential administration. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-531, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the above. 【0212】 In some embodiments, the additional active agent is selected from the group consisting of alpha-1 antitrypsin protein (AAT) and recombinant AAT derived from the plasma of a healthy human donor. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) derived from the plasma of a healthy human donor. In some embodiments, the additional active agent is alpha-1 antitrypsin protein (AAT) derived from the plasma of a healthy human donor. 【0213】 As described above, the pharmaceutical compositions disclosed herein may optionally further include at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. When used herein, the at least one pharmaceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersing aid, suspension aid, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compounds of this disclosure, for example, by producing any undesirable biological effect or otherwise interacting in a detrimental manner with any other component of the pharmaceutical composition, its use is intended to be within the scope of this disclosure. 【0214】 Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates, glycine, sorbic acid, and potassium sorbate), partially glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose). This includes, but is not limited to, substances such as ammonium compounds, ethylcellulose, and cellulose acetate, tragacanth powder, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogenic substance-removed water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants. 【0215】 In another aspect of this disclosure, AATD is treated using the compounds and pharmaceutical compositions described herein. In some embodiments, the subjects requiring treatment with the compounds and compositions of this disclosure harbor the ZZ mutation. In some embodiments, the subjects requiring treatment with the compounds and compositions of this disclosure harbor the SZ mutation. 【0216】 In some embodiments, the methods of the present disclosure involve administering to a patient in need a compound selected from any of the compounds of formula (I), (IIa) to (IIf), (IIIa) to (IIIb), (IVa) to (IVb), (Va) to (Vb), (VIa) to (VIe), (VIIa) to (VIIe), and (IXa) to (IXe), these compounds, tautomers of these compounds, deuterated derivatives of these compounds or tautomers, and any pharmaceutically acceptable salts of the foregoing. In some embodiments, the compounds are selected from compounds 1-457, compounds 458-532, compounds B1-B25, compounds W1-W32, and compounds P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the patient requiring it has a Z mutation in the alpha-1 antitrypsin gene. In some embodiments, the patient requiring it is homozygous for the Z mutation in the alpha-1 antitrypsin gene. 【0217】 Another aspect of the present disclosure provides a method for modulating alpha-1 antitrypsin activity, comprising the step of contacting the alpha-1 antitrypsin with at least one compound of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the method for modulating alpha-1-antitrypsin activity includes contacting the alpha-1-antitrypsin with at least one compound selected from compounds 1-457, 458-532, B1-B25, W1-W32, and P1-P225 (e.g., compounds 1-457, or e.g., compounds 1-142, 144-177, 179-399, 401-422, 425-433, and 435-457), tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. 【0218】 In some embodiments, the method for modulating alpha-1 antitrypsin activity is performed in vivo. In some embodiments, the method for modulating alpha-1 antitrypsin activity is performed ex vivo, and the alpha-1 antitrypsin is derived from a biological sample obtained from a human subject. In some embodiments, the method for modulating AAT is performed in vitro, and the alpha-1 antitrypsin is derived from a biological sample obtained from a human subject. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is a sample taken from a liver biopsy. 【0219】 III. Preparation of Compounds All general formulas, quasi-general formulas, and specific compound formulas disclosed herein are considered to be part of the present invention. 【0220】 A. Compounds of formula I The compounds of the present invention can be prepared according to standard chemical practices or as described herein. Throughout the following synthesis schemes and in the descriptions for preparing compounds of formula (I), (IIa)-(IIf), (IIIa)-(IIIb), (IVa)-(IVb), (Va)-(Vb), (VIa)-(VIe), (VIIa)-(VIIe), and (IXa)-(IXe), compounds 1-457, compounds 458-532, compounds B1-B25, compounds W1-W32, compounds P1-P225, tautomers of these compounds, deuterated derivatives of these compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, the following abbreviations are used. Abbreviation BrettPhos Pd G4 = Dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphan, methanesulfonic acid, N-methyl-2-phenylaniline, palladium DIPEA = N,N-diisopropylethylamine or N-ethyl-N-isopropyl-propane-2-amine DMA = Dimethylacetamide DMAP = dimethylaminopyridine DME = Dimethoxyethane DMF = Dimethylformamide DMSO = Dimethyl sulfoxide EtOH = Ethanol alkyl = ethyl acetate HATU = [dimethylamino(triazolo[4,5-b]pyridine-3-yloxy)methylene]-dimethyl-ammonium(phosphate hexafluoride ion) MeOH = methanol MP-TMT scavenger resin = macroporous polystyrene-bonded trimercaptotriazine, equivalent resin bond of 2,4,6-trimercaptotriazine (TMT) MTBE = Methyl tert-butyl ether NMM = N-methylmorpholine NMP = N-methylpyrrolidine Pd(dppf)2Cl2=[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) PdCl2 = Palladium(II) dichloride PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride SFC = Supercritical Fluid Chromatography SPhos Pd G3 = (2-dicyclohexylphosphin-',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TBAF = Tetrabutylammonium fluoride tBuXPhos Pd G1 = Chloro[2-(di-tert-butylphosphin)-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) or t-BuXPhos palladium(II) phenethylamine chloride tBuXPhos Pd G3=[(2-di-tert-butylphosphin-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuXPhos Pd G4 = Ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphan, dichloromethane, methanesulfonate, N-methyl-2-phenylanilynpalladium(II) TEA = Triethylamine TFA = Trifluoroacetic acid THF = Tetrahydrofuran XPhos Pd G1 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride or (XPhos)palladium(II)phenethylamine chloride 【0221】 In some embodiments, the process for preparing the compound of formula (I), its tautomer, deuterated derivatives of those compounds and tautomers, or any pharmaceutically acceptable salt thereof, includes reacting the compound of formula (I), its tautomer, its deuterated derivative, or any pharmaceutically acceptable salt thereof with a deprotection agent, as shown in schemes 1 to 11 below (wherein all variables are as defined for formula (I) above). 【0222】 [ka] Scheme 1 shows a method for preparing the compound of formula 1-2. PG 1 These are alcohol protecting groups such as benzyl (Bn), methoxymethyl (MOM), or methyl (Me). In some examples, PG 1 When the group is a benzyl group, the compounds of formula 1-2 can be prepared by hydrogen decomposition of the compound of formula 1-1 using a palladium-carbon catalyst under a hydrogen atmosphere. The reaction can be carried out under high pressure. Solvents such as MeOH, EtOH, or SiO can be used. PG 1 However, if the group is MOM or similar, the compound of formula (I) can be prepared by treatment with an acid such as HCl. PG 1 However, in cases where it is a methyl group, this group can be removed by treatment with AlCl3 in the presence of octanthiol. In some cases... 