Regulators of transmembrane conductance regulatory factors in cystic fibrosis

Abstract

The present disclosure provides modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) having a core structure (I), pharmaceutical compositions comprising at least one such modulator, methods of treating CFTR-mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and combination therapies, and processes and intermediates for making such modulators. Further aspects of the disclosure provide intermediates and methods for making the compounds and pharmaceutical compositions disclosed herein. TIFF2023545762000865.tif5086

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 088,799, filed on 7 October 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] This disclosure relates to regulators of cystic fibrosis membrane conductance regulators (CFTRs), pharmaceutical compositions comprising such regulators, methods for treating CFTR-mediated diseases, including cystic fibrosis, using such regulators, combination therapies and combination pharmaceutical compositions employing such regulators, and processes and intermediates for producing such regulators. [Background technology]

[0003] Cystic fibrosis (CF) is a recessive genetic disorder that affects approximately 70,000 children and adults worldwide. Despite advances in treatment, there is no cure for CF.

[0004] In patients with cystic fibrosis (CF), mutations in the endogenously expressed CFTR in the respiratory epithelium lead to decreased apical anion secretion and imbalances in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lungs, ultimately leading to microbial infections that can be fatal to CF patients. In addition to respiratory illness, CF patients typically suffer from gastrointestinal disorders and pancreatic insufficiency that, if left untreated, can be fatal. Furthermore, the majority of men with cystic fibrosis are infertile, and women with cystic fibrosis have low fertility.

[0005] Sequence analysis of the CFTR gene has revealed various disease-causing mutations (Cutting, G et al. (1990) Nature 346:366-369, Dean, M. et al. (1990) Cell 61:863:870, and Kerem, BS. et al. (1989) Science 245:1073-1080, Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, more than 2,000 mutations have been identified in the CF gene, and currently the CFTR2 database contains information on only 432 of these identified mutations, with sufficient evidence to define 352 mutations as disease-causing. The most common disease-causing mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This makes it impossible for the mutant protein to exit the endoplasmic reticulum (ER) and be transported to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is far fewer than that observed in cells expressing wild-type CFTR, i.e., CFTR without the mutation. In addition to the trafficking impairment, this mutation results in a defect in channel gating. Together, the reduced number of channels in the membrane and defective gating lead to a decrease in anion and fluid transport across the epithelium. (Quinton, PM (1990), FASEB J.4:2709-2727). Channels defective due to the F508del mutation are less functional than wild-type CFTR channels, but are still functional. (Dalemans et al. (1991), Nature Lond. 354:526-528, Pasyk and Foskett (1995), J. Cell. Biochem. 270:12347-50). In addition to F508del, other disease-causing mutations in the CFTR resulting in defective transport, synthesis, and / or channelgating can be upregulated or downregulated to alter anion secretion and modify disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, which regulates the transmembrane anion flux and the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is essential for maintaining systemic electrolyte transport, including in respiratory and digestive tissues. CFTR is composed of 1480 amino acids encoding a protein consisting of tandem repeats of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. The two transmembrane domains are linked by a large polarity-regulating (R) domain with multiple phosphorylation sites that control channel activity and cell transport.

[0008] Chloride transport results from the coordinated activity of ENaC and CFTR present on the apical membrane, as well as the Na + -K + -ATPase pump and Cl-channel on the basolateral surface of the cell. Secondary active transport of chloride from the lumen side accumulates intracellular chloride, and then chloride can passively leave the cell through the Cl - channel and be transported in a certain direction. The arrangement of the Na + / 2Cl - / K + cotransporter, the Na + -K + -ATPase pump and the basolateral membrane K + channel, as well as CFTR on the lumen side, regulate chloride secretion through CFTR on the lumen side. Since water is probably never actively transported by itself, the flow of water through the epithelium depends on the small trans-epithelial osmotic gradient generated by the overall flow of sodium and chloride. Several CFTR modulatory compounds have recently been identified. However, compounds that can treat cystic fibrosis and other CFTR-mediated diseases, particularly the more severe forms of these diseases, or reduce their severity, are still needed.

Prior Art Documents

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

[0010] One aspect of the present disclosure provides novel compounds comprising a compound of formula I, compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0011] Formula I encompasses compounds with the following structure: [ka] , comprising tautomers of those compounds, deuterated derivatives of any of those compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing, Ring A is ■C6~C 10 Ariel, ■C3~C 10 Cycloalkyl, ■3-10 member heterocyclyl, and ■Selected from 5-10 member heteroaryls, Ring B is ■C6~C 10 Ariel, ■C3~C 10 Cycloalkyl, ■3-10 member heterocyclyl, and ■Selected from 5-10 member heteroaryls, V is selected from O and NH. W 1 However, selected from N and CH, W 2 However, it is selected from N and CH, but W 1 and W 2 Assuming that at least one of them is N, Z is O, NR ZN , and C(R ZC ) Selected from 2, however, L 2 If Z is absent, then C(R ZC ) Provided that it is 2, Each L 1 However, independently, C(R L1 ) Selected from 2, Each L 2 However, independently, C(R L2 ) Selected from 2, Each R 3 However, they became independent, ■Halogen, ■C1~C6 alkyl, ■C1-C6 alkoxy, ■C3~C 10 Cycloalkyl, ■C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 Aryl, and ■Selected from 3-10 member heterocyclines, R 4 However, hydrogen and C1-C6 alkyl are selected, Each R 5 However, they became independent, ■ Hydrogen, ■Halogen, ■ Hydroxyl, ■N(R N )2, ■-SO-Me, ■Both R LC Together, C3~C 10 -CH=C(R) LC )2, ■C1-C6 alkyl groups, independently, ○ Hydroxyl, ○ Independently C1-C6 alkoxy and C6-C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ○C3~C 10 Cycloalkyl, ○-(O) groups that are optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl and C1-C6 alkoxy groups. 0~1 -(C6~C 10 Ariel), ○3-10 membered heterocyclils, and ○N(R N )2, C1-C6 alkyl groups optionally substituted with 1-3 groups selected from, ■C1-C6 alkoxys, independently, ○Halogen, ○C6~C 10 Aryl, and ○C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups. 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from cycloalkyl groups, ■C1-C6 fluoroalkyl groups, ■C3~C 10 Cycloalkyl, ■C6~C 10 Ariel, and ■Selected from 3-10 member heterocyclines, R ZN but, ■ Hydrogen, ■C1-C9 alkyl groups, independently, ○ Hydroxyl, ○Oxo, ○Cyano, ○C1-C6 alkoxy groups that are optionally substituted with 1-3 groups independently selected from halogens and C1-C6 alkoxy groups. ○N(R N )2, ○SO2Me, ○C3~C 10 Cycloalkyl, independently, ◆Hydroxyl, ◆Independently, hydroxyl, oxo, C1-C6 alkoxy, C6-C 10 Aryl, and N(R N )C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, ◆C1-C6 fluoroalkyl, ◆C1-C6 alkoxys, and ◆COOH ◆N(R N )2, ◆C6~C 10 Ariel, and ◆Independently selected from 3-10 membered heterocyclyls optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, C3-C6 alkyl groups optionally substituted with 1-3 groups. 10 Cycloalkyl, ○C6~C 10 It is an army, and independently, ◆Halogen, ◆Hydroxyl, ◆Cyano, ◆SiMe3, ◆SO2Me, ◆SF5, ◆N(R N )2, ◆P(O)Me2, ◆-(O) groups are optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl groups. 0~1 -(C3~C 10 Cycloalkyl), ◆Independently, hydroxyl, oxo, C1-C6 alkoxy, 5-10 member heteroaryl, SO2Me, and N(R) N )C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, ◆Independently, hydroxyl, oxo, N(R) N )2, and C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆C1-C6 fluoroalkyl, ◆3-10 membered heterocyclines, independently substituted with 1-3 groups selected from C1-C6 alkyl groups, ◆-(O) 0~1 -(C6~C 10 Aryl), and ◆Hydroxyl, oxo, N(R) N )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, and C3-C 10 -(O) optionally substituted with cycloalkyl groups 0~1 -(5-10 member heteroaryl), C6-C, optionally substituted with 1-3 groups selected from 10 Ariel, ○3-10 membered heterocyclines, independently, ◆Hydroxyl, ◆Oxo, ◆N(R N )2, ◆C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy groups), ◆C1-C6 alkoxy, ◆C1-C6 fluoroalkyl, ◆C6~C 10 Aryl, and ◆ 3-10 membered heterocyclyls, optionally substituted with 1-4 groups, selected from 5-10 membered heteroaryls, and ○A 5-10 member heteroaryl, independently, ◆Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆B(OH)2, ◆N(R N )2, ◆Independently, hydroxyl, oxo, C1-C6 alkoxy (optionally substituted with 1-3 -SiMe3), and N(R) N )C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, ◆Independently, hydroxyl, oxo, C1-C6 alkoxy, N(R) N )2, and C3~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from cycloalkyl groups, ◆C1-C6 fluoroalkyl, ◆-(O) groups are arbitrarily substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups. 0~1 -(C3~C 10 Cycloalkyl), ◆-(O) 0~1 -(C6~C 10 Ariel), ◆Independently, hydroxyl, oxo, halogen, cyano, N(R) N )2, C1~C6 alkyl (independently, hydroxyl, oxo, N(R) N )2, and optionally substituted with 1 to 3 groups selected from C1-C6 alkoxys), C1-C6 alkoxys, C1-C6 fluoroalkyls, 3-10 member heterocyclines (independently optionally substituted with 1 to 3 groups selected from C1-C6 fluoroalkyls) -(O) 0~1 -(3-10 member heterocyclyl), and ◆Independently C1-C6 alkyl and C3-C 10 A 5-10 membered heteroaryl selected from cycloalkyls, a 3-10 membered heterocyclyl selected from 1-3 groups, a C1-C9 alkyl selected from 1-3 groups, ■C1-C6 fluoroalkyl groups, ■C3~C 10 Cycloalkyl, independently, ○ Hydroxyl, ○Oxo, ○Halogen, ○Cyano, ○N(R N )2, ○C1-C6 alkyl groups, independently, ◆Hydroxyl, ◆Oxo, ◆ N(R N )2, ◆ C1-C6 alkoxy, and ◆ C6-C 10 aryl, optionally substituted with 1-3 groups selected from C1-C6 alkyl optionally substituted with 1-3 groups selected from C1-C6 alkyl, ○ Independently, halogen, oxo, C6-C 10 aryl, and N(R N )2, optionally substituted with 1-3 groups selected from C1-C6 alkoxy optionally substituted with 1-3 groups selected from C1-C6 alkoxy, ○ Halogen, ○ C3-C 10 cycloalkyl, ○ 3-10 membered heterocyclyl optionally substituted with 1-3 groups independently selected from C1-C6 alkyl, and ○ 5-10 membered heteroaryl, independently, ◆ Hydroxyl, ◆ Cyano, ◆ Oxo, ◆ Halogen, ◆ N(R N )2, ◆ Independently, hydroxyl, oxo, C1-C6 alkoxy, and N(R N )2, optionally substituted with 1-3 groups selected from C1-C6 alkyl optionally substituted with 1-3 groups selected from C1-C6 alkyl, ◆ Independently, hydroxyl, C1-C6 alkoxy, N(R N )2, and C3-C 10 cycloalkyl, optionally substituted with 1-3 groups selected from C1-C6 alkoxy optionally substituted with 1-3 groups selected from C1-C6 alkoxy, ◆ C1-C6 fluoroalkyl, ◆ Independently, optionally substituted with 1-3 groups selected from C1-C6 alkyl -(O) 0~1 -(C3-C 10 cycloalkyl), ◆ C6-C 10 aryl, and ◆ A 5- to 10-member heteroaryl optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl, a 3- to 10-member heterocyclic group optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl, a C3-C 10 cycloalkyl, ■ A C6-C 10 aryl, ■ A 3- to 10-member heterocyclic group, independently, ○ Oxo, ○ A C1-C6 alkyl, independently, ◆ Oxo, ◆ Hydroxyl, ◆ N(R N )2, ◆ Independently, a C1-C6 alkoxy optionally substituted with 1 to 3 groups selected from halogen and C6-C 10 aryl, and ◆ -(O) 0~1 -(C3-C 10 cycloalkyl), a C1-C6 alkyl optionally substituted with 1 to 3 groups selected from the above, ○ A C1-C6 fluoroalkyl, ○ A C3-C 10 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen, and ○ A 3- to 10-member heterocyclic group optionally substituted with 1 to 3 groups selected from the above, ■ A 5- to 10-member heteroaryl, independently, ○ Halogen, ○ Independently, a C1-C6 alkyl optionally substituted with 1 to 3 groups selected from oxo, C1-C6 alkoxy, and N(R N )2, and ○ Independently a C1-C6 alkyl (oxo, C1-C6 alkoxy, and C6-C 103-10 member heterocyclils, which are optionally substituted with 1-3 groups selected from aryls, 5-10 member heteroaryls, which are optionally substituted with 1-3 groups selected from aryls, and ■R F , selected from, Each R ZC However, they became independent, ■ Hydrogen, ■Independently C6~C 10 C1-C6 alkyl groups that are optionally substituted with 1-3 groups selected from aryl groups (independently selected from C1-C6 alkyl groups), ■C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 Aryl, and ■R F , can be selected from, or two R ZC They come together to form an oxo group, Each R L1 However, they became independent, ■ Hydrogen, ■Two N(R) N )2 is not bonded to the same carbon, N(R N )2, ■C1-C9 alkyl groups, independently, ○Halogen, ○ Hydroxyl, ○Oxo, ○N(R N )2, ○ Independently C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ○C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 10 Cycloalkyl, ○C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 Aryl, and ○ A 3-10 membered heterocyclyl, which is independently selected from C1-C6 alkyl groups (which are independently optionally substituted with 1-3 groups selected from hydroxyl and oxo groups), and a C1-C9 alkyl group, which is independently selected from C1-C6 alkyl groups (which are independently optionally substituted with 1-3 groups selected from hydroxyl and oxo groups), which is independently selected from C1-C9 alkyl groups, which are independently selected from C1-C6 alkyl groups (which are independently optionally substituted with 1-3 groups selected from hydroxyl and oxo groups), ■C3~C 10 Cycloalkyl, ■C6~C 10 It is an army, and independently, ○Halogen, ○Cyano, ○SiMe3, ○POMe2, ○C1-C7 alkyl groups, independently, ◆Hydroxyl, ◆Oxo, ◆Cyano, ◆SiMe3, ◆N(R N )2, and ◆C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups. 10 C1-C7 alkyl groups optionally substituted with 1-3 groups selected from cycloalkyl groups. ○C1-C6 alkoxys, independently, ◆C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups. 10 Cycloalkyl, and ◆C1-C6 alkoxys, which are selected from C1-C6 alkoxys and optionally substituted with 1-3 groups. ○C1-C6 fluoroalkyl groups, ○C3-C6 alkyl and C1-C6 fluoroalkyl groups are independently and optionally substituted with 1-3 groups selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups. 10 Cycloalkyl, ○C6~C 10 Ariel, ○3-10 membered heterocyclines, which are independently and optionally substituted with 1-3 groups selected from C1-C6 alkyl groups, and ○C6-C6, optionally substituted with 1-4 groups, selected from 5-10 membered heteroaryls. 10 Ariel, ■3-10 member heterocyclines, independently, ○C1-C6 alkyl groups, independently, ◆Oxo, and ◆C1-C6 alkoxys, C ■A 5-10 member heteroaryl, independently, ○C1-C6 alkyl groups, independently, ◆C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups. 10 Cycloalkyls, C1-C6 alkyls optionally substituted with 1-3 groups selected from, and ○C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 aryls, 5-10 membered heteroaryls optionally substituted with 1-3 groups selected from, and ■R F , can be selected from, or two R on the same carbon atom L1 They come together to form an oxo group, Each R L2 However, hydrogen and R are independent F Selected from, or two R on the same carbon atom L2 These combine to form an oxo group, however, at least one R L1 or R L2 R F The condition is that, Each R N However, they became independent, ■ Hydrogen, ■C1-C8 alkyl groups, independently, ○Oxo, ○Halogen, ○ Hydroxyl, ○NH2, ○NHMe, ○NMe2, ○ Independently C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ○-(O) 0~1 -(C3~C 10 Cycloalkyl), ○C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from halogens and C1-C6 alkyl groups. 10 Ariel, ○ 3-14 membered heterocyclils independently and optionally substituted with 1-4 groups selected from oxo and C1-C6 alkyl groups, and ○ Selected from 5-14 membered heteroaryls independently substituted with 1-4 groups selected from oxo and C1-C6 alkyl groups, C1-C8 alkyls optionally substituted with 1-3 groups, ■C3~C 10 Cycloalkyl, independently, ○ Hydroxyl, ○NH2, and ○NHMe, and ○C1-C6 alkyl groups, independently selected from hydroxyl groups and optionally substituted with 1-3 groups, and C3-C6 alkyl groups, independently substituted with 1-3 groups. 10 Cycloalkyl, ■C6~C 10 Ariel, and ■Selected from 3-10 member heterocyclines, or two R on the same nitrogen atom N However, together with the nitrogen atoms to which they are bound, they form 3-10 membered heterocyclines, and these 3-10 membered heterocyclines can independently... ■ Hydroxyl, ■Oxo, ■Cyano, ■ Independently, oxo, hydroxyl, C1-C6 alkoxy, and N(R) N2 ) C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, where each R N2However, independently, hydrogen and a C1-C6 alkyl selected from C1-C6 alkyl, ■C1-C6 alkoxys, and ■Optionally substituted with 1 to 3 groups selected from C1 to C6 fluoroalkyl groups, or one R 4 and one R L1 These combine to form C6-C8 alkylenes. Two R's F However, together with the atoms to which they are bonded, ■C3-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 Cycloalkyl, ■C6~C 10 It is an army, and independently, ○Halogen, ○C1~C6 alkyl, ○N(R N )2, and ○ 3-10 membered heterocyclils, selected from hydroxyls, which are arbitrarily substituted with 1-3 groups, and C6-C6, which are arbitrarily substituted with 1-3 groups. 10 Ariel, ■3-11 member heterocyclils, independently, ○Oxo, ○N(R N )2, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆-SO2-(C1~C6 alkyl), ◆Independently, halogen, C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, hydroxyl, halogen, cyano, C1-C6 alkyl (independently substituted with 1-3 groups selected from oxo and C1-C6 alkoxy), C1-C6 alkoxy (independently C6-C10 (Optionally substituted with 1 to 3 groups selected from aryls), -(O) 0~1 -(C1~C6 fluoroalkyl), and C6~C 10 C6-C6 alkoxy molecules (arbitrarily substituted with 1-3 groups selected independently from C1-C6 alkoxy molecules) 10 Ariel, ◆Independently, hydroxyl, halogen, N(R N )2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), C1-C6 fluoroalkyl, and C6-C 10 -(O) is optionally substituted with 1 to 4 groups selected from aryl groups. 0~1 -(C3~C 10 Cycloalkyl), ◆Independently oxo, C1-C6 alkyl (independently C6-C 10 Aryl (optionally substituted with 1 to 3 groups selected independently from halogens), C1-C6 alkoxy, C3-C 10 Cycloalkyl, and R N A 3-10 member heterocycline, optionally substituted with 1-3 groups selected from the following: ◆Independently, C6~C 10 -O-(5-12 member heteroaryls) which are optionally substituted with aryls (optionally substituted with 1-3 groups independently selected from halogens) and 1-3 groups selected from C1-C6 alkyls, and ◆Independently, hydroxyl, oxo, N(R) N )2, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from cyano), C1-C6 alkoxy, -(O) 0~1 -(C1~C6 fluoroalkyl), -O-(C6~C 10 Aryl), and C3~C 10A 5-10 membered heteroaryl selected from cycloalkyls, a C1-C9 alkyl selected from 5-10 membered heteroaryl ○ Independently, C3-C3 groups are optionally substituted with 1-4 groups selected from halogens, C1-C6 alkyl groups, and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Ariel, ○3-10 membered heterocyclils, and ○Independently, C1-C6 alkoxy, C1-C6 fluoroalkyl, and N(R) N ) 5-10 member heteroaryls selected from 2, 3-11 member heterocyclines selected from 2, and 3-11 member heterocyclines selected from 2, and ■Independently, groups are formed from 5-12 membered heteroaryls that are optionally substituted with 1-3 groups selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups.

[0012] In some embodiments of formula I, two R F When these come together to form a 3-11 member heterocycline, the 3-11 member heterocycline can be optionally substituted with a 5-10 member heteroaryl, and the 5-10 member heteroaryl can be optionally substituted with a C1-C6 alkoxy, and the C1-C6 alkoxy can be C6-C 10 It can be optionally replaced with an aryl character.

[0013] Formula I is also a compound of formula Ia: [ka] , including tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, ring A, ring B, W 1 , W 2 Z, L 1 , L 2 , R 3 , R 4 , R5 , and R F This is defined for equation I.

[0014] Formula I is also a compound of Formula IIa: [ka] This also includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, rings B, W 1 , W 2 Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R F This is defined for equation I.

[0015] Formula I is also the compound of Formula IIb: [ka] , also includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, rings A, W 1 , W 2 Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R F This is defined for equation I.

[0016] Formula I is also a compound of Formula III: [ka] , also includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, W 1 , W 2 Z, L 1 , L 2 , R 4 , R5 , and R F This is defined for equation I.

[0017] Formula I is also a compound of Formula IV: [ka] , also includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, Z, L 1 , L 2 , R 4 , R 5 , and R F This is defined for equation I.

[0018] Formula I is also a compound of formula V: [ka] , also includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, Z, L 1 , L 2 , R 4 , R 5 , and R F This is defined for equation I.

[0019] Formula I is also a compound of formulas Va and Vb: [ka] This also includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, Z, L 1 , L 2 , R 4 , R 5 , and R F This is defined for equation I.

[0020] Formula I is also a compound of formula VI: [ka] , also includes tautomers of those compounds, deuterated derivatives of any of the compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, L 1 , R 4 , R 5 , and R F This is defined for equation I.

[0021] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from novel compounds disclosed herein, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier, the composition may further comprise at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is at least one other CFTR modulator. In some embodiments, the at least one other CFTR modulator is selected from CFTR enhancers. In some embodiments, the at least one other CFTR modulator is selected from CFTR correctors. In some embodiments, the at least one other CFTR modulator comprises enhancers and correctors. In some embodiments, one or more other CFTR modulosides are selected from tezacaftol, lumacaftol, ibacaftol, deutivacaftol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, as well as any of the aforementioned deuterated derivatives and pharmaceutically acceptable salts.