、 Reagents such as BBr3 may be used. The compounds of formula 1-2 can be prepared from the compounds of formula 1-1 using any other standard method suitable for removing the alcohol protecting group. 【0223】 [ka] Scheme 2 shows a method for preparing the compounds of formula 2-5. Q 1 R is a halogen such as Br, I, or Cl. The compound of formula 2-3 is any suitable alkyl group (such as Me, Et, etc.) or hydrogen R. 20It is a boronic acid or ester having . All other variables are defined as above. The compound of formula 2-1 can be converted to the compound of formula 2-2 using any suitable method for halogenation of the aromatic ring. For example, N-iodosuccinimide (NIS) or N-bromosuccinimide (NBS) in a solvent such as dichloromethane can be used. The compound of formula 2-4 can be prepared from 2-2 and 2-3 using standard Suzuki coupling conditions. In some examples, the Suzuki coupling conditions may include a catalyst such as Pd(dppf)Cl2 and a base such as Na2CO3. In some examples, a catalyst such as Pd2(dba)3 can be used in the presence of a ligand such as XPhos, for example. A solvent such as DMF or DME may be used. The reaction is carried out in the presence of additional heating (e.g., 90°C). The compound of formula 2-5 can be prepared from formula 2-4 using any suitable method for removal of the alcohol protecting group. 【0224】 [ka] The process for preparing the compounds of formula 3-4 is shown in Scheme 3. PG 2 is any suitable carboxylic acid protecting group. For example, PG 2 is Me, Et, benzyl, or tert-butyl. All other variables are defined as above. The compound of formula 3-2 can be prepared from the compound of formula 3-1 using any suitable method for Suzuki coupling. For example, Pd(dppf)Cl2 may be used in the presence of Na2CO3. The compound of formula 3-3 can be prepared from the compound of formula 3-2 using any suitable method for removing the carboxylic acid protecting group. For example, PG 2 If it is a methyl ester, hydrolysis using a base such as LiOH or NaOH in a solvent such as THF and water can be used. PG 2 However, if the group is such as tert-butyl, for example, the compound of formula 3-3 can be obtained by treatment with an acid such as TFA or HCl. In some examples, PG 1 and PG2 If both are benzyl groups, the compounds of formula 3-4 can be prepared directly from the compounds of formula 3-2 by hydrogenation. 【0225】 [ka] Scheme 4 shows the process for preparing the compound of formula 4-4. All variables are defined as above. The compound of formula 4-2 can be prepared by reductive alkylation between the indole of formula 2-1 and the ketone of formula 4-1. In some examples, the reductive alkylation can be carried out in the presence of a reagent such as triethylsilane and an acid (such as trifluoroacetic acid or methanesulfonic acid). The reaction may also be carried out in a solvent such as dichloromethane. 【0226】 [ka] Scheme 5 shows a method for preparing the compounds of formula 5-4. All variables are defined as above. The compounds of formula 5-2 can be prepared from the ketone or aldehyde of formula 5-1 and the indole of formula 2-1 using any suitable conditions for carrying out reductive alkylation. In some examples, the reaction can be carried out in the presence of triethylsilane and trifluoroacetic acid. Solvents such as dichloromethane may be used. The reaction can also be carried out in the presence of additional heating (e.g., 40°C). 【0227】 [ka] Scheme 6 shows the process for preparing indole in Equation 2-1. Q 2 and Q 3 This is a halogen such as Br, Cl, or I. 1 Q is either hydrogen or SiMe3. For example, in some processes, 2 Q is iodine, 3is bromine. In some examples, the compounds of formula 6-3 can be prepared from the compounds of formula 6-1 and the alkynes of formula 6-2 using any suitable conditions for carrying out the Sonogashira coupling. In some examples, catalysts such as Pd(PPh3)2Cl2 in the presence of CuI may be used. Bases such as triethylamine or diisopropylethylamine may also be used. The reaction can be carried out in a solvent such as DMF in the presence of additional heating. In some examples, E 1 However, if SiMe3 is used, the reaction can be carried out in the presence of TBAF. The compounds of formula 6-5 can be prepared from the compounds of formula 6-3 by transition metal-catalyzed amination using the amine of formula 6-4. The amination can be carried out in the presence of a palladium catalyst such as tBuXPhosPd G3, tBu XPhosPd G, or any other catalyst suitable for Buchwald amination. A base such as NaOtBu may also be used. The reaction can be carried out in a solvent such as xylene. The reaction can be carried out at room temperature or in the presence of additional heating. In some examples, cyclization to the compounds of formula 2-1 occurs spontaneously in the amination reaction. In some examples, the compounds of formula 2-1 from formulas 6-5 are prepared by treatment with PdCl2 in a solvent such as MeCN. The reaction can be carried out with additional heating (e.g., 50°C). 【0228】 [ka] Scheme 7 shows an alternative process for preparing the compound of formula 6-5. Q 4 R is a halogen such as Br or I. 21is hydrogen or a suitable alkyl group, such as ethyl or methyl. The aniline of formula 7-1 can be arylated with a boronic acid or ester 7-2 using any suitable N-arylation conditions to obtain the compound of formula 7-3. In some examples, a Cu(OAc)2 catalyst can be used. The reaction can be carried out in the presence of a base such as K2CO3. A solvent such as DMSO may also be used. The compound of formula 6-5 can be prepared by Sonogashira coupling of the compound of formula 7-3 with the alkyne of formula 7-4 to obtain the compound of formula 6-5. 【0229】 [ka] Scheme 8 shows a process for preparing compounds of formula 8-7 from dihaloaryl compounds of general formula 8-1. Q 5 is a halogen such as Cl, Br, or I. In some embodiments, group A is an aromatic ring or an aromatic heterocycle. Compound 8-3 is obtained by amination of the compound of formula 8-1 with the amine of formula 8-2. Any suitable method for amination of aryl halides with amines may be used. For example, the reaction may be carried out in the presence of a ligand such as dppf and a catalyst such as Pd(OAc)2. In some examples, the reaction may be carried out in the presence of tBuXPhosPd G1. The reaction may be carried out in the presence of a base such as NaOtBu. The indole of formula 8-5 can be prepared by reacting the compound of formula 8-3 with the disubstituted alkyne of formula 8-4 in the presence of a suitable palladium catalyst. For example, catalysts such as Pd(tBu3P)2 or JackiePhosPd G3 may be used. In some alternative embodiments, Pd(OAc)2 may be used. The reaction is carried out in the presence of a suitable ligand. For example, dicyclohexylmethylamine (cHx)2NMe can be used. The reaction may be carried out in a solvent such as 1,4-dioxane in the presence of additional heating (e.g., 60°C). 