[0022] Accordingly, another aspect of the present disclosure provides a method for treating cystic fibrosis, a CFTR-mediated disease, comprising administering to a subject in need of treatment, at least one compound selected from novel compounds disclosed herein, their tautomers, deuterated derivatives of those compounds and tautomers, and any of the pharmaceutically acceptable salts thereof, as part of a pharmaceutical composition optionally comprising at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is at least one other CFTR modifier. In some embodiments, the at least one other CFTR modifier is selected from CFTR enhancers. In some embodiments, the at least one other CFTR modifier is selected from CFTR correctors. In some embodiments, the at least one other CFTR modifier includes enhancers and correctors. In some embodiments, one or more other CFTR modulosides are selected from tezacaftol, lumakhatol, ibakhatol, dutivakhatol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, as well as any of the aforementioned deuterated derivatives and pharmaceutically acceptable salts.

[0023] In certain embodiments, the pharmaceutical compositions of the present disclosure comprise at least one (i.e., one or more) compounds selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing.In some embodiments, at least one (i.e., one or more) compounds selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, is optionally (a)(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-I (Lu)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indole-5-yl)cyclopropanecarboxamide (Tezacafthol), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxyl-5-yl)cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid (Lumakhthol), and deuteration induction of tezacaftol and lumakhthol At least one (i.e., one or more) compound selected from body and pharmaceutically acceptable salts, and / or (b) N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (ibacafthol), N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydro The present invention further comprises noline-3-carboxamide (dutivacaftol), (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and at least one (i.e., one or more) compounds selected from any of the aforementioned deuterated derivatives and pharmaceutically acceptable salts.

[0024] Another aspect of the present disclosure provides a method for treating cystic fibrosis, a CFTR-mediated disease, comprising administering to a patient in need of treatment at least one compound selected from the novel compounds disclosed herein, their deuterated derivatives, and any pharmaceutically acceptable salts thereof, further optionally comprising administering one or more additional CFTR modifiers. Further aspects of the present disclosure provide a pharmaceutical composition of the present disclosure for use in therapeutic purposes or in the manufacture of a pharmacopoeia, comprising at least one compound selected from the compounds of formula I, formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, and optionally one or more CFTR modifiers. In some embodiments, the optional one or more additional CFTR modifiers are selected from CFTR enhancing factors. In some embodiments, the one or more additional CFTR modifiers are selected from CFTR correcting factors. In some embodiments, one or more additional CFTR modifiers are selected from tezacaphthol, lumakhthol, ibakhthol, dutivakhthol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and any of the aforementioned deuterated derivatives and pharmaceutically acceptable salts.

[0025] Further aspects of this disclosure provide intermediates and methods for preparing the compounds and pharmaceutical compositions disclosed herein. [Modes for carrying out the invention]

[0026] definition As used herein, "Tezacafthol" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indole-5-yl)cyclopropanecarboxamide, which can be represented by the following structure. [ka] . Tezacaphthol may be in the form of a deuterated derivative or a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Tezacaphthol and methods for preparing and using tezacaphthol are disclosed in WO2010 / 053471, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, WO2015 / 160787, and US2009 / 0131492, each incorporated herein by reference.

[0027] As used throughout this disclosure, “ibakhtol” means N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, which is represented by the following structure. [ka] . Ibakhtol may be in the form of a deuterated derivative or a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Ibakhtol and methods for preparing and using ibakhtol are disclosed in WO2006 / 002421, WO2007 / 079139, WO2010 / 108162, and WO2010 / 019239, which are each incorporated herein by reference.

[0028] In some embodiments, specific deuterated derivatives of ibacaphthol (dutivacaphthol) are used in the compositions and methods disclosed herein. The chemical name of dutivacaphthol is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, represented by the following structure. [ka] . Dutivacaftol may be in the form of further deuterated derivatives, pharmaceutically acceptable salts, or pharmaceutically acceptable salts of further deuterated derivatives. Dutivacaftol and methods for preparing and using dutivacaftol are disclosed in WO2012 / 158885, WO2014 / 078842, and U.S. Patent No. 8,865,902, which are incorporated herein by reference, respectively.

[0029] As used herein, "lumakhtol" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid, represented by the following chemical structure. [ka] . Lumacafthol may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Lumacafthol and methods for preparing and using lumacafthol are disclosed in WO2007 / 056341, WO2009 / 073757, and WO2009 / 076142, which are incorporated herein by reference, respectively.

[0030] As used herein, the term "alkyl" refers to saturated or partially saturated branched or unbranched aliphatic hydrocarbons containing carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms) in which one or more bonds between adjacent carbon atoms may be double (alkenyl) or triple (alkynyl) bonds. Alkyl groups may be substituted or unsubstituted.

[0031] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, for example, a fluoroalkyl group, which refers to an alkyl group substituted with one or more fluorine atoms.

[0032] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom. The alkoxy group may be substituted or unsubstituted.

[0033] As used herein, the term "haloalkoxyl group" refers to an alkoxy group substituted with one or more halogen atoms.

[0034] As used herein, “cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon group having 3 to 12 carbon atoms (e.g., 3 to 10 carbon atoms), which may contain one or more unsaturated bonds. “Cycloalkyl” groups include monocyclic, bicyclic, tricyclic, crosslinked, condensed, and spiro rings, including monospiro rings and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.

[0035] As used herein, the term “aryl” refers to a functional group or substituent derived from an aromatic ring, encompassing monocyclic aromatic rings as well as bicyclic, tricyclic, and fusion ring systems in which at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalenyl.

[0036] As used herein, the term “heteroaryl ring” refers to an aromatic ring containing at least one ring atom that is a heteroatom, such as O, N, or S. Heteroaryl groups include monocyclic rings, as well as bicyclic, tricyclic, bridging, condensed, and spirocyclic systems (including monospiro and dispiro rings), in which at least one ring in the system is aromatic. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, and indoline.

[0037] As used herein, the term “heterocyclyl ring” refers to a non-aromatic hydrocarbon containing 3 to 12 atoms (e.g., 3 to 10 atoms) in a ring containing at least one ring atom, which is a heteroatom such as O, N, or S and may contain one or more unsaturated bonds. “Heterocyclyl” rings include monocyclic, bicyclic, tricyclic, polycyclic, bridging, condensed, and spiro rings, including monospiro rings and dispiro rings.

[0038] "Substituted" means that at least one hydrogen of the "substituted" group is replaced by a substituent, whether or not the term "optionally" precedes it. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each of its substitutable positions, and if more than one position in any given structure can be substituted by more than one substituent selected from the specified group, the substituents may be the same or different at each position.

[0039] Examples of nitrogen protecting groups include, for example, t-butyl carbamate (Boc), benzyl carbamate (Bn), para-methoxybenzyl carbamate (PMB), tetrahydropyranyl carbamate (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloc or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. A comprehensive list of nitrogen protecting groups can be found in Wuts, PGM, “Greene's Protective Groups in Organic Synthesis: Fifth Edition,” 2014, John Wiley and Sons.

[0040] The terms "selected" and "chosen" are used interchangeably.

[0041] As used herein, “deuterated derivative” refers to a compound having the same chemical structure as the reference compound, wherein one or more hydrogen atoms are replaced by deuterium atoms. In some embodiments, the one or more hydrogens replaced by deuterium are part of an alkyl group. In some embodiments, the one or more hydrogens replaced by deuterium are part of a methyl group.

[0042] As used herein, "CFTR" means cystic fibrosis membrane conductance regulator.

[0043] The terms “CFTR regulator” and “CFTR modifier” are used interchangeably herein to refer to compounds that increase the activity of CFTR. The increase in activity resulting from CFTR regulators includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0044] The term “CFTR corrective factor” is used interchangeably herein to refer to compounds that promote the processing and transport of CFTR in order to increase the amount of CFTR on the cell surface. The novel compounds disclosed herein are CFTR corrective factors. Other corrective factors may be used in combination therapy with the novel compounds disclosed herein to treat CFTR-mediated diseases such as cystic fibrosis. Such other corrective factors include, for example, tezacaftol, lumakhtol, and their deuterated derivatives and pharmaceutically acceptable salts.

[0045] The terms “enhancement factor” and “CFTR enhancement factor” are used interchangeably herein to refer to compounds that increase the channel activity of CFTR proteins located on the cell surface, resulting in enhanced ion transport. Ibacaftol and dutivacaftol disclosed herein are CFTR enhancement factors. Enhancement factors may be used in combination with the novel compounds disclosed herein to treat CFTR-mediated diseases such as cystic fibrosis. Such enhancement factors include, for example, ibacaftol, dutivacaftol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatetricyclo[12.3.1.12.5]nonadeca-1(18), 2,4,14,16-pentaen-6-ol, and their deuterated derivatives and pharmaceutically acceptable salts.

[0046] When descriptions of combinations of compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and compounds selected from any of the pharmaceutically acceptable salts described herein, and other designated CFTR modifiers are provided herein, it should be understood that typically, though not necessarily, the combination or therapeutic regimen will include, for example, ibacaftol, dutivacaftol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and their deuterated derivatives and pharmaceutically acceptable salts. It should also be understood that, though not always, typically a single enhancing factor may be used in a combination pharmaceutical composition or therapy. In some embodiments, a combination of a compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the pharmaceutically acceptable salts of the foregoing, and other designated CFTR modifiers may include, for example, ibacaftol, dutivacaftol, (6R,12R)-17-amine This would include both CFTR correctors such as no-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and their deuterated derivatives and pharmaceutically acceptable salts, and other CFTR correctors such as tezacaphthol, lumacafthol, and their deuterated derivatives and pharmaceutically acceptable salts.

[0047] As used herein, “at least one compound selected from” means one or more compounds from the specified groups.

[0048] References to Compounds 1-426 in this disclosure are intended to refer to each of Compounds 1-426 individually, or to a group of compounds such as Compounds 1-371, Compounds 372-385, and Compounds 386-426.

[0049] As used herein, the terms “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refer to a biologically active compound.

[0050] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0051] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to the amount of compound administered that produces the desired effect (e.g., improvement of CF or symptoms of CF, or reduction of the severity of CF or symptoms of CF). 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).

[0052] As used herein, terms such as “treatment” and “to treat” generally mean improvement of one or more symptoms of CF in the subject, or reduction of the severity of CF or one or more symptoms of CF. As used herein, “treatment” includes, but is not limited to, increased growth, increased weight gain, reduced mucus in the lungs, improved pancreatic and / or hepatic function, reduction of lung infections, and / or reduction of cough or shortness of breath in the subject. Improvement or reduction of the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art. Any reference herein to a method of treatment (e.g., a method of treating a CFTR-mediated disease or a method of treating cystic fibrosis) using one or more compounds of the present disclosure in combination with one or more additional CFTR modifiers (e.g., a compound of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1-426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing, in combination with one or more additional CFTR modifiers, in combination with one or more additional CFTR modifiers, should also be understood to be a reference to: -One or more compounds for use in a method of treating cystic fibrosis, for example, in combination with one or more additional CFTR modifiers (for example, compounds selected from compounds of formula I, any one of compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing, in combination with one or more additional CFTR modifiers, and / or - For example, the use of one or more compounds (e.g., compounds selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing, in the manufacture of a drug for the treatment of cystic fibrosis).

[0053] Furthermore, any reference herein to a method of treatment (e.g., a method of treating a CFTR-mediated disease or a method of treating cystic fibrosis) using a pharmaceutical composition of this disclosure (e.g., a pharmaceutical composition comprising a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the pharmaceutically acceptable salts of the foregoing, and optionally further comprising one or more additional CFTR modifiers) should also be understood to be a reference to: - For example, a pharmaceutical composition for use in a method of treating cystic fibrosis (a pharmaceutical composition comprising, for example, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the pharmaceutically acceptable salts of the foregoing, and optionally further comprising one or more additional CFTR modifiers), and / or - For example, the use of a pharmaceutical composition in the manufacture of a drug for treating cystic fibrosis (for example, a pharmaceutical composition comprising a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the pharmaceutically acceptable salts of the foregoing, and optionally further comprising one or more additional CFTR modifiers).

[0054] As used herein, the term "in combination with" means administering two or more compounds, drugs, or active pharmaceutical ingredients to a patient before each other, simultaneously, or afterward, when referring to two or more compounds, drugs, or additional active pharmaceutical ingredients.

[0055] The terms “about” and “approximately” may refer to an acceptable error to a particular value as determined by those skilled in the art, which in part depends on how that value is measured or determined. In some embodiments, the terms “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

[0056] As used herein, the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of the product > 1 g / L).

[0057] As used herein, the terms "room temperature" or "ambient temperature" mean a temperature between 15°C and 30°C.

[0058] It should be understood that certain compounds in this disclosure may exist as separate stereoisomers or enantiomers, and / or mixtures thereof.

[0059] Certain compounds disclosed herein may exist as tautomers even if only a single tautomer structure is shown, and both tautomer forms are intended. For example, a description of compound X is understood to include its tautomer compound Y, and vice versa, as well as mixtures thereof. [ka] .

[0060] As used herein, “minimal function (MF) mutations” refer to CFTR gene mutations associated with minimal CFTR function (CFTR proteins that are little to no function), and these mutations include, for example, mutations associated with severe deficiencies in the ability of CFTR channels to open and close, known as channel gating deficiencies or “gating mutations,” mutations associated with severe deficiencies in CFTR cellular processing and its delivery to the cell surface, mutations associated with no or minimal CFTR synthesis, and mutations associated with severe deficiencies in channel conductance.

[0061] As used herein, the term “pharmaceutically acceptable salt” refers to a salt form of the compound of the Disclosure in which the salt is nontoxic. pharmaceutically acceptable salts of the compounds of the Disclosure include those derived from suitable inorganic and organic acids and bases. The “free base” form of the compound does not include, for example, ionic salts.

[0062] The phrase "and its deuterated derivatives and pharmaceutically acceptable salts" is used interchangeably with "and any of the aforementioned deuterated derivatives and pharmaceutically acceptable salts" with respect to one or more compounds or formulas of the present invention. These phrases are intended to encompass any one pharmaceutically acceptable salt of the reference compounds, any one deuterated derivative of the reference compounds, and pharmaceutically acceptable salts of those deuterated derivatives.

[0063] Those skilled in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound corresponds to the concentration of the free base of the compound. Note that the amounts of compounds or pharmaceutically acceptable salts disclosed herein are based on their free base forms.

[0064] Suitable pharmaceutically acceptable salts are disclosed, for example, in SMBerge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that paper provides the following pharmaceutically acceptable salts. [Table 1]

[0065] Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- Examples include ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, 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 metal salts 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, lower alkyl sulfons, and aryl sulfons. Other preferred non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts.

[0066] Furthermore, this specification also discloses compounds 1 to 426, their tautomers, deuterated derivatives of these compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing.

[0067] Treatment method For example, any of the novel compounds disclosed herein, such as the compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing, can act as CFTR regulators, i.e., regulate CFTR activity in the body. Individuals suffering from mutations in the gene encoding CFTR may benefit from accepting CFTR regulators. CFTR mutations may affect CFTR levels, i.e., the number of CFTR channels on the cell surface, or CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations affecting CFTR levels include mutations that cause synthesis defects (class I defects), mutations that cause processing and transport defects (class II defects), mutations that cause decreased CFTR synthesis (class V defects), and mutations that reduce the surface stability of CFTR (class VI defects). Mutations affecting CFTR function include mutations that cause gating deficiencies (Class III deficiencies) and mutations that cause conductance deficiencies (Class IV deficiencies). Some CFTR mutations exhibit characteristics of multiple classes. Certain mutations in the CFTR gene result in cystic fibrosis.

[0068] Accordingly, in some embodiments, the present disclosure provides a method for treating, reducing the severity of, or symptomatically treating cystic fibrosis in a patient, comprising administering to the patient any of the novel compounds disclosed herein, such as, for example, the compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, either alone or in combination with another active ingredient such as a CFTR modulator. In some embodiments, one (or more) CFTR modulators are corrective factors. In some embodiments, one (or more) CFTR modulators are enhancing factors. In some embodiments, the CFTR modulators include both corrective and enhancing factors. In some embodiments, one or more CFTR modifiers are selected from enhancing factors: ibacaftol, dutivacaftol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-ol, and any of the aforementioned deuterated derivatives and pharmaceutically acceptable salts; and correcting factors: lumakhatol, tezacaftol, and their deuterated derivatives and pharmaceutically acceptable salts.

[0069] In some embodiments, the patient being treated has the F508del / minimal function (MF) genotype, the F508del / F508del genotype (homozygous for the F508del mutation), the F508del / gating genotype, or the F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0070] In some embodiments, 5 mg to 500 mg of the compounds disclosed herein, their tautomers, deuterated derivatives of the compounds or tautomers, or any pharmaceutically acceptable salt of any of the foregoing is administered daily.

[0071] In some embodiments, the patient being treated has at least one F508del mutation in the CFTR gene. In some embodiments, the patient has a CFTR gene mutation that responds to the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of the Disclosure, based on in vitro data. In some embodiments, the patient is heterozygous, having an F508del mutation in one allele and a mutation selected from Table 2 in the other allele. [Table 2-1] [Table 2-2] [Table 2-3]

[0072] In some embodiments, the disclosure also covers methods of treatment using isotopically labeled compounds of the aforementioned compounds or pharmaceutically acceptable salts thereof, the formulas and variables of such compounds and salts being, independently, as described above or as described in any other embodiments described above, provided that one or more atoms therein are replaced (isotopically labeled) by atoms having an atomic mass or mass number different from that of atoms normally found in nature. Examples of commercially available isotopes suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P,35 S, 18 F, and 36 Cl is one example.

[0073] Isotope-labeled compounds and salts can be used in several beneficial ways. They may be suitable for various types of assays, such as drug and / or substrate tissue distribution assays. For example, tritium ( 3 H) Labeling and / or carbon-14 ( 14 C) Labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detection ability. For example, deuterium ( 2 H) Labeled compounds are therapeutically useful, non 2 It has superior therapeutic potential compared to H-labeled compounds. Generally speaking, deuterium ( 2 H) Labeled compounds and salts may have higher metabolic stability compared to unlabeled compounds due to the kinetic isotope effects described below. Higher metabolic stability directly translates to a desired increase in in vivo half-life or lower dosage. Isotopically labeled compounds and salts can typically be prepared by performing the procedures disclosed in the Synthesis Schemes and Related Descriptions, Examples, and Preparations sections of this specification, and by replacing unisotopically labeled reactants with readily available isotopically labeled reactants.

[0074] In some embodiments, the isotope-labeled compound and salt are deuterium ( 2 H) Labeled compounds and salts. In some specific embodiments, the isotope-labeled compounds and salts are deuterium ( 2 H) Labeled, in which one or more hydrogen atoms are replaced by deuterium. In the chemical structure, deuterium is represented as "D".

[0075] The concentration of the isotope (e.g., deuterium) incorporated into the isotope-labeled compounds and salts of this disclosure may be defined by the isotope enrichment factor. As used herein, the term “isotope enrichment factor” means the ratio between the isotopic abundance and the natural abundance of a given isotope. In some embodiments, when a substituent in a compound of the present disclosure is represented as deuterium, such a compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), 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), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0076] Combination therapy One embodiment disclosed herein provides a method for treating cystic fibrosis and other CFTR-mediated diseases using, in combination with at least one additional active pharmaceutical ingredient, any of the novel compounds disclosed herein, such as the compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing.

[0077] In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatorys.

[0078] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhalation powder (TIP); azithromycin; aztreonam, including an aerosolized form of aztreonam; amikacin, including a liposomal formulation of amikacin; ciprofloxacin, including a formulation of ciprofloxacin suitable for administration by inhalation; levoflaxacin, including an aerosolized formulation of levoflaxacin; and a combination of two antibiotics, for example, fosfomycin and tobramycin.

[0079] In some embodiments, additional agents are mucolytics. An exemplary mucolytic useful herein is Pulmozyme®.

[0080] In some embodiments, additional agents are bronchodilators. Exemplary bronchodilators include albuterol, metaproterenol sulfate, pyrbuterol acetate, salmeterol, or tetrabrine sulfate.

[0081] In some embodiments, additional agents are anti-inflammatory agents, i.e., agents that can reduce inflammation in the lungs. Exemplary such agents useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.

[0082] In some embodiments, the additional agent is a nutritional supplement. Exemplary nutritional supplements include pancrelipase (pancreatic enzyme substitute), such as Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomasase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional supplement is pancrelipase.

[0083] In some embodiments, at least one additional active pharmaceutical ingredient is selected from CFTR modifiers. In some embodiments, the additional active pharmaceutical ingredient is selected from CFTR enhancers. In some embodiments, the enhancers are selected from ibacaftol, dutivacaftol, and (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, as well as any of the aforementioned deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, the additional active pharmaceutical ingredient is selected from CFTR correctors. In some embodiments, the correctors are selected from lumakhtol, tezacaftol, deuterated derivatives of lumakhtol and tezacaftol, and any of the aforementioned pharmaceutically acceptable salts. In some embodiments, additional active pharmaceutical ingredients include both CFTR enhancing factors and CFTR correcting factors.

[0084] In some embodiments, at least one additional active pharmaceutical ingredient is selected from (a) tezacaphthol, lumakhthol, and their deuterated derivatives and pharmaceutically acceptable salts, and (b) ibakhthol, dutivakhthol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and any of the aforementioned deuterated derivatives and pharmaceutically acceptable salts. Accordingly, in some embodiments, the combination therapies provided herein include (a) a compound selected from the compounds of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from tezacaphthol, lumakhthol, and their deuterated derivatives and pharmaceutically acceptable salts; or (c) at least one compound selected from ibakhthol, dutivakhthol, and any deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, the combination therapies provided herein include (a) at least one compound selected from the compounds of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from tezacaphthol, lumakhthol, their deuterated derivatives, and pharmaceutically acceptable salts; and (c) at least one compound selected from ibacaphthol, dutivacaphthol, and any pharmaceutically acceptable derivatives, and pharmaceutically acceptable salts thereof.In some embodiments, the combination therapy provided herein comprises (a) at least one compound selected from the compounds of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing, and (b) tezacaphthol, lumacafthol, and their deuterated derivatives and pharmaceutically acceptable salts The compound comprises at least one compound selected from the salts acceptable for (c)(6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and at least one compound selected from any of the deuterated derivatives and pharmaceutically acceptable salts of the aforementioned.

[0085] In some embodiments, at least one compound selected from the compounds of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with tezacaftol and at least one compound selected from its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the compounds of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with lumakhthol and at least one compound selected from its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the compounds of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with ivacaftol and at least one compound selected from its deuterated derivatives and pharmaceutically acceptable salts.In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts.

[0086] In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with at least one compound selected from tezacaftol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from ibacaftol and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with at least one compound selected from tezacaftol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from dutivacaftol and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with at least one compound selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts.

[0087] In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with at least one compound selected from lumakhthol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from ibakhthol and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with at least one compound selected from lumakhthol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from dutivakhthol and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in combination with at least one compound selected from lumacafthol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts.