【0230】 [ka] As shown in Scheme 9, any preferred conditions for the Sonogashira coupling of the compound of formula 9-1 and the alkyne of formula 9-2 can be used for the preparation of the compound of formula 9-3. PG 4 is any suitable ester protecting group (e.g., benzyl, methyl, tert-butyl), and all other variables are defined as above. The compounds of formula 9-5 can be prepared from the compounds of formula 9-3 and the amines of formula 9-4 using any suitable method for the amination of aryl halides. In some embodiments, the reaction is carried out in the presence of a tBuXPhosPd G3 catalyst and NaOtBu. Solvents such as m-xylene may be used. The compounds of formula 9-6 can be prepared from the indole of formula 9-5 using any suitable halogenating reagent. For example, N-iodosuccinimide or N-bromosuccinimide can be used. In some embodiments, the compounds of formula 9-8 can be prepared by Suzuki coupling of the compounds of formula 9-7 and 9-6 using a suitable palladium catalyst and base. For example, Pd(dppf)Cl2 and K2CO3 can be used. The compounds of formulas 9-10 can be prepared from the compounds of formula 9-8 using standard methods for removing ester and alcohol protecting groups, suitable for the protecting groups used in the embodiments. 【0231】 [ka] Scheme 10 shows the process for preparing the compound of formula 10-7. Q 8 These are halogens such as Br, I, or Cl. PG 4 These are standard amine protecting groups (e.g., Bn, Boc, CBz). PG 5is an ester protecting group such as Me, Et, or tert-butyl. Compounds of formula 10-3 can be prepared from the compound of formula 10-1 and the 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 carried out in the presence of a base such as sodium tert-butoxide. Compounds of formula 10-5 can be prepared from the alkynes of 10-3 and 10-4 using any suitable conditions for the Laroc indole cyclization. For example, a catalyst 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 carried out in the presence of a suitable ligand. For example, dicyclohexylmethylamine (cHx)2NMe can be used. The reaction may be carried out in a solvent such as 1,4-dioxane and in the presence of additional heating (e.g., 60°C). The compounds of formula 10-6 can be prepared from 10-5 using any preferred method for removing the ester protecting group. For example, PG 5 If the group is methyl, a base such as LiOH or NaOH may be used. Compounds of formula 10-7 can be prepared from 10-6 using any suitable conditions for the removal of the nitrogen protecting group. For example, PG 4 If the group is a benzyl group, hydrogenation using a palladium-carbon catalyst under a hydrogen atmosphere can be used. In some embodiments, the reaction can be carried out in a solvent such as THF. 【0232】 [ka] Scheme 11 describes another method for preparing the compounds of formula 11-3. Ring B is an alkyl or alkoxy group. Compounds of formula 11-3 are obtained by a reductive amination reaction between an amine of formula 11-1 and a ketone or aldehyde of formula 11-2. In some examples, the reductive amination can be carried out using a reagent such as sodium triacetoxyborohydride. A solvent such as AcOH may also be used. The reaction may be carried out at room temperature. [Examples] 【0233】 The following examples are provided so that the disclosures described herein may be understood more fully. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way. 【0234】 Example 1 Compound Synthesis All specific and general compounds, methods for producing those compounds, and intermediates disclosed for producing those compounds are considered to be part of the disclosures disclosed herein. 【0235】 A. Synthesis of starting materials The preparation of S1 to S22 describes the synthetic route to the intermediates used in the synthesis of compounds 1 to 457. 【0236】 Preparation of S1 4-benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-tetrahydropyran-4-yl-indole(S1) [ka] Step 1. Synthesis of 1-benzyloxy-3-bromo-2-iodobenzene (C2) A solution of 3-bromo-2-iodophenol C1 (129 g, 431.6 mmol) in acetone (1.5 L) was stirred for 5 minutes. K2CO3 (75 g, 542.7 mmol), NaI (21 g, 140.1 mmol), and bromomethylbenzene (55 mL, 462.4 mmol) were added. The reaction mixture was stirred at 55°C for 7 hours. The mixture was then cooled to room temperature, filtered, and washed with acetone (2 × 100 mL). The combined filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane (1.5 L) and washed with water (2 × 100 mL) and brine (100 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. The product was obtained as a white solid (162 g, 96%) by purification by silica gel chromatography (0-50% ethyl acetate in heptane). 1 ¹H NMR (300MHz, chloroform-d) δ 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, 1.3Hz, 1H), 7.15 (t, J=8.1Hz, 1H), 6.76 (dd, J=8.2, 1.3Hz, 1H), 5.16 (s, 2H). 【0237】 Step 2.4 - Synthesis of [2-(2-benzyloxy-6-bromophenyl)ethynyl]tetrahydropyran (C3) 1-Benzyloxy-3-bromo-2-iodobenzene C2 (200 g, 514.1 mmol), trimethyl(2-tetrahydropyran-4-ylethynyl)silane (140 g, 767.8 mmol), 1,4-dioxane (1200 mL), NET3 (430 mL, 3.09 mol), TBAF (720 mL from 1 M, 720.0 mmol solution in THF), and water (20 mL, 1.1 mol). The mixture was purged with N2 for a further 10 minutes, and CuI (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, and after 6.5 hours, the heat was removed and the mixture was stirred at room temperature overnight. Water (1 L) and saturated NH4Cl (500 mL) were added, the mixture was stirred for 10 minutes, and then divided into two equal parts. Each part was extracted with toluene (1.5 L), and the organic extract was sequentially washed with 1 M HCl (1 L) solution and brine (1 L), then dried (MgSO4), filtered, and concentrated. The two parts were combined and dissolved in dichloromethane (300 mL). The product was obtained as an amber-colored oil (151 g, 79%) by silica gel chromatography (1.6 kg silica gel; gradient: 0-40% toluene in heptane). 1 H NMR (300MHz, chloroform-d) δ7.33-7.25(m,2H), 7.25-7.10(m,3H), 7.03(dd,J=8. 1,1.0Hz,1H), 6.89(t,J=8.2Hz,1H), 6.68(dd,J=8.3,1.0Hz,1H), 4.97(s,2H) , 3.79(ddd,J=11.6,6.9,3.4Hz,2H), 3.40(ddd,J=11.2,7.2,3.3Hz,2H), 2.84 (tt,J=7.7,4.2Hz,1H), 1.85-1.70(m,2H), 1.61(dtd,J=13.2,7.3,3.2Hz,2H). 【0238】 Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline (C4) A solution of 4-[2-(2-benzyloxy-6-bromophenyl)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, followed by bubbling with N2 for 15 minutes. 3,4-difluoroaniline (84 mL) was added, followed by purging with N2 for 15 minutes. tBuXPhos Pd G3 (15 g, 18.9 mmol) was added, followed by purging with N2 for a further 10 minutes. The mixture was stirred, and after 90 minutes, the internal temperature rose from 21°C to 29°C. After a further 2.5 hours, the internal temperature decreased 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 was stirred at 50°C for a further 2 hours. The reaction mixture was poured into ice water (6 L), and then 2-MeTHF (3 L) was added. After stirring, the layers were separated. The organic layer was successively washed with water (4 L), 1 M aqueous HCl (3 L), saturated aqueous NaHCO3 (3 L), and brine (3 L). The organic layer was then dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (3 kg silica gel; gradient: 0-40% ethyl ethyl phosphate in heptane) yielded product 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline C4 as a brown oily substance in a 2:1 mixture with cyclization product C5 (277 g, 94%). The mixture was carried over to the next step without further purification. 【0239】 Step 4. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole (C5) A solution of 3-benzyloxy-N-(3,4-difluorophenyl)-2-(2-tetrahydropyran-4-ylethynyl)aniline (277 g, 660.4 mmol) (a mixture of approximately 2:1 aniline C4:indole C5) in MeCN (1.9 L) was purged with nitrogen for 15 minutes. PdCl2 (3.5 g, 19.7 mmol) was added, and the reaction mixture was placed under positive pressure of N2 and 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, the solid was collected, washed with heptane (400 mL), and dried under suction to obtain approximately 150 g of an off-white solid. The filtrate was concentrated to obtain approximately 100 g of the product as a dark oily substance, which was purified by silica gel chromatography (1.6 kg silica gel column, gradient: 0-40% ethyl acetate in heptane) (Note: the compound precipitates on the column, resulting in product loss) to obtain an additional product (approximately 90 g) as an off-white solid. This portion of the product from column chromatography was combined with the product isolated from the reaction mixture. The mixture was treated with ethyl acetate (300 mL), the slurry was heated under 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 obtain the product (224.6 g) as slightly off-white crystals. The filtrate yielded an additional 8.0 g of off-white crystals, which were combined with the first harvest to obtain the product 4-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole (232.6 g, 84%). 1¹H NMR (300MHz, chloroform-d) δ 7.59-7.51 (m, 2H), 7.48-7.31 (m, 4H), 7.24 (ddd, J=10.4, 7.0, 2.5Hz, 1H), 7.14 (dddd, J=8.7, 4.1, 2.5, 1.6Hz, 1H), 7.09-7.00 (m, 1H), 6. 66(d,J=0.7Hz,1H), 6.64(s,2H), 5.26(s,2H), 4.00(ddd,J=11.7,4.2,1.8Hz,2H ), 3.37(td,J=11.7,2.4Hz,2H), 2.80(tt,J=11.4,4.0Hz,1H), 1.95-1.66(m,4H). 19F NMR (282MHz, chloroform-d) δ -134.09 (d, J = 21.5 Hz), -136.75 (d, J = 21.7 Hz). LCMS m / z 419.9[M+1] + . 【0240】 Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (S1) To a solution of 4-benzyloxy-1-(3,4-difluorophenyl)-2-tetrahydropyran-4-yl-indole C5 (159 g, 379.1 mmol) in CH2Cl2 (2.5 L) cooled to 0°C (ice / water bath), 1-iodopyrrolidine-2,5-dione (96 g, 413.9 mmol) was added 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 solution of Na2S2O3 (600 mL). The organic layer was separated and successively washed with saturated aqueous solution of NaHCO3 (approximately 600 mL) and brine (approximately 600 mL each). The organic layer was dried (MgSO4), filtered, and concentrated. The residue was treated with siRNA (approximately 200 mL) and heated under reflux for 15 minutes to obtain a suspension. The suspension was treated with heptane (approximately 1 L), and the resulting suspension was slowly allowed to return to room temperature over 14 hours (overnight) before being filtered. The collected solid was washed with heptane (100 mL) and then dried in a vacuum oven at 45°C for 2 hours to obtain the product as a yellowish-brown solid (180 g, 86%). 1H NMR(300MHz,DMSO-d6)δ7.81-7.54(m,4H), 7.49-7.37(m,2H), 7.37-7.26(m,2H), 6.99(t,J=8.1Hz,1H), 6.73(d,J=7.9Hz,1H), 6.43(d,J=8.2Hz, 1H), 5.26(s,2H), 3.86(dd,J=11.5,4.1Hz,2H), 3.21(ddd,J=12.0,9.8,5 .1Hz,2H), 3.06-2.84(m,1H), 2.19(dt,J=12.7,4.7Hz,2H), 1.56(s,2H). 19 F NMR (282MHz, DMSO-d6) δ -135.42, -135.50, -136.83, -136.91. LCMS m / z 545.21[M+1] + . 【0241】 Preparation of S2 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole(S2) [ka] Step 1. Synthesis of 3-benzyloxy-2-bromo-4-fluoroaniline C7 KOtBu (8.68 g, 77.4 mmol) was added to a solution of 3-amino-2-bromo-6-fluorophenol C6 (15.6 g, 75.8 mmol) and chloromethylbenzene (9.6 g, 75.8 mmol) in DMF (120 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with SiO2, and washed with water. The organic layer was dried and concentrated. The crude product was purified over silica gel (gradient: hexane, 10-40% SiO2) to obtain the product. 3-benzyloxy-2-bromo-4-fluoroaniline (17.8 g, 75%) LCMS m / z 295.94 [M+H] + . 【0242】 Step 2.3 Synthesis of benzyloxy-4-fluoro-2-iodoaniline (C8) 3-Benzyloxy-2-bromo-4-fluoroaniline (7.36 g, 24.9 mmol), NaI (15 g, 100.1 mmol), N,N'-dimethylethane-1,2-diamine (780 mg, 8.9 mmol), and CuI (980 mg, 5.146 mmol) were mixed in 1,4-dioxane (60 mL). The reaction mixture was stirred in a sealed container and heated overnight at 140°C. The reaction mixture was cooled to room temperature, diluted with SiO2 (100 mL), and filtered through a Celite® plug. The filtrate was washed with water and brine and dried over Na2SO4. After removing the solvent, the crude product was purified over silica gel (220 g column, 10-90% SiO2 in hexane) to obtain the desired product. 3-Benzyloxy-4-fluoro-2-iodoaniline (7.5g, 84%) LCMS m / z 344.17[M+H] + . 【0243】 Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-iodoaniline (C9) 3-Benzyloxy-4-fluoro-2-iodoaniline (2.68 g, 7.810 mmol), (3,4-difluorophenyl)boronic acid (1.82 g, 11.53 mmol), K2CO3 (3.2 g, 23.15 mmol), and diacetoxy copper (1.68 g, 9.25 mmol) were mixed in DMSO (20 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with siRNA and filtered through a Celite® plug. The filtrate was washed with water. The organic layer was dried and concentrated. The crude product was purified by silica gel (120 g column, 10-40% siRNA in hexane) to obtain the desired product: 3-Benzoyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-iodoaniline (1.8 g, 41%). LCMS m / z calculated value: 455.87 [M+H] + . 【0244】 Step 4. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (C10) 3-Benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-iodoaniline (1.8 g, 3.56 mmol), 4-ethynyltetrahydropyran (600 mg, 5.45 mmol), PdCl2(PPh3)2 (400 g, 569.9 mmol), and CuI (110 mg, 0.58 mmol) were mixed in 1,4-dioxane (10 mL) and Et3N (10 mL), and the reaction was degassed with nitrogen for 30 seconds. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The organic layer was dried and concentrated. The crude product was purified by silica gel (4 g column, 10-40% Hex: ethyl acetate) to obtain the desired product. 3-Benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (1.2g, 75%) LCMS m / z 438.1[M+1]+. 【0245】 Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl-indole (C11) 3-Benzyloxy-N-(3,4-difluorophenyl)-4-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (1.6 g, 3.658 mmol) was dissolved in MeCN (20 mL), and PdCl2 (120 mg, 0.68 mmol) was added. The reaction mixture was heated overnight at 45°C. The reaction mixture was cooled to room temperature and filtered through a Celite® plug. The crude product was diluted with ethyl acetate and washed with water. The organic layer was dried and concentrated. The product was purified by silica gel chromatography (40 g column, 10-90% ethyl acetate in hexane) to obtain the product: 4-Benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl-indole (1.4 g, 77%). 1H NMR(400MHz,DMSO-d6)δ7.76(ddd,J=11.2,7.2,2.6Hz,1H), 7.68(dt,J=10.6,8.9Hz,1H), 7.58-7.49(m,2H), 7.47-7.39(m, 2H), 7.39-7.29(m,2H), 6.95(dd,J=11.8,8.8Hz,1H), 6.65(ddd,J=8.8,3.5,0.8Hz,1H), 6.60(d,J=0.8Hz,1H), 5.29(s,2H). LCMS m / z 438.06[M+1] + 【0246】 Step 6. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (S2) A solution of 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-2-tetrahydropyran-4-yl-indole (730 mg, 1.33 mmol) in dichloromethane (10 mL) and 1-iodopyrrolidine-2,5-dione (345 mg, 1.533 mmol) was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The organic layer was dried and concentrated. The crude product was purified using silica gel (4 g column, 10-40% Hex: ethyl acetate) to obtain the desired product: 4-benzyloxy-1-(3,4-difluorophenyl)-5-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (720 mg, 81%). 1H NMR(400MHz,DMSO-d6)δ7.80(ddd,J=11.1,7.3,2.6Hz,1H), 7.71(dt,J=10.6,8.9Hz,1H) , 7.64-7.57(m,2H), 7.50-7.32(m,4H), 7.06(dd,J=11.5,8.9Hz,1H), 6.61(dd,J=8.9,3. 7Hz,1H), 5.13(s,2H), 3.87(dd,J=11.5,4.2Hz,2H), 3.22(tdd,J=12.0,7.2,2.0Hz,2H), 2.93(tt,J=12.4,3.6Hz,1H), 2.21(tq,J=16.6,5.7,4.4Hz,2H), 1.58(t,J=10.1Hz,2H). LCMS m / z 563.08[M+H] + . 【0247】 Preparation of S3 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole(S3) [ka] Step 1. Synthesis of 1-benzyloxy-3-bromo-5-fluoro-2-iodobenzene (C13) A mixture of 3-bromo-5-fluoro-2-iodophenol C12 (50 g, 157.8 mmol), bromomethylbenzene (27.8 g, 162.5 mmol), NaI (4 g, 26.7 mmol), and K2CO3 (45 g, 325.6 mmol) in acetone (500 mL) was stirred overnight at room temperature. The reaction mixture was then filtered through Celite®, the filtrate was concentrated to dryness, and purified by silica gel chromatography (gradient: 0-40% CH2Cl2 in heptane) to obtain the product as a white solid: 1-benzyloxy-3-bromo-5-fluoro-2-iodobenzene (55 g, 81%). LCMS m / z 406.56 [M+1] + . 【0248】 Step 2.4 - Synthesis of [2-(2-benzyloxy-6-bromo-4-fluorophenyl)ethynyl]tetrahydropyran (C14) A solution of 1-benzyloxy-3-bromo-5-fluoro-2-iodobenzene C13 (19 g, 46.7 mmol), PdCl2(PPh3)2 (1.98 g, 2.8 mmol), and CuI (890 mg, 4.673 mmol) in anhydrous DMF (150 mL) was degassed for 10 minutes. Then, trimethyl(2-tetrahydropyran-4-ylethynyl)silane (9.78 g, 53.64 mmol) and diethylamine (7.22 mL, 69.8 mmol) were added, followed by TBAF (54 mL from 1 M, 54.00 mmol in THF). The reaction mixture was stirred overnight at 65°C. After cooling the mixture to room temperature, the mixture was diluted with water and extracted with ethylethanol. The organic layer was concentrated to dryness. The product was purified by silica gel chromatography (gradient: 0-30% ethylethanol in heptane) to obtain a pale yellow solid. 4-[2-(2-benzyloxy-6-bromo-4-fluorophenyl)ethynyl]tetrahydropyran (11.3g, 62%). 1 H NMR (400MHz, chloroform-d) δ7.51-7.42(m,2H), 7.41-7.35(m,3H), 6.96(dd,J=8.1,2.4Hz,1H), 6.61(dd,J=10.3,2.4Hz,1H), 5.10( s,2H), 3.94(ddd,J=11.5,6.9,3.3Hz,2H), 3.61-3.53(m,2H), 2.99(tt,J=7.7,4.2Hz,1H), 1.97-1.88(m,2H), 1.83-1.72(m,2H). 【0249】 Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (C15) A solution of 4-[2-(2-benzyloxy-6-bromo-4-fluorophenyl)ethynyl]tetrahydropyran C14 (2 g, 5.14 mmol) and 3,4-difluoroaniline (930 mg, 7.2 mmol) in xylene (30 mL) (a light brown solution) was purged with nitrogen for 10 minutes, and then NaOtBu (1.5 g, 15.61 mmol) and tBuXPhos Pd G3 (200 mg, 0.25 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to room temperature, and then ice water (20 mL) and siRNA (50 mL) were added. The organic layer was separated and washed with brine. The product was purified by silica gel chromatography (gradient: 0-30% siRNA in hexane) to obtain a pale yellow solid. 3-Benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline (2.2g, 97%). 1 ¹H NMR (400MHz, chloroform-d) δ 7.54-7.45 (m, 2H), 7.42 (ddd, J=7.9, 7.0, 1.1Hz, 2H), 7.39-7.31 (m, 1H), 7.16 (dt, J=10.0, 8.8Hz, 1H), 7.06 (ddd, J=11.6, 6.9, 2.7Hz, 1H), 6.92 (dddd, J=8.5, 4.0, 2.6, 1.6Hz, 1H), 6.50 (s, 1H), 6.43 (dd,J=11.0,2.3Hz,1H), 6.21(dd,J=10.5,2.3Hz,1H), 5.13(s,2H), 3.94(ddd,J=11.6,6.2,3.5Hz,2H), 3.56(d dd,J=11.4,8.0,3.1Hz,2H), 3.01(tt,J=8.2,4.1Hz,1H), 2.03-1.89(m,2H), 1.78(dtd,J=13.3,8.1,3.5Hz,2H). LC-MS m / z 438.3[M+1] + . 【0250】 Step 4. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-tetrahydropyran-4-yl-indole (C16) A solution of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(2-tetrahydropyran-4-ylethynyl)aniline C15 (14.5 g, 33.0 mmol) in MeCN (150 mL) (a light brown solution) was mixed with PdCl2 (600 mg, 3.4 mmol). The reaction mixture was heated at 60°C for 12 hours. The solution was concentrated to dryness and purified by silica gel chromatography (gradient: 0-25% ethyl acetate in heptane) to obtain a white solid. 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-tetrahydropyran-4-yl-indole (13.6 g, 94%) LCMS m / z 438.3 [M+1] + . 【0251】 Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (S3) To a solution of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-tetrahydropyran-4-yl-indole C16 (46.7 g, 106.8 mmol) in dichloromethane (875 mL) at 3.5 °C (ice bath), N-iodosuccinimide (26.4 g, 117.3 mmol) was added. The ice bath was gradually warmed to room temperature, and the reaction mixture was stirred for 18 hours. The reaction mixture was successively washed with 1 M sodium thiosulfate aqueous solution, saturated NaHCO3 aqueous solution, and brine (800 mL each), then dried (MgSO4), filtered, and concentrated. The residue was treated with siRNA (100 mL), and the resulting suspension was evaporated in a rotary evaporator at 75 °C for 1 hour. The suspension was treated with heptane (100 mL) and then left at room temperature for 2 hours. The obtained crystals were isolated by filtration, washed with heptane (100 mL), and then dried under suction to obtain the product as an off-white solid: 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-tetrahydropyran-4-yl-indole (54.6 g, 91%). 1H NMR(300MHz,DMSO-d6)δ7.82-7.56(m,4H), 7.49-7.38(m,2H), 7.38-7.26(m, 2H), 6.70(dd,J=12.0,2.1Hz,1H), 6.24(dd,J=9.4,2.1Hz,1H), 5.28(s,2H), 3 .85(dd,J=11.4,4.1Hz,2H), 3.20(tdd,J=11.7,5.4,2.0Hz,2H), 2.91(ddd,J =12.5,8.8,3.7Hz,1H), 2.16(dq,J=17.6,7.2,6.2Hz,2H), 1.65-1.44(m,2H). 19 F NMR (282MHz, DMSO-d6) δ -116.95, -135.20 (d, J = 22.9 Hz), -136.62 (d, J = 22.9 Hz). LCMS m / z 563.12[M+1]+. 【0252】 Preparation of S4 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole(S4) [ka] Step 1.4 Synthesis of (2-benzyloxy-6-bromo-4-fluorophenyl)-2,2-dimethylbuta-3-in-1-ol (C17) A solution of 1-benzyloxy-3-bromo-5-fluoro-2-iodobenzene C13 (5 g, 12.3 mmol) and 2,2-dimethylbuta-3-in-1-ol (1.8 g, 18.3 mmol) in 1,4-dioxane (40 mL) and Et3N (40 mL) was purged with nitrogen for 10 minutes, and then CuI (157 mg, 0.82 mmol) and PdCl2(PPh3)2 (500 mg, 0.71 mmol) were added. The resulting reaction mixture was heated to 50°C and stirred overnight. The reaction mixture was cooled to room temperature, poured into water (50 mL), and partitioned between saturated NH4Cl aqueous solution (approximately 50 mL) and ethyl acetate (approximately 150 mL). After stirring for 10 minutes, the organic layer was separated, washed with 1N HCl solution (2 × 50 mL), water (30 mL), and brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 0-70% ethyl acetate in heptane) to obtain the product as a clear yellow viscous oil: 4-(2-benzyloxy-6-bromo-4-fluorophenyl)-2,2-dimethylbuta-3-in-1-ol (4.23 g, 90%). 1 H NMR (400MHz, chloroform-d) δ7.49(dtd,J=6.9,1.4,0.7Hz,2H), 7.46-7.32(m,3H), 6.98(dd,J=8. 0,2.4Hz,1H), 6.65(dd,J=10.2,2.4Hz,1H), 5.12(s,2H), 3.49(d,J=7.1Hz,2H), 1.34(s,6H). LCMS m / z 377.01[M+1] + . 【0253】 Step 2. Synthesis of 1-benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3-dimethylbuta-1-inyl)benzene (C18) Under nitrogen, a mixture of 4-(2-benzyloxy-6-bromo-4-fluorophenyl)-2,2-dimethylbuta-3-in-1-ol C17 (3.65 g, 9.5 mmol) and iodomethane (1.5 mL, 24.1 mmol) in THF (50 mL) was cooled to 0°C. NaH (600 mg, 15.0 mmol) was added, and the resulting reaction mixture was stirred and warmed to room temperature. The mixture was poured into water (50 mL), partitioned between saturated NH4Cl aqueous solution (approximately 50 mL) and ethyl acetate (approximately 150 mL), and then stirred for 10 minutes. The organic layer was separated and washed sequentially with 1N HCl solution (2 × 50 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the product as a dark oily substance, which was converted to a brown solid under vacuum. 