[0088] Each of the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing may be administered independently once daily, twice daily, or three times daily. In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing is administered once daily. In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing is administered twice daily.

[0089] In some embodiments, a compound of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, and tezacaftol and its deuterated derivatives and at least one compound selected from the aforementioned pharmaceutically acceptable salts, is administered once daily. In some embodiments, a compound of formula I, any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, and tezacaftol and its deuterated derivatives, is administered twice daily.

[0090] In some embodiments, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 371, compounds 372 to 385, compounds 386 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, and ibacaftol, dutivacaftol, and its deuterated derivatives and pharmaceutically acceptable salts are administered once daily. In some embodiments, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salt of the foregoing, and at least one compound selected from tezacaphthol and its deuterated derivatives, and at least one compound selected from ibacaphthol, dutivacaphthol, and their deuterated derivatives and pharmaceutically acceptable salts, is administered twice daily.

[0091] In some embodiments, a compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the pharmaceutically acceptable salts described above, and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts is administered once daily. In some embodiments, a compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the pharmaceutically acceptable salts described above, and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts is administered twice daily.

[0092] In some embodiments, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, tezacaftol and its deuterated derivatives and pharmaceutically acceptable salts, and ibacaftol, dutivacaftol and its deuterated derivatives and pharmaceutically acceptable salts are administered once daily. In some embodiments, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, tezacaftol and its deuterated derivatives and pharmaceutically acceptable salts, and ibacaftol, dutivacaftol and its deuterated derivatives and pharmaceutically acceptable salts are administered twice daily.

[0093] In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, at least one compound selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts is administered once daily. In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, at least one compound selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts is administered twice daily.

[0094] In some embodiments, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, ibacaftol, dutivacaftol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from lumakhthol and its pharmaceutically acceptable salts are administered once daily. In some embodiments, a compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, ibacaftol, dutivacaftol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from lumakhthol and its pharmaceutically acceptable salts are administered twice daily.

[0095] In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from lumaphthol and its pharmaceutically acceptable salts is administered once daily. In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from lumaphthol and its pharmaceutically acceptable salts is administered twice daily.

[0096] In some embodiments, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, and tezacaftol and its deuterated derivatives and pharmaceutically acceptable salts are administered once daily, and ibacaftol and its deuterated derivatives and pharmaceutically acceptable salts are administered twice daily. In some embodiments, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, and lumakhthol and its deuterated derivatives and pharmaceutically acceptable salts are administered once daily, and ibakhthol and its deuterated derivatives and at least one compound selected from pharmaceutically acceptable salts are administered twice daily.

[0097] In some embodiments, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, and at least one compound selected from tezacaphthol, lumakhthol, ibakhthol, dutivakhthol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and its deuterated derivatives and pharmaceutically acceptable salts may be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Such pharmaceutical compositions may be administered once daily, or multiple times daily, such as twice or three times daily. As used herein, the phrase that a given amount of API (e.g., tezacaftol, lumakhatol, ibakhatol, dutivakhatol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, or any deuterated derivative or pharmaceutically acceptable salt of any of the foregoing) is administered once daily or twice daily means that the given amount is administered once daily or twice daily per dose.

[0098] In some embodiments, at least one compound selected from the compound of formula I, any compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in a first pharmaceutical composition; at least one compound selected from tezacaftol, its deuterated derivatives, and pharmaceutically acceptable salts is administered in a second pharmaceutical composition; and at least one compound selected from ibacaftol, its deuterated derivatives, and pharmaceutically acceptable salts is administered in a third pharmaceutical composition.

[0099] In some embodiments, at least one compound selected from the compound of formula I, any compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in a first pharmaceutical composition; at least one compound selected from tezacaftol, its deuterated derivatives, and pharmaceutically acceptable salts is administered in a second pharmaceutical composition; and at least one compound selected from dutivacaftol, its deuterated derivatives, and pharmaceutically acceptable salts is administered in a third pharmaceutical composition.

[0100] In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in a first pharmaceutical composition; at least one compound selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts is provided in a second pharmaceutical composition; and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts is provided in a third pharmaceutical composition.

[0101] In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in a first pharmaceutical composition; at least one compound selected from ibakhtol, its deuterated derivatives, and pharmaceutically acceptable salts is provided in a second pharmaceutical composition; and at least one compound selected from lumakhtol, its deuterated derivatives, and pharmaceutically acceptable salts is provided in a third pharmaceutical composition.

[0102] In some embodiments, at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof is administered in a first pharmaceutical composition; at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts is provided in a second pharmaceutical composition; and at least one compound selected from lumakhthol and its deuterated derivatives and pharmaceutically acceptable salts is provided in a third pharmaceutical composition.

[0103] In some embodiments, a compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof are administered in a first pharmaceutical composition, and a second pharmaceutical composition provides tezacaftol and its deuterated derivatives and pharmaceutically acceptable salts, and ibacaftol, dutivacaftol and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, the second pharmaceutical composition comprises half of a daily dose of ibacaftol or its pharmaceutically acceptable salt, and the remaining half of a daily dose of ibacaftol or its pharmaceutically acceptable salt is administered in a third pharmaceutical composition.

[0104] In some embodiments, a compound of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof are administered in a first pharmaceutical composition, and a compound of at least one selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts, and a compound of at least one selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts are provided in a second pharmaceutical composition.

[0105] In some embodiments, the first pharmaceutical composition provides a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, tezacaftol and its deuterated derivatives and pharmaceutically acceptable salts, and ibacaftol, dutivacaftol, and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, the first pharmaceutical composition is administered to the patient twice daily. In some embodiments, the first pharmaceutical composition is administered once daily. In some embodiments, the first pharmaceutical composition is administered once daily, and a second composition containing only ibacaftol is administered once daily.

[0106] In some embodiments, the first pharmaceutical composition provides a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts, tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts, and at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts. In some embodiments, the first pharmaceutical composition is administered to the patient twice daily. In some embodiments, the first pharmaceutical composition is administered once daily. In some embodiments, the first pharmaceutical composition is administered once daily, and a second composition comprising only (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol (or its deuterated derivative or pharmaceutically acceptable salt) is administered once daily.

[0107] Any suitable pharmaceutical composition can be used with the compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, tezacaphthol, lumakhthol, ibakhthol, dutivakhthol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and their tautomers, deuterated derivatives of these compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing. Several exemplary pharmaceutical compositions of tezacaphthol and its pharmaceutically acceptable salts can be found in WO2011 / 119984 and WO2014 / 014841, respectively, which are incorporated herein by reference. Several exemplary pharmaceutically acceptable compositions of ibacaftol and its pharmaceutically acceptable salts can be found in WO2007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, and WO2013 / 130669, and several exemplary pharmaceutically acceptable compositions of dutivacaftol and its pharmaceutically acceptable salts can be found in US8,865,902, US9,181,192, US9,512,079, WO2017 / 053455, and WO2018 / 080591, all of which are incorporated herein by reference. Several exemplary pharmaceutical compositions of lumakhthol and its pharmaceutically acceptable salts can be found in WO2010 / 037066, WO2011 / 127421, and WO2014 / 071122, all of which are incorporated herein by reference.

[0108] Pharmaceutical composition Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound of formula I, one compound of any one of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0109] In some embodiments, the Disclosure provides a pharmaceutical composition comprising, in combination with at least one additional active pharmaceutical component, a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and at least one compound selected from any of the aforementioned pharmaceutically acceptable salts. In some embodiments, the at least one additional active pharmaceutical component is a CFTR regulator. In some embodiments, the at least one additional active pharmaceutical component is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical component is a CFTR enhancer. In some embodiments, the pharmaceutical composition comprises at least one compound selected from the compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, and at least two additional active pharmaceutical components, one of which is a CFTR corrector and the other is a CFTR enhancer.

[0110] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts; and (c) at least one pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from lumakhthol and its deuterated derivatives and pharmaceutically acceptable salts; and (c) at least one pharmaceutically acceptable carrier.

[0111] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from ibacaftol, dutivacaftol, their deuterated derivatives, and pharmaceutically acceptable salts; and (c) at least one pharmaceutically acceptable carrier.

[0112] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and any pharmaceutically acceptable derivatives thereof and pharmaceutically acceptable salts thereof; and (c) at least one pharmaceutically acceptable carrier.

[0113] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts; (c) at least one compound selected from ibacaphthol and its deuterated derivatives and pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier.

[0114] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from the compounds of formula I, any one of the compounds of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts; (c) at least one compound selected from dutivacaphthol and its deuterated derivatives and pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier.

[0115] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) at least one compound selected from a compound of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof; (b) at least one compound selected from ibacaphthol, dutivacaphthol, their deuterated derivatives, and pharmaceutically acceptable salts; (c) at least one compound selected from lumaphthol and its pharmaceutically acceptable salts; and (d) at least one pharmaceutically acceptable carrier.

[0116] In some embodiments, the Disclosure provides (a) at least one compound selected from the compounds of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, and (b) at least one selected from tezacaphthol and its deuterated derivatives and pharmaceutically acceptable salts. The present invention provides a pharmaceutical composition comprising (c) a compound, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts, and (d) at least one pharmaceutically acceptable carrier. In some embodiments, the Disclosure provides (a) at least one compound selected from the compounds of formula I, any one compound of formulas Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, and (b) at least one selected from lumacafthol and its deuterated derivatives and pharmaceutically acceptable salts. The present invention provides a pharmaceutical composition comprising (c) a compound, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and its deuterated derivatives and pharmaceutically acceptable salts, and (d) at least one pharmaceutically acceptable carrier.

[0117] Any pharmaceutical composition disclosed herein may comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0118] The pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR-mediated diseases.

[0119] As described above, the pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and 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 becomes 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.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose). Examples of ingredients include, but are not limited to, sodium sodium, ethylcellulose, and cellulose acetate, tragacanth powder, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants.