1-Benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3-dimethylbuta-1-inyl)benzene (3.8g, 100%). 1 H NMR(400MHz,CD3CN)δ7.51(dtd,J=6.9,1.4,0.7Hz,2H), 7.46-7.32(m,3H), 7.06(dd,J=8.4,2 .4Hz,1H), 6.87(dd,J=10.8,2.4Hz,1H), 5.13(s,2H), 3.32(s,3H), 3.31(s,2H), 1.27(s,6H). LCMS m / z 390.96[M+1] + . 【0254】 Step 3. Synthesis of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(4-methoxy-3,3-dimethylbuta-1-inyl)aniline (C19) To a solution of 1-benzyloxy-3-bromo-5-fluoro-2-(4-methoxy-3,3-dimethylbuta-1-inyl)benzene C18 (667 mg, 1.71 mmol) and 3,4-difluoroaniline (330 mg, 2.56 mmol) in degassed xylene (12 mL), NaOtBu (500 mg, 5.20 mmol) was added, followed by 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), the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic matter was concentrated to dryness and purified by elution using silica gel chromatography (gradient: 0-25% ethyl acetate in heptane), yielding the product as a brown oily substance. 3-Benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(4-methoxy-3,3-dimethyl-buta-1-inyl)aniline (667 mg, 89%). 1 H NMR (400MHz, chloroform-d) δ7.53(d,J=7.3Hz,2H), 7.42(dd,J=8.1,6.8Hz,3H), 7. 39-7.33(m,1H), 7.16(dt,J=10.4,8.9Hz,1H), 7.07(ddd,J=11.8,6.9,2.6Hz,1H ), 7.01-6.89(m,2H), 6.46(dt,J=11.1,1.7Hz,1H), 6.18(dt,J=10.7,1.5Hz,1H ), 5.14(s,2H), 3.41(d,J=1.0Hz,3H), 3.37(d,J=1.1Hz,2H), 1.43-1.33(m,6H). LCMS m / z 440.42[M+1] + . 【0255】 Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-(2-methoxy-1,1-dimethyl-ethyl)indole (C20) To a solution of 3-benzyloxy-N-(3,4-difluorophenyl)-5-fluoro-2-(4-methoxy-3,3-dimethyl-buta-1-inyl)aniline C19 (515 mg, 1.17 mmol) in MeCN (5 mL), PdCl2 (21 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. The mixture was diluted with ice water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were concentrated to dryness and purified by silica gel chromatography (gradient: 0-25% ethyl acetate in heptane) to obtain a white solid: 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-(2-methoxy-1,1-dimethyl-ethyl)indole (483 mg, 94%). 1 H NMR (400MHz, chloroform-d) δ7.45-7.38(m,2H), 7.38-7.30(m,2H), 7.30-7.20(m,2H), 7.18-7.10(m,1H), 7.06(dddd,J=8.5,4.0,2.5,1.6Hz,1H), 6.52 (d,J=0.8Hz,1H), 6.29(dd,J=11.6,2.0Hz,1H), 5.89(ddd,J=9.4,1.9,0.7 Hz,1H), 5.08(s,2H), 3.15(s,3H), 3.06(s,2H), 1.20(s,3H), 1.16(s,3H). LCMS m / z 440.37[M+1] + . 【0256】 Step 6. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (S4) 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-2-(2-methoxy-1,1-dimethyl-ethyl)indole C2O (357 mg, 0.81 mmol) was added to dichloromethane (5 mL) with N-iodosuccinimide (190 mg, 0.84 mmol) at room temperature and stirred for 1 hour. The combined organic matter was concentrated to dryness and purified by silica gel chromatography (gradient: 0-25% siRNA in hexane) to obtain the product as a white solid. 4-benzyloxy-1-(3,4-difluorophenyl)-6-fluoro-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (432 mg, 93%). LCMS m / z 565.3[M+1] + . 【0257】 Preparation of S5 4-benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole(S5) [ka] Step 1. Synthesis of 4-(2-benzyloxy-6-bromophenyl)-2,2-dimethylbuta-3-in-1-ol (C21) A 3 L three-necked RB flask equipped with an overhead stirrer, temperature probe, reflux condenser, and nitrogen inlet was loaded with 1,4-dioxane (1.1 L), 1-benzyloxy-3-bromo-2-iodobenzene C2 (160 g, 411.3 mmol), and 2,2-dimethylbuta-3-in-1-ol (51 g, 519.6 mmol), and stirred for 5 minutes. Then, N-isopropylpropan-2-amine (370 mL, 2.64 mol) was added. The reaction mixture was purged with nitrogen for approximately 15 minutes, and then iodocopper (3.7 g, 19.4 mmol) and PdCl2 (12.5 g, 17.8 mmol) were added. The resulting reaction mixture was heated to 50°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and poured into water (300 mL). A saturated aqueous solution of NH4Cl (approximately 400 mL), followed by ethyl acetate (approximately 2 L), was added, and the mixture was stirred for 15 minutes. The organic layer was separated, washed with 1N HCl solution (2 × 200 mL) and brine (200 mL), then dried over MgSO4, filtered, and concentrated under reduced pressure. 【0258】 The product was purified by silica gel chromatography (gradient: 0-50% ethyl acetate in heptane) to obtain a yellow solid: 4-(2-benzyloxy-6-bromophenyl)-2,2-dimethylbuta-3-in-1-ol (130 g, 88%). 1 H NMR (400MHz, chloroform-d) δ7.48(ddt,J=7.4,1.5,0.7Hz,2H), 7.44-7.37(m,2H), 7.36-7.29(m,1H), 7.19(dd,J=8.1,1.0Hz,1H ), 7.08(t,J=8.2Hz,1H), 6.86(dd,J=8.3,1.0Hz,1H), 5.13(s,2H), 3.48(d,J=7.2Hz,2H), 2.12(t,J=7.2Hz,1H), 1.33(s,6H). LCMS m / z 359.02[M+1] + . 【0259】 Step 2. Synthesis of [4-(2-benzyloxy-6-bromophenyl)-2,2-dimethylbuta-3-inoxy]-tert-butyl-dimethyl-silane (C22) A 3 L three-necked RB flask equipped with an overhead stirrer, temperature probe, reflux condenser, and nitrogen inlet was loaded with 4-(2-benzyloxy-6-bromophenyl)-2,2-dimethylbuta-3-in-1-ol C21 (130 g, 361.9 mmol) in DMF (850 mL). The mixture was stirred at ambient temperature for 5 minutes, then imidazole (64 g, 940.1 mmol) and TBSCl (64 g, 424.6 mmol) were added (observed Tmax = 31 °C). The reaction mixture was poured into ice water (approximately 1 L) and extracted with MTBE (2 × 1 L). The organic phase was washed with 1 N HCl (2 × 200 mL) and brine (200 mL), then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column: 1.5 kg Isco, gradient, 0-50% ethyl acetate in heptane) to obtain the product as a clear, pale yellow oil: [4-(2-benzyloxy-6-bromophenyl)-2,2-dimethyl-buta-3-inoxy]-tert-butyl-dimethyl-silane (164 g, 96%). 1 H NMR (400MHz, chloroform-d) δ7.55-7.44(m,2H), 7.42-7.35(m,2H), 7.35-7.28(m,1H), 7.19(dd,J=8.1,1.0Hz,1H), 7. 04(t,J=8.2Hz,1H), 6.83(dd,J=8.4,1.0Hz,1H), 5.12(s,2H), 3.59(s,2H), 1.31(s,6H), 0.90(s,9H), 0.05(s,6H). 【0260】 Step 3. Synthesis of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethylbuta-1-inyl]-N-(3,4-difluorophenyl)aniline (C23) To a solution of [4-(2-benzyloxy-6-bromophenyl)-2,2-dimethyl-buta-3-inoxy]-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, NaOtBu (6 g, 62.4 mmol) was added, followed by tBuXPhos Pd G3 (315 mg, 0.40 mmol). The reaction mixture was stirred overnight at room temperature. The reaction product was diluted with water and saturated NH4Cl aqueous solution and extracted with siRNA (×2). The combined organic matter was concentrated to dryness and purified by silica gel chromatography (column: 220 g silica; gradient: 0-50% siRNA in heptane) to obtain the product as a yellow oily substance. 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-buta-1-inyl]-N-(3,4-difluorophenyl)aniline (11.6g, 96%). 1 H NMR (400MHz, chloroform-d) δ7.49(ddt,J=7.4,1.3,0.7Hz,2H), 7.38-7.32(m,2H), 7.31-7.25(m,1H), 7.10-6.96(m,3H), 6.86-6 .80(m,1H), 6.70(dd,J=8.3,0.8Hz,1H), 6.43-6.39(m,2H), 5.11(s,2H), 3.53(s,2H), 1.28(s,6H), 0.84(s,9H), 0.00(s,6H). LCMS m / z 522.52[M+1] + . 【0261】 Step 4.2 - Synthesis of [4-benzyloxy-1-(3,4-difluorophenyl)indole-2-yl]-2-methylpropan-1-ol (C24) A solution of 3-benzyloxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-3,3-dimethylbuta-1-inyl]-N-(3,4-difluorophenyl)aniline C23 (11.6 g, 22.2 mmol) in MeOH (100 mL) and siRNA (50.7 mL) was purged with nitrogen for 1 hour. PdCl2(CH3CN)2 (336 mg, 1.30 mmol) was added, and the mixture was heated overnight at 60°C. The reaction product was concentrated under reduced pressure and then purified by silica gel chromatography (gradient: 0-75% siRNA in heptane) to obtain a white solid: 2-[4-benzyloxy-1-(3,4-difluorophenyl)indole-2-yl]-2-methyl-propan-1-ol (8.2 g, 91%). 