[0120] Exemplary Embodiments A non-limiting list of embodiments is provided below: 1. Compounds of formula I: [ka] , its tautomer, compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, in the formula, Ring A is ■C6~C 10Ariel, ■C3~C 10 Cycloalkyl, ■3-10 member heterocyclyl, and ■Selected from 5-10 member heteroaryls, Ring B is ■C6~C 10 Ariel, ■C3~C 10 Cycloalkyl, ■3-10 member heterocyclyl, and ■Selected from 5-10 member heteroaryls, V is selected from O and NH. W 1 However, selected from N and CH, W 2 However, it is selected from N and CH, but W 1 and W 2 Assuming that at least one of them is N, Z is O, NR ZN , and C(R ZC ) Selected from 2, however, L 2 If Z is absent, then C(R ZC ) Provided that it is 2, Each L 1 However, independently, C(R L1 ) Selected from 2, Each L 2 However, independently, C(R L2 ) Selected from 2, Each R 3 However, they became independent, ■Halogen, ■C1~C6 alkyl, ■C1-C6 alkoxy, ■C3~C 10 Cycloalkyl, ■C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 Aryl, and ■Selected from 3-10 member heterocyclines, R 4 However, hydrogen and C1-C6 alkyl are selected, Each R 5However, they became independent, ■ Hydrogen, ■Halogen, ■ Hydroxyl, ■N(R N )2, ■-SO-Me, ■Both R LC Together, C3~C 10 -CH=C(R) LC )2, ■C1-C6 alkyl groups, independently, ○ Hydroxyl, ○ Independently C1-C6 alkoxy and C6-C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ○C3~C 10 Cycloalkyl, ○-(O) groups that are optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl and C1-C6 alkoxy groups. 0~1 -(C6~C 10 Ariel), ○3-10 membered heterocyclils, and ○N(R N )2, C1-C6 alkyl groups optionally substituted with 1-3 groups selected from, ■C1-C6 alkoxys, independently, ○Halogen, ○C6~C 10 Aryl, and ○C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups. 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from cycloalkyl groups, ■C1-C6 fluoroalkyl groups, ■C3~C 10 Cycloalkyl, ■C6~C 10 Ariel, and ■Selected from 3-10 member heterocyclines, R ZN but, ■ Hydrogen, ■C1-C9 alkyl groups, independently, ○ Hydroxyl, ○Oxo, ○Cyano, ○C1-C6 alkoxy groups that are optionally substituted with 1-3 groups independently selected from halogens and C1-C6 alkoxy groups. ○N(R N )2, ○SO2Me, ○C3~C 10 Cycloalkyl, independently, ◆Hydroxyl, ◆Independently, hydroxyl, oxo, C1-C6 alkoxy, C6-C 10 Aryl, and N(R N )C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, ◆C1-C6 fluoroalkyl, ◆C1-C6 alkoxys, and ◆COOH, ◆N(R N )2, ◆C6~C 10 Ariel, and ◆3-10 membered heterocyclyls, independently selected from oxo and C1-C6 alkyl groups, optionally substituted with 1-3 groups, and C3-C6 alkyl groups, optionally substituted with 1-3 groups. 10 Cycloalkyl, ○C6~C 10 It is an army, and independently, ◆Halogen, ◆Hydroxyl, ◆Cyano, ◆SiMe3, ◆SO2Me, ◆SF5, ◆N(R N )2, ◆P(O)Me2, ◆-(O) groups are optionally substituted with 1 to 3 groups independently selected from C1-C6 fluoroalkyl groups. 0~1 -(C3~C 10 Cycloalkyl), ◆Independently, hydroxyl, oxo, C1-C6 alkoxy, 5-10 member heteroaryl, SO2Me, and N(R) N )C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, ◆Independently, hydroxyl, oxo, N(R) N )2, and C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆C1-C6 fluoroalkyl, ◆3-10 membered heterocyclines, independently substituted with 1-3 groups selected from C1-C6 alkyl groups, ◆-(O) 0~1 -(C6~C 10 Aryl), and ◆Hydroxyl, oxo, N(R) N )2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, and C3-C 10 -(O) optionally substituted with cycloalkyl groups 0~1 -(5-10 member heteroaryl), C6-C, optionally substituted with 1-3 groups selected from 10 Ariel, ○3-10 membered heterocyclines, independently, ◆Hydroxyl, ◆Oxo, ◆N(R N )2, ◆C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from oxo and C1-C6 alkoxy groups), ◆C1-C6 alkoxy, ◆C1-C6 fluoroalkyl, ◆C6~C 10 Aryl, and ◆ 3-10 membered heterocyclyls, optionally substituted with 1-4 groups, selected from 5-10 membered heteroaryls, and ○A 5-10 member heteroaryl, independently, ◆Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆B(OH)2, ◆N(R N )2, ◆Independently, hydroxyl, oxo, C1-C6 alkoxy (optionally substituted with 1-3 -SiMe3), and N(R) N )C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, ◆Independently, hydroxyl, oxo, C1-C6 alkoxy, N(R) N )2, and C3~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from cycloalkyl groups, ◆C1-C6 fluoroalkyl, ◆-(O) groups are arbitrarily substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups. 0~1 -(C3~C 10 Cycloalkyl), ◆-(O) 0~1 -(C6~C 10 Ariel), ◆Independently, hydroxyl, oxo, halogen, cyano, N(R) N )2, C1~C6 alkyl (hydroxyl, oxo, N(R N )2, and optionally substituted with 1 to 3 groups selected from C1-C6 alkoxys), C1-C6 alkoxys, C1-C6 fluoroalkyls, 3-10 member heterocyclines (independently optionally substituted with 1 to 3 groups selected from C1-C6 fluoroalkyls) -(O) 0~1 -(3-10 member heterocyclyl), and ◆Independently C1-C6 alkyl and C3-C 10 A 5-10 membered heteroaryl selected from cycloalkyls, a 3-10 membered heterocyclyl selected from 1-3 groups, a C1-C9 alkyl selected from 1-3 groups, ■C1-C6 fluoroalkyl groups, ■C3~C 10 Cycloalkyl, independently, ○ Hydroxyl, ○Oxo, ○Halogen, ○Cyano, ○N(R N )2, ○C1-C6 alkyl groups, independently, ◆Hydroxyl, ◆Oxo, ◆N(R N )2, ◆C1-C6 alkoxys, and ◆C6~C 10 C1-C6 alkyl groups, optionally substituted with 1-3 groups selected from aryl groups. ○Independently, halogen, oxo, C6~C 10 Aryl, and N(R N ) C1-C6 alkoxys optionally substituted with 1-3 groups selected from 2, ○Halogen, ○C3~C 10 Cycloalkyl, ○3-10 membered heterocyclines, which are independently and optionally substituted with 1-3 groups selected from C1-C6 alkyl groups, and ○A 5-10 member heteroaryl, independently, ◆Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆N(R N )2, ◆Independently, hydroxyl, oxo, C1-C6 alkoxy, and N(R) N )C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, ◆Independently, hydroxyl, C1-C6 alkoxy, N(R) N )2, and C3~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from cycloalkyl groups, ◆C1-C6 fluoroalkyl, ◆-(O) groups are arbitrarily substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups. 0~1 -(C3~C 10 Cycloalkyl), ◆C6~C 10 Aryl, and ◆Selected from 3-10 membered heterocyclyls that are independently and optionally substituted with 1-3 groups selected from C1-C6 alkyl groups, selected from 5-10 membered heteroaryls that are optionally substituted with 1-3 groups, selected from C3-C6 alkyl groups. 10 Cycloalkyl, ■C6~C 10 Ariel, ■3-10 member heterocyclines, independently, ○Oxo, ○C1-C6 alkyl groups, independently, ◆Oxo, ◆Hydroxyl, ◆N(R N )2, ◆Independently, halogen and C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, and ◆-(O) 0~1 -(C3~C 10 C1-C6 alkyl groups, optionally substituted with 1-3 groups selected from cycloalkyl groups, ○C1-C6 fluoroalkyl groups, ○C3-C3 are optionally substituted with 1-3 groups independently selected from halogens. 10 Cycloalkyl, and ○ 3-10 member heterocyclils, selected from 3-10 member heterocyclils, which are arbitrarily substituted with 1-3 groups. ■A 5-10 member heteroaryl, independently, ○Halogen, ○ Independently, oxo, C1-C6 alkoxy, and N(R) N )C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, and ○ Independently C1-C6 alkyl (oxo, C1-C6 alkoxy, and C6-C 10 3-10 member heterocyclils, which are optionally substituted with 1-3 groups selected from aryls, 5-10 member heteroaryls, which are optionally substituted with 1-3 groups selected from aryls, and ■R F , selected from, Each R ZC However, they became independent, ■ Hydrogen, ■Independently C6~C 10 C1-C6 alkyl groups that are optionally substituted with 1-3 groups selected from aryl groups (independently selected from C1-C6 alkyl groups), ■C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 Aryl, and ■R F , can be selected from, or two R ZC They come together to form an oxo group, Each R L1 However, they became independent, ■ Hydrogen, ■Two N(R) N )2 is not bonded to the same carbon, N(R N )2, ■C1-C9 alkyl groups, independently, ○Halogen, ○ Hydroxyl, ○Oxo, ○N(R N )2, ○ Independently C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ○C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 10 Cycloalkyl, ○C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups.10 Aryl, and ○ A 3-10 membered heterocyclyl, which is independently selected from C1-C6 alkyl groups (which are independently optionally substituted with 1-3 groups selected from hydroxyl and oxo groups), and a C1-C9 alkyl group, which is independently selected from C1-C6 alkyl groups (which are independently optionally substituted with 1-3 groups selected from hydroxyl and oxo groups), which is independently selected from C1-C9 alkyl groups, which are independently selected from C1-C6 alkyl groups (which are independently optionally substituted with 1-3 groups selected from hydroxyl and oxo groups), ■C3~C 10 Cycloalkyl, ■C6~C 10 It is an army, and independently, ○Halogen, ○Cyano, ○SiMe3, ○POMe2, ○C1-C7 alkyl groups, independently, ◆Hydroxyl, ◆Oxo, ◆Cyano, ◆SiMe3, ◆N(R N )2, and ◆C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups. 10 C1-C7 alkyl groups optionally substituted with 1-3 groups selected from cycloalkyl groups. ○C1-C6 alkoxys, independently, ◆C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups. 10 Cycloalkyl, and ◆C1-C6 alkoxys, which are selected from C1-C6 alkoxys and optionally substituted with 1-3 groups. ○C1-C6 fluoroalkyl groups, ○C3-C6 alkyl and C1-C6 fluoroalkyl groups are independently and optionally substituted with 1-3 groups selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups. 10 Cycloalkyl, ○C6~C 10 Ariel, ○3-10 membered heterocyclines, which are independently and optionally substituted with 1-3 groups selected from C1-C6 alkyl groups, and ○C6-C6, optionally substituted with 1-4 groups, selected from 5-10 membered heteroaryls. 10 Ariel, ■3-10 member heterocyclines, independently, ○C1-C6 alkyl groups, independently, ◆Oxo, and ◆C1-C6 alkoxys, or 3-10 membered heterocyclines ■A 5-10 member heteroaryl, independently, ○C1-C6 alkyl groups, independently, ◆C3-C6 fluoroalkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 fluoroalkyl groups. 10 Cycloalkyls, C1-C6 alkyls optionally substituted with 1-3 groups selected from, and ○C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 aryls, 5-10 membered heteroaryls optionally substituted with 1-3 groups selected from, and ■R F , can be selected from, or two R on the same carbon atom L1 They come together to form an oxo group, Each R L2 However, hydrogen and R are independent F Selected from, or two R on the same carbon atom L2 These combine to form an oxo group, however, at least one R L1 or R L2 R F The condition is that, Each R N However, they became independent, ■ Hydrogen, ■C1-C8 alkyl groups, independently, ○Oxo, ○Halogen, ○ Hydroxyl, ○NH2, ○NHMe, ○NMe2, ○ Independently C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ○-(O) 0~1 -(C3~C 10 Cycloalkyl), ○C6-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from halogens and C1-C6 alkyl groups. 10 Ariel, ○ 3-14 membered heterocyclils independently and optionally substituted with 1-4 groups selected from oxo and C1-C6 alkyl groups, and ○ Selected from 5-14 membered heteroaryls independently substituted with 1-4 groups selected from oxo and C1-C6 alkyl groups, C1-C8 alkyls optionally substituted with 1-3 groups, ■C3~C 10 Cycloalkyl, independently, ○ Hydroxyl, ○NH2, and ○NHMe, and ○C1-C6 alkyl groups, independently selected from hydroxyl groups and optionally substituted with 1-3 groups, and C3-C6 alkyl groups, independently substituted with 1-3 groups. 10 Cycloalkyl, ■C6~C 10 Ariel, and ■Selected from 3-10 member heterocyclines, or two R on the same nitrogen atom N However, together with the nitrogen atoms to which they are bound, they form 3-10 membered heterocyclines, and these 3-10 membered heterocyclines can independently... ■ Hydroxyl, ■Oxo, ■Cyano, ■ Independently, oxo, hydroxyl, C1-C6 alkoxy, and N(R) N2 ) C1-C6 alkyl groups optionally substituted with 1-3 groups selected from 2, where each R N2However, independently, hydrogen and a C1-C6 alkyl selected from C1-C6 alkyl, ■C1~C6 alkoxys, and ■Optionally substituted with 1 to 3 groups selected from C1 to C6 fluoroalkyl groups, or one R 4 and one R L1 These combine to form C6-C8 alkylenes. Two R's F However, together with the atoms to which they are bonded, ■C3-C6 alkyl groups are optionally substituted with 1-3 groups independently selected from C1-C6 alkyl groups. 