1 H NMR (400MHz, chloroform-d) δ7.55(dt,J=6.3,1.4Hz,2H), 7.48-7.41(m,2H), 7.41-7.31(m,2H), 7.31-7.24(m,3H), 7.22-7.15(m,1H), 7.02(t,J=8.0 Hz,1H), 6.74(d,J=0.8Hz,1H), 6.63(d,J=7.8Hz,1H), 6.33(d,J=8.2Hz,1H), 5.26(s,2H), 3.53(dd,J=6.0,1.6Hz,2H), 1.28(s,3H), 1.27(s,3H). LCMS m / z 408.37[M+1] + . 【0262】 Step 5. Synthesis of 4-benzyloxy-1-(3,4-difluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indole (C25) At 0°C, 2-[4-benzyloxy-1-(3,4-difluorophenyl)indole-2-yl]-2-methylpropan-1-ol C24 (500 mg, 1.23 mmol) and MeI (120 μL, 1.928 mmol) in THF (5 mL) were combined with 60 mg, 1.5 mmol of NaH (from 60% w / w) and the mixture was heated to room temperature. After 1 hour, the reaction was complete. Water (5 mL) and saturated NH4Cl (5 mL) were added to the reaction mixture, followed by extraction with  (3 × 5 mL). The combined organic fraction was washed with brine (1 × 2 mL), dried over MgSO4, and concentrated to 4-benzyloxy-1-(3,4-difluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indole (509 mg, 99%). 1 H NMR (400MHz, chloroform-d) δ7.52-7.45(m,2H), 7.42-7.34(m,2H), 7.33-7.17(m,3H), 7.13(dddd,J=8.6,4.0,2.5,1.6Hz,1H), 6.92(t,J=8.0Hz,1 H), 6.63(d,J=0.9Hz,1H), 6.54(dd,J=7.8,0.6Hz,1H), 6.25(dt,J=8.3,0.7Hz,1H), 5.18(s,2H), 3.20(s,3H), 3.14(s,2H), 1.26-1.20(m,6H). LCMS m / z calculated value: 421.18533, measured value: 422.37 [M+H] + . 【0263】 Step 6. 4-Benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (S5) 4-benzyloxy-1-(3,4-difluorophenyl)-2-(2-methoxy-1,1-dimethyl-ethyl)indole C25 (518.4 mg, 1.23 mmol) was added to NIS (290 mg, 1.29 mmol) in dichloromethane (5 mL) and stirred for 2 hours. The mixture was concentrated and dissolved in dichloromethane. The product was purified by silica gel chromatography (gradient: 0-20% siRNA in hexane) to obtain a white solid. 4-benzyloxy-1-(3,4-difluorophenyl)-3-iodo-2-(2-methoxy-1,1-dimethyl-ethyl)indole (675 mg, 98%) 1 ¹H NMR (400MHz, chloroform-d) δ 7.65 (ddt, J=7.4, 1.3, 0.7Hz, 2H), 7.48-7.39 (m, 2H), 7.39-7.35 (m, 1H), 7.34-7.28 (m, 1H), 7.26-7.18 (m, 1H), 7.13 (dddd, J=8.5, 4.0, 2.5, 1.6Hz, 1H), 6.9 7(dd,J=8.3,7.9Hz,1H), 6.63(dd,J=7.9,0.8Hz,1H), 6.28(dd,J=8.3,0.7Hz,1H), 5.26(s ,2H), 3.79(d,J=9.1Hz,1H), 3.71(d,J=9.1Hz,1H), 1.59(s,3H), 1.42(s,3H), 1.36(s,3H). LCMS m / z 547.28[M+H] + . 【0264】 Preparation of S6 1-(3-chloro-4-fluorophenyl)-3-iodo-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole(S6) [ka] Step 1. Synthesis of 1-bromo-2-iodo-3-(methoxymethoxy)benzene (C27) To a solution of 3-bromo-2-iodophenol C26 (5.2 g, 17.40 mmol) and DIPEA (4.5 mL, 25.8 mmol) in 50 mL of dichloromethane at 0°C, chloro(methoxy)methane (1.6 mL, 21.1 mmol) in 10 mL of dichloromethane was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. 20 mL of NH4Cl aqueous solution and 10 mL of water were added, and the mixture was stirred for 5 minutes. The organic layer was separated, dried over sodium sulfate, and concentrated to obtain the product as a brown liquid, which was used directly in the next step: 1-bromo-2-iodo-3-(methoxymethoxy)benzene (6.1 g, 100%). 1 ¹H NMR (400MHz, chloroform-d): δ 7.34 (dd, J=8.0, 1.3Hz, 1H), 7.18 (t, J=8.1Hz, 1H), 6.99 (dd, J=8.3, 1.3Hz, 1H), 5.26 (s, 2H), 3.53 (s, 3H). LCMS m / z 342.22 [M+H] + . 【0265】 Step 2.4 - Synthesis of [2-[2-bromo-6-(methoxymethoxy)phenyl]ethynyl]tetrahydropyran (C28) To a solution of 1-bromo-2-iodo-3-(methoxymethoxy)benzene 27 (2 g, 5.8 mmol) and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (1.28 g, 7.02 mmol) in DMF (11 mL) and triethylamine (11 mL), water (250 μL, 13.9 mmol) was added, 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 CuI (115 mg, 0.60 mmol) were added, and the reaction mixture was heated to 90°C overnight. The mixture was cooled, and triethylamine was removed under vacuum. Ice water (100 mL) was added, and the mixture was extracted with ether (3 × 100 mL). The organic layer was washed with water (200 mL), then with brine (200 mL), and concentrated. Purification by silica gel chromatography (gradient: 0-30% ethyl acetate in heptane) yielded the product as a pale yellow oily substance: 4-[2-[2-bromo-6-(methoxymethoxy)phenyl]-ethynyl]tetrahydropyran (1.43 g, 75%). 1 H NMR (400MHz, chloroform-d) δ7.24(dd,J=7.2,1.8Hz,1H), 7.11-7.01(m,2H), 5.23(s,2H), 4.02(ddd,J=11.5,7.0,3.4Hz,2 H), 3.62(ddd,J=11.1,7.2,3.3Hz,2H), 3.51(s,3H), 3.01(tt,J=7.7,4.2Hz,1H), 2.01-1.91(m,2H), 1.87-1.77(m,2H). LCMS m / z 325.09[M+H] + . 【0266】 Step 3. N-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-2-(2-tetrahydropyran-4-ylethynyl)aniline (C29) and 1-(3-chloro-4-fluorophenyl)-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole (C30) A solution of 4-[2-[2-bromo-6-(methoxymethoxy)phenyl]ethynyl]tetrahydropyran C28 (1.5 g, 4.61 mmol) and 3-chloro-4-fluoroaniline (940 mg, 6.46 mmol) in xylene (30 mL) was degassed for 5 minutes. Sodium t-butoxide (1.33 g, 13.8 mmol) was added, and the solution was degassed for another 5 minutes. tBuXPhos Pd G3 (529.6 mg, 0.66 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. Ice water (50 mL) and toluene (50 mL) were added. After stirring for 5 minutes, the aqueous layer was isolated and washed with toluene (20 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. Products C29 and C30 were obtained by purification by silica gel chromatography (gradient: 0-40% toluene in heptane). N-(3-chloro-4-fluorophenyl)-3-(methoxymethoxy)-2-(2-tetrahydropyran-4-ylethynyl)aniline C29 (1.39g, 75%). 1 H NMR (400MHz, chloroform-d) δ7.25(dd,J=6.3,2.7Hz,1H), 7.11(t,J=8.5Hz,2H), 7.05(ddd,J=8 .9,4.2,2.7Hz,1H), 6.78(dd,J=8.3,0.8Hz,1H), 6.63(dd,J=8.3,0.8Hz,1H), 6.36(s,1H), 5.27(s,2H), 4.00(ddd,J=11.6,6.0,3.6Hz,2H), 3.62(ddd,J=11.5,8.3,3.0Hz,2H), 3.55( s,3H), 3.02(tt,J=8.3,4.1Hz,1H), 2.05-1.94(m,2H), 1.82(dtd,J=13.4,8.3,3.6Hz,2H). LCMS m / z 390.27[M+H] + . 【0267】 1-(3-chloro-4-fluorophenyl)-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole C30 (0.37g, 19%). 1H NMR (400MHz, chloroform-d) δ7.21(dd,J=6.3,2.7Hz,1H), 7.14-7.01(m,4H), 6.97(ddt,J=8.9,4.0,2.2 Hz,1H), 6.79(dd,J=8.3,0.8Hz,1H), 6.68(ddd,J=8.7,4.1,2.6Hz,1H), 6.58(dd,J=8.3,0.9Hz,1H), 6.34(s,1H), 5.79(d,J=2.7Hz,1H), 5.26(s,2H), 4.00(ddd,J=11.6,6.0,3.6Hz,2H), 3.61(ddd,J=11 .5,8.2,3.1Hz,2H), 3.55(s,3H), 3.02(tt,J=8.3,4.1Hz,1H), 2.06-1.93(m,2H), 1.89-1.77(m,2H). 【0268】 Step 4. Synthesis of 1-(3-chloro-4-fluorophenyl)-3-iodo-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole (S6) To a solution of 1-(3-chloro-4-fluorophenyl)-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole C30 in dichloromethane (20 mL), N-iodosuccinimide (755 mg, 3.36 mmol) was added. 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%  in heptane) yielded the product as a white solid, which was used in the next step: 1-(3-chloro-4-fluorophenyl)-3-iodo-4-(methoxymethoxy)-2-tetrahydropyran-4-yl-indole (1.38 g, 83%). 1¹H NMR (400MHz, chloroform-d) δ 7.43-7.37 (m, 1H), 7.35 (dd, J=8.5, 1.5Hz, 1H), 7.21 (ddd, J=8.7, 4.2, 2.4Hz, 1H), 7.05 (td, J=8.1, 2.4Hz, 1H), 6.81 (ddd, J=7.9, 4.4, 0.8Hz, 1H), 6.53 (ddd, J=1 4.5,8.3,0.7Hz,1H), 5.36(s,2H), 4.02(dd,J=11.5,4.6Hz,2H), 3.63(d,J=3.9Hz,3H), 3.39 (tdd,J=11.9,5.6,2.0Hz,2H), 3.11(tt,J=12.5,3.6Hz,1H), 2.55-2.17(m,2H), 1.60(s,2H). LCMS m / z 515.32[M+H] + . 