10 Cycloalkyl, ■C6~C 10 It is an army, and independently, ○Halogen, ○C1~C6 alkyl, ○N(R N )2, and ○ 3-10 membered heterocyclils, selected from hydroxyls, which are arbitrarily substituted with 1-3 groups, and C6-C6, which are arbitrarily substituted with 1-3 groups. 10 Ariel, ■3-11 member heterocyclils, independently, ○Oxo, ○N(R N )2, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆-SO2-(C1~C6 alkyl), ◆Independently, halogen, C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, hydroxyl, halogen, cyano, C1-C6 alkyl (independently substituted with 1-3 groups selected from oxo and C1-C6 alkoxy), C1-C6 alkoxy (independently C6-C10 (Optionally substituted with 1 to 3 groups selected from aryls), -(O) 0~1 -(C1~C6 fluoroalkyl), and C6~C 10 C6-C6 alkoxy molecules (arbitrarily substituted with 1-3 groups selected independently from C1-C6 alkoxy molecules) 10 Ariel, ◆Independently, hydroxyl, halogen, N(R N )2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), C1-C6 fluoroalkyl, and C6-C 10 -(O) is optionally substituted with 1 to 4 groups selected from aryl groups. 0~1 -(C3~C 10 Cycloalkyl), ◆Independently oxo, C1-C6 alkyl (independently C6-C 10 Aryl (optionally substituted with 1 to 3 groups selected independently from halogens), C1-C6 alkoxy, C3-C 10 Cycloalkyl, and R N A 3-10 member heterocycline, optionally substituted with 1-3 groups selected from the following: ◆Independently, C6~C 10 -O-(5-12 member heteroaryls) which are optionally substituted with aryls (optionally substituted with 1-3 groups independently selected from halogens) and 1-3 groups selected from C1-C6 alkyls, and ◆Independently, hydroxyl, oxo, N(R) N )2, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from cyano), C1-C6 alkoxy, -(O) 0~1 -(C1~C6 fluoroalkyl), -O-(C6~C 10 Aryl), and C3~C 10A 5-10 membered heteroaryl selected from cycloalkyls, a C1-C9 alkyl selected from 5-10 membered heteroaryl ○ Independently, C3-C3 groups are optionally substituted with 1-4 groups selected from halogens, C1-C6 alkyl groups, and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Ariel, ○3-10 membered heterocyclils, and ○Independently, C1-C6 alkoxy, C1-C6 fluoroalkyl, and N(R) N ) 5-10 member heteroaryls selected from 2, 3-11 member heterocyclines selected from 2, and 3-11 member heterocyclines selected from 2, and ■ Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts that independently form groups selected from 5-12 membered heteroaryls, which are optionally substituted with 1-3 groups selected from C1-C6 alkyl and C1-C6 fluoroalkyl groups. 1A. In some cases of Embodiment 1, two R F When these come together to form a 3-11 member heterocycline, the 3-11 member heterocycline can be optionally substituted with a 5-10 member heteroaryl, and the 5-10 member heteroaryl can be optionally substituted with a C1-C6 alkoxy, and the C1-C6 alkoxy can be C6-C 10 It can be optionally replaced with an aryl character. 2. Ring A is C6~C 10 A compound, salt, or deuterated derivative according to Embodiment 1, selected from aryls, 3-10 membered heterocyclines, and 5-10 membered heteroaryls. 3. The compound, salt, or deuterated derivative according to Embodiment 1 or 2, wherein ring A is selected from phenyl, pyridinyl, pyrazolyl, 1H-pyrrolyl, indolinyl, and piperidinyl. 4. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 3, wherein ring A is phenyl. 5. Ring B is C6~C10 A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 4, selected from aryl compounds. 6. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 5, wherein ring B is phenyl. 7. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 6, wherein V is O. 8. A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 6, wherein V is NH. 9.W 1 However, N is W 2 The compound, salt, or deuterated derivative according to any one of Embodiments 1 to 8, wherein N is present. 10.Z is NR ZN and C(R ZC A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 9, selected from 2. 11.Each R 3 However, independently, a compound, salt, or deuterated derivative according to any one of Embodiments 1 to 10, selected from C1 to C6 alkyl groups. 12.Each R 3 The compound, salt, or deuterated derivative according to any one of Embodiments 1 to 11, wherein the compound is methyl. 13.R 3 However, the compound, salt, or deuterated derivative described in any one of Embodiments 1 to 10 is absent. 14.R 4 However, a compound, salt, or deuterated derivative according to any one of Embodiments 1 to 13, selected from hydrogen and methyl. 15.R 4 The compound, salt, or deuterated derivative described in any one of Embodiments 1 to 14, wherein the compound is methyl. 16.R 4 The compound, salt, or deuterated derivative described in any one of Embodiments 1 to 14, wherein the compound is hydrogen. 17.Each R 5 However, independently selected from C1-C6 alkyl and C1-C6 alkoxy compounds, salts, or deuterated derivatives according to any one of Embodiments 1 to 16. 18.Each R 5 However, independently, methyl, [ka] A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 17, selected from the above. 19.R ZN However, hydrogen and R F A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 18, selected from the above. 20.R ZN The compound, salt, or deuterated derivative described in any one of Embodiments 1 to 19, wherein the compound is hydrogen. 21.R ZN However, R F The compound, salt, or deuterated derivative described in any one of Embodiments 1 to 19. 22.R ZC However, it is either hydrogen or two R ZC A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 21, wherein these groups combine to form an oxo group. 23.Each R L1 However, independently, hydrogen, independently, C6~C 10 C1-C9 alkyl groups, and R, which are optionally substituted with 1-3 groups selected from aryl groups. F A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 22, selected from the above. 24.Each R L2 However, independently, hydrogen and R F Selected from, or two R on the same carbon atom L2 However, the compound, salt, or deuterated derivative according to any one of Embodiments 1 to 23, which together form an oxo group. 25.Each R N However, independently, hydrogen and C1-C8 alkyl (independently, oxo, C1-C6 alkoxy, C3-C 10 Cycloalkyl, and C6-C 10 A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 24, selected from (substituted with 1 to 3 groups selected from aryl groups). 26. Two R's F However, together with the atoms to which they are bonded, ■C6~C 10 Aryl, and ■3-11 member heterocyclils, independently, ○Oxo, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆Independent C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, C6-C6 alkyl groups are optionally substituted with 1-3 groups selected from hydroxy, cyano, and C1-C6 alkyl groups. 10 Ariel, ◆Independently, N(R) N )2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), and C1-C6 fluoroalkyl -(O) 0~1 -(C3~C 10 Cycloalkyl), ◆3-10 membered heterocyclines, independently and optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, and ◆Independently, N(R) N )2, C1~C6 alkyl, and -O-(C6~C 10 5-10 membered heteroaryls selected from aryls, C1-C9 alkyl ○C3-C6 fluoroalkyl groups are optionally substituted with 1-4 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Aryl, and ○ A compound, salt, or deuterated derivative according to any one of Embodiments 1 to 25, which is selected from 3 to 10-membered heterocyclils, or 3 to 11-membered heterocyclils that are optionally substituted with 1 to 3 groups, forming a group. 27. Compounds of formula Ia: [ka] , its tautomer, compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, ring A, ring B, W 1 , W 2 Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R F However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in Embodiment 1. 28. Ring A is C6~C 10 A compound, salt, or deuterated derivative according to Embodiment 27, selected from aryls, 3-10 membered heterocyclines, and 5-10 membered heteroaryls. 29. The compounds, salts, or deuterated derivatives according to Embodiment 27 or 28, wherein ring A is selected from phenyl, pyridinyl, pyrazolyl, 1H-pyrrolyl, indolinyl, and piperidinyl. 30. A compound, salt, or deuterated derivative according to any one of Embodiments 27 to 29, wherein ring A is phenyl. 31. Ring B is C6~C 10 A compound, salt, or deuterated derivative according to any one of embodiments 27 to 30, selected from aryl compounds. 32. A compound, salt, or deuterated derivative according to any one of Embodiments 27 to 31, wherein ring B is phenyl. 33.W 1 However, N is W 2 The compound, salt, or deuterated derivative according to any one of embodiments 27 to 32, wherein N is present. 34.Z is NR ZN and C(R ZCA compound, salt, or deuterated derivative according to any one of embodiments 27 to 33, selected from 2. 35.Each R 3 However, independently, a compound, salt, or deuterated derivative according to any one of Embodiments 27 to 34, selected from C1 to C6 alkyl groups. 36.Each R 3 The compound, salt, or deuterated derivative according to any one of Embodiments 27 to 35, wherein the compound is methyl. 37.R 3 However, the compound, salt, or deuterated derivative described in any one of embodiments 27 to 34 is absent. 38.R 4 However, a compound, salt, or deuterated derivative according to any one of Embodiments 27 to 37, selected from hydrogen and methyl. 39.R 4 The compound, salt, or deuterated derivative according to any one of Embodiments 27 to 38, wherein the compound is methyl. 40.R 4 However, the compound, salt, or deuterated derivative according to any one of embodiments 27 to 38 is hydrogen. 41.Each R 5 However, independently selected from C1-C6 alkyl and C1-C6 alkoxy compounds, salts, or deuterated derivatives according to any one of Embodiments 27-40. 42.Each R 5 However, independently, methyl, [ka] A compound, salt, or deuterated derivative according to any one of embodiments 27 to 41, selected from the above. 43.R ZN However, hydrogen and R F A compound, salt, or deuterated derivative according to any one of embodiments 27 to 42, selected from the above. 44.R ZN However, the compound, salt, or deuterated derivative described in any one of Embodiments 27 to 43 is hydrogen. 45.R ZN However, R FThe compound, salt, or deuterated derivative described in any one of embodiments 27 to 44. 46.R ZC However, it is either hydrogen or two R ZC A compound, salt, or deuterated derivative according to any one of Embodiments 27 to 45, wherein these groups combine to form an oxo group. 47.Each R L1 However, independently, hydrogen, independently, C6~C 10 C1-C9 alkyl groups, and R, which are optionally substituted with 1-3 groups selected from aryl groups. F A compound, salt, or deuterated derivative according to any one of embodiments 27 to 46, selected from the above. 48.Each R L2 However, independently, hydrogen and R F Selected from, or two R on the same carbon atom L2 However, the compound, salt, or deuterated derivative according to any one of Embodiments 27 to 47, which together form an oxo group. 49.Each R N However, independently, hydrogen and C1-C8 alkyl (independently, oxo, C1-C6 alkoxy, C3-C 10 Cycloalkyl, and C6-C 10 A compound, salt, or deuterated derivative according to any one of Embodiments 27 to 48, selected from (substituted with 1 to 3 groups selected from aryl groups). 50. Two R's F However, together with the atoms to which they are bonded, ■C6~C 10 Aryl, and ■3-11 member heterocyclils, independently, ○Oxo, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆Independent C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, C6-C6 alkyl groups are optionally substituted with 1-3 groups selected from hydroxy, cyano, and C1-C6 alkyl groups. 