【0269】 Preparation of S7 4-benzyloxy-6-fluoro-1-(4-fluoro-3-methylphenyl)-3-iodo-2-tetrahydropyran-4-yl-indole(S7) [ka] Step 1.4 - Synthesis of [2-(2-bromo-4-fluoro-6-methoxyphenyl)ethynyl]tetrahydropyran (C34) A 5 L three-necked RB flask equipped with an overhead stirrer, temperature probe, and nitrogen inlet was loaded with 1,4-dioxane (1.5 L), 1-bromo-5-fluoro-2-iodo-3-methoxybenzene C33 (264 g, 797.8 mmol), and trimethyl(2-tetrahydropyran-4-ylethynyl)silane (250 g, 1.3 mol). The mixture was stirred for 5 minutes, then iPrNH2 (650 mL, 4.64 mol) was added, followed by CuI (6 g, 31.5 mmol), PdCl2(PPh3)2 (22 g, 31.3 mmol), and TBAF hydrate (300 g, 950.8 mmol). The reaction mixture was heated at 60 °C for 12 hours. The reaction mixture was cooled to room temperature and poured into a mixture of water (approximately 1 L), saturated NH4Cl aqueous solution (approximately 2 L), and ethyl acetate (approximately 3 L), and then stirred for 10 minutes. The organic phase was separated and washed sequentially with 1N HCl solution (2 × 500 mL) and brine (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (gradient: heptane with 0-30% ethyl acetate) to obtain a yellow solid (151 g, yield 60%). 【0270】 The mixed fraction was purified by an additional silica gel chromatography column (gradient: 0-50% ethyl acetate in heptane) to obtain an additional product (50 g, yield 20%). The batches of purified product were combined (151 g + 50 g) and dried under vacuum to obtain 4-[2-(2-bromo-4-fluoro-6-methoxyphenyl)ethynyl]tetrahydropyran (200 g, 80%) as a yellow solid. 1 H NMR (400MHz,DMSO-d6chloroform-d)δ6.95(dd,J=8.0,2.4Hz,1H), 6.57(dd,J=10.4,2.4Hz,1H), 4.01(ddd,J=11.6,6.9,3.4Hz,2H),3. 86(s,3H), 3.61(ddd,J=11.2,7.3,3.3Hz,2H), 3.00(dq,J=7.7,3.8Hz,1H), 2.03-1.90(m,2H), 1.81(dtd,J=13.1,7.4,3.1Hz,2H). 19F NMR (376 MHz, chloroform-d) δ-108.45. LC-MS m / z 314.97 [M+1] + . 【0271】 Step 2: Synthesis of 5-fluoro-N-(4-fluoro-3-methylphenyl)-3-methoxy-2-(2-tetrahydropyran-4-ylethynyl)aniline (C35) A solution of 4-[2-(2-bromo-4-fluoro-6-methoxyphenyl)ethynyl]tetrahydropyran C34 (92 g, 293.8 mmol), 4-fluoro-3-methylaniline (55.2 g, 441.1 mmol), tBuXPhos (3.75 g, 8.83 mmol), and NaOtBu (70.6 g, 734.6 mmol) in m-xylene (1.3 L) was purged with nitrogen for 10 minutes. tBuXPhos Pd G3 (7.01 g, 8.83 mmol) was added, and the mixture was heated at 60°C for 3 hours. The mixture was cooled, and then saturated NH4Cl (1 L) and HCl (64 mL, 384.0 mmol from 6 M) were added, and the mixture was stirred overnight. The mixture was extracted with RINKAN (×2) and the organic layer was concentrated. The product was purified by silica gel chromatography (gradient: 0-90% ethyl ammonium in heptane) to obtain 5-fluoro-N-(4-fluoro-3-methylphenyl)-3-methoxy-2-(2-tetrahydropyran-4-ylethynyl)aniline (98 g, 93%) as a black oily substance. 1 H NMR (300MHz, chloroform-d) δ6.87-6.76(m,3H), 6.24(s,1H), 6.13(dd,J=11.2,2.3Hz,1H), 5.90(dd,J=10.7,2.3Hz,1H), 3.80(ddd,J=11.6,5.6,3.6H z,2H), 3.68(s,3H), 3.40(ddd,J=11.5,8.4,3.0Hz,2H), 2.82(tt,J=8.4, 4.1Hz,1H), 2.11(d,J=1.8Hz,3H), 1.86-1.73(m,2H), 1.71-1.54(m,2H). LCMS m / z 358.22[M+1] + . 【0272】 Step 3. Synthesis of 6-fluoro-1-(4-fluoro-3-methylphenyl)-4-methoxy-2-tetrahydropyran-4-yl-indole (C36) 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), PdCl2 (2.08 g, 11.7 mmol) was added. The mixture was heated overnight at 60°C. The mixture was then concentrated to dryness, and MBTE (300 mL) was added. After stirring for 10 minutes, the mixture was filtered to obtain a solid product (40 g). The black filtrate was purified by silica gel chromatography (gradient: 0-60% siRNA in dichloromethane) to obtain a further 33 g of product. The two product batches were combined to obtain a single batch of the product: 6-fluoro-1-(4-fluoro-3-methyl-phenyl)-4-methoxy-2-tetrahydropyran-4-yl-indole (73 g, 70%). 1 H NMR (300MHz, chloroform-d) δ7.15(td,J=8.2,7.6,4.2Hz,3H), 6.49(s,1H), 6.42-6.24(m,2H), 3.97(s,5H), 3. 35(td,J=11.6,2.7Hz,2H), 2.76(ddd,J=15.4,11.2,4.4Hz,1H), 2.38(d,J=1.8Hz,3H), 1.90-1.64(m,4H). LCMS m / z 358.12[M+1] + . 【0273】 Step 4. Synthesis of 6-fluoro-1-(4-fluoro-3-methylphenyl)-2-tetrahydropyran-4-ylindole-4-ol (C37) In a 1 L three-necked RB flask, 6-fluoro-1-(4-fluoro-3-methylphenyl)-4-methoxy-2-tetrahydropyran-4-yl-indole C36 (15.1 g, 42.3 mmol) was loaded into 250 mL of dichloromethane, stirred for 5 minutes, and then cooled to 0°C in an ice / water bath. AlCl3 (20.4 g, 153.0 mmol) was added and stirred for 10 minutes, then octan-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 (approximately 120 mL). 2N HCl (approximately 120 mL) and ethyl acetate (400 mL) were added, and the mixture was stirred for approximately 20 minutes. The organic phase was separated, washed with brine (approximately 300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was pulverized with approximately 10% MTBE in heptane (approximately 400 mL), dried under vacuum, and the product was obtained as a yellowish-brown solid: 6-fluoro-1-(4-fluoro-3-methylphenyl)-2-tetrahydropyran-4-yl-indole-4-ol (13.2 g, 91%). 1 H NMR(300MHz,DMSO-d6)δ9.98(s,1H), 7.35(t,J=8.8Hz,2H), 7.27(ddd,J=8.2,4.6,2.7Hz,1H), 6.45(s,1H), 6.26(dd,J=11.5,2.1Hz,1H), 6.10(dd ,J=9.8,1.6Hz,1H), 3.82(d,J=10.9Hz,2H), 3.22(td,J=11.2,3.2Hz,3H) , 2.76(dt,J=10.3,5.4Hz,1H), 2.32(d,J=1.6Hz,4H), 1.74-1.49(m,2H). LCMS m / z 344.14[M+1] + . 【0274】 Step 5. Synthesis of 4-benzyloxy-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-tetrahydropyran-4-yl-indole (C38) A solution of 6-fluoro-1-(4-fluoro-3-methylphenyl)-2-tetrahydropyran-4-ylindole-4-ol C37 (15 g, 43.69 mmol) in THF (163 mL) and DMF (32 mL) was stirred for 5 minutes until a clear, pale brown solution was formed. Cs2CO3 (29.1 g, 89.3 mmol) and benzyl bromide (6.3 mL, 53.0 mmol) were added, and the resulting reaction mixture (white suspension) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (130 mL), stirred for 10 minutes, and the resulting white suspension was filtered through a medium frit funnel and washed with ethyl acetate (50 mL). The combined filtrate was washed with water (approximately 200 mL) and brine (approximately 200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was pulverized with 10% MTBE in heptane (approximately 300 mL) and dried under vacuum to obtain the product as a white solid: 4-benzyloxy-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-tetrahydropyran-4-yl-indole (16.1 g, 85%). 1 H NMR (300MHz, chloroform-d) δ7.57-7.49(m,2H), 7.49-7.33(m,3H), 7.24-7.08(m,3H), 6.55(s,1H), 6.43(dd,J=11.6,2.0Hz,1H), 6.32(dd,J=9 .5,1.9Hz,1H), 5.22(s,2H), 4.03-3.91(m,2H), 3.35(td,J=11.6,2.7Hz,2H), 2.83-2.69(m,1H), 2.38(d,J=1.9Hz,3H), 1.90-1.64(m,4H). LCMS m / z 434.15[M+1] + . 【0275】 Step 6. Synthesis of 4-benzyloxy-6-fluoro-1-(4-fluoro-3-methylphenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (S7) A solution of 4-benzyloxy-6-fluoro-1-(4-fluoro-3-methylphenyl)-2-tetrahydropyran-4-yl-indole C38 (64.5 g, 148.8 mmol) in dichloromethane (1 L) was stirred for 5 minutes to obtain a clear, colorless solution. The reaction mixture was cooled to 0°C using an ice / water bath, and then 1-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 for 1 hour. The reaction product was then washed with an aqueous mixture of 1NNa2S2O3 solution (approx. 300 mL), saturated NaHCO3 (150 mL), and then brine (approx. 300 mL). The mixture was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was concentrated to obtain the product as a white solid. 4-Benzyloxy-6-fluoro-1-(4-fluoro-3-methylphenyl)-3-iodo-2-tetrahydropyran-4-yl-indole (83g, 100%). 1 H NMR (300MHz, chloroform-d) δ7.64(d,J=7.0Hz,2H), 7.50-7.32(m,3H), 7.19...

Images