10 Ariel, ◆Independently, N(R) N )2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), and C1-C6 fluoroalkyl -(O) 0~1 -(C3~C 10 Cycloalkyl), ◆3-10 membered heterocyclines, independently and optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, and ◆Independently, N(R) N )2, C1~C6 alkyl, and -O-(C6~C 10 5-10 membered heteroaryls selected from aryls, C1-C9 alkyl ○C3-C6 fluoroalkyl groups are optionally substituted with 1-4 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Aryl, and ○ A compound, salt, or deuterated derivative according to any one of Embodiments 27 to 49, which is selected from 3 to 10-membered heterocyclines, or 3 to 11-membered heterocyclines that are optionally substituted with 1 to 3 groups, forming a group. 51. Compounds of formula IIa: [ka] , its tautomer, compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, ring B, W 1 , W 2 Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R FHowever, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in Embodiment 1. 52. Ring B is C6~C 10 A compound, salt, or deuterated derivative according to Embodiment 51, selected from aryl compounds. 53. The compound, salt, or deuterated derivative according to Embodiment 51 or 52, wherein ring B is phenyl. 54.W 1 However, N is W 2 The compound, salt, or deuterated derivative according to any one of embodiments 51 to 53, wherein N is present. 55.Z is NR ZN and C(R ZC A compound, salt, or deuterated derivative according to any one of embodiments 51 to 54, selected from 2. 56.Each R 3 However, independently, a compound, salt, or deuterated derivative according to any one of embodiments 51 to 55, selected from C1 to C6 alkyl groups. 57.Each R 3 The compound, salt, or deuterated derivative according to any one of embodiments 51 to 56, wherein the compound is methyl. 58.R 3 However, the compound, salt, or deuterated derivative described in any one of embodiments 51 to 55 is absent. 59.R 4 However, a compound, salt, or deuterated derivative according to any one of embodiments 51 to 58, selected from hydrogen and methyl. 60.R 4 The compound, salt, or deuterated derivative according to any one of embodiments 51 to 59, wherein the compound is methyl. 61.R 4 The compound, salt, or deuterated derivative described in any one of Embodiments 51 to 59, wherein the compound is hydrogen. 62.Each R 5 However, independently selected from C1-C6 alkyl and C1-C6 alkoxy compounds, salts, or deuterated derivatives according to any one of Embodiments 51-61. 63.Each R 5 However, independently, methyl, [ka] A compound, salt, or deuterated derivative according to any one of embodiments 51 to 62, selected from the above. 64.R ZN However, hydrogen and R F A compound, salt, or deuterated derivative according to any one of embodiments 51 to 63, selected from the above. 65.R ZN The compound, salt, or deuterated derivative described in any one of embodiments 51 to 64, wherein the compound is hydrogen. 66.R ZN However, R F The compound, salt, or deuterated derivative described in any one of embodiments 51 to 64. 67.R ZC However, it is either hydrogen or two R ZC A compound, salt, or deuterated derivative according to any one of embodiments 51 to 66, wherein these groups combine to form an oxo group. 68.Each R L1 However, independently, hydrogen, independently, C6~C 10 C1-C9 alkyl groups, and R, which are optionally substituted with 1-3 groups selected from aryl groups. F A compound, salt, or deuterated derivative according to any one of embodiments 51 to 67, selected from the above. 69.Each R L2 However, independently, hydrogen and R F Selected from, or two R on the same carbon atom L2 However, the compound, salt, or deuterated derivative according to any one of embodiments 51 to 68, which together form an oxo group. 70.Each R N However, independently, hydrogen and C1-C8 alkyl (independently, oxo, C1-C6 alkoxy, C3-C 10 Cycloalkyl, and C6-C 10 A compound, salt, or deuterated derivative according to any one of embodiments 51 to 69, selected from (substituted with 1 to 3 groups selected from aryl groups). 71. Two R's FHowever, together with the atoms to which they are bonded, ■C6~C 10 Aryl, and ■3-11 member heterocyclils, independently, ○Oxo, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆Independent C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, C6-C6 alkyl groups are optionally substituted with 1-3 groups selected from hydroxy, cyano, and C1-C6 alkyl groups. 10 Ariel, ◆Independently, N(R) N )2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), and C1-C6 fluoroalkyl -(O) 0~1 -(C3~C 10 Cycloalkyl), ◆3-10 membered heterocyclines, independently and optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, and ◆Independently, N(R) N )2, C1~C6 alkyl, and -O-(C6~C 10 5-10 membered heteroaryls selected from aryls, C1-C9 alkyl ○C3-C6 fluoroalkyl groups are optionally substituted with 1-4 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Aryl, and ○ A compound, salt, or deuterated derivative according to any one of embodiments 51 to 70, selected from 3 to 10-membered heterocyclines, which are optionally substituted with 1 to 3 groups, to form a group, selected from 3 to 11-membered heterocyclines. 72. Compounds of formula IIb: [ka] , its tautomer, compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, ring A, W 1 , W 2 Z, L 1 , L 2 , R 3 , R 4 , R 5 , and R F However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in Embodiment 1. 73. Ring A is C6~C 10 A compound, salt, or deuterated derivative according to Embodiment 72, selected from aryls, 3-10 membered heterocyclines, and 5-10 membered heteroaryls. 74. The compounds, salts, or deuterated derivatives according to Embodiment 72 or 73, wherein ring A is selected from phenyl, pyridinyl, pyrazolyl, 1H-pyrrolyl, indolinyl, and piperidinyl. 75. A compound, salt, or deuterated derivative according to any one of embodiments 72 to 74, wherein ring A is phenyl. 76.W 1 However, N is W 2 The compound, salt, or deuterated derivative according to any one of embodiments 72 to 75, wherein N is present. 77.Z is NR ZN and C(R ZC A compound, salt, or deuterated derivative according to any one of embodiments 72 to 76, selected from )2. 78.Each R 3 However, independently, a compound, salt, or deuterated derivative according to any one of Embodiments 2 to 77, selected from C1 to C6 alkyl groups. 79.Each R3 The compound, salt, or deuterated derivative according to any one of embodiments 72 to 78, wherein the compound is methyl. 80.R 3 However, the compound, salt, or deuterated derivative described in any one of embodiments 72 to 77 is absent. 81.R 4 However, a compound, salt, or deuterated derivative according to any one of embodiments 72 to 80, selected from hydrogen and methyl. 82.R 4 The compound, salt, or deuterated derivative according to any one of embodiments 72 to 81, wherein the compound is methyl. 83.R 4 The compound, salt, or deuterated derivative described in any one of embodiments 72 to 81, wherein the compound is hydrogen. 84.Each R 5 However, independently selected from C1-C6 alkyl and C1-C6 alkoxy compounds, salts, or deuterated derivatives according to any one of embodiments 72-83. 85.Each R 5 However, independently, methyl, [ka] A compound, salt, or deuterated derivative according to any one of embodiments 72 to 84, selected from the above. 86.R ZN However, hydrogen and R F A compound, salt, or deuterated derivative according to any one of embodiments 72 to 85, selected from the above. 87.R ZN The compound, salt, or deuterated derivative described in any one of embodiments 72 to 86, wherein the compound is hydrogen. 88.R ZN However, R F The compound, salt, or deuterated derivative described in any one of embodiments 72 to 86. 89.R ZC However, it is either hydrogen or two R ZC A compound, salt, or deuterated derivative according to any one of embodiments 72 to 88, wherein these groups combine to form an oxo group. 90.Each R L1 However, independently, hydrogen, independently, C6~C 10 C1-C9 alkyl groups, and R, which are optionally substituted with 1-3 groups selected from aryl groups. F A compound, salt, or deuterated derivative according to any one of embodiments 72 to 89, selected from the above. 91.Each R L2 However, independently, hydrogen and R F Selected from, or two R on the same carbon atom L2 However, the compound, salt, or deuterated derivative described in any one of Embodiments 72 to 90, which together form an oxo group. 92.Each R N However, independently, hydrogen and C1-C8 alkyl (independently, oxo, C1-C6 alkoxy, C3-C 10 Cycloalkyl, and C6-C 10 A compound, salt, or deuterated derivative according to any one of embodiments 72 to 91, selected from (substituted with 1 to 3 groups selected from aryl groups). 93. Two R's F However, together with the atoms to which they are bonded, ■C6~C 10 Aryl, and ■3-11 member heterocyclils, independently, ○Oxo, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆Independent C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, C6-C6 alkyl groups are optionally substituted with 1-3 groups selected from hydroxy, cyano, and C1-C6 alkyl groups. 10 Ariel, ◆Independently, N(R) N)2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), and C1-C6 fluoroalkyl -(O) 0~1 -(C3~C 10 Cycloalkyl), ◆3-10 membered heterocyclines, independently and optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, and ◆Independently, N(R) N )2, C1~C6 alkyl, and -O-(C6~C 10 5-10 membered heteroaryls selected from aryls, C1-C9 alkyl ○C3-C6 fluoroalkyl groups are optionally substituted with 1-4 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Aryl, and ○ A compound, salt, or deuterated derivative according to any one of Embodiments 72 to 92, selected from 3 to 10-membered heterocyclines, or 3 to 11-membered heterocyclines optionally substituted with 1 to 3 groups, forming a group. 94. Compounds of formula III: [ka] , its tautomer, compound or deuterated derivative of the tautomer, or any pharmaceutically acceptable salt of the above, W 1 , W 2 Z, L 1 , L 2 , R 4 , R 5 , and R F However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in Embodiment 1. 95.W 1 However, N is W 2The compound, salt, or deuterated derivative described in Embodiment 94, wherein N is present. 96.Z is NR ZN and C(R ZC A compound, salt, or deuterated derivative according to Embodiment 94 or 95, selected from 2. 97.R 4 However, a compound, salt, or deuterated derivative according to any one of embodiments 94 to 96, selected from hydrogen and methyl. 98.R 4 The compound, salt, or deuterated derivative according to any one of embodiments 94 to 97, wherein the compound is methyl. 99.R 4 However, the compound, salt, or deuterated derivative described in any one of embodiments 94 to 97 is hydrogen. 100.Each R 5 However, independently selected from C1-C6 alkyl and C1-C6 alkoxy compounds, salts, or deuterated derivatives according to any one of Embodiments 94-99. 101.Each R 5 However, independently, methyl, [ka] A compound, salt, or deuterated derivative according to any one of embodiments 94 to 100, selected from the above. 102.R ZN However, hydrogen and R F A compound, salt, or deuterated derivative according to any one of embodiments 94 to 101, selected from the above. 103.R ZN However, the compound, salt, or deuterated derivative described in any one of Embodiments 94 to 102 is hydrogen. 104.R ZN However, R F The compound, salt, or deuterated derivative described in any one of embodiments 94 to 102. 105.R ZC However, it is either hydrogen or two R ZC The compound, salt, or deuterated derivative according to any one of Embodiments 94 to 104, wherein these groups combine to form an oxo group. 106.Each R L1 However, independently, hydrogen, independently, C6~C 10 C1-C9 alkyl groups, and R, which are optionally substituted with 1-3 groups selected from aryl groups. F A compound, salt, or deuterated derivative according to any one of embodiments 94 to 105, selected from the above. 107.Each R L2 However, independently, hydrogen and R F Selected from, or two R on the same carbon atom L2 However, the compound, salt, or deuterated derivative according to any one of embodiments 94 to 106, which together form an oxo group. 108.Each R N However, independently, hydrogen and C1-C8 alkyl (independently, oxo, C1-C6 alkoxy, C3-C 10 Cycloalkyl, and C6-C 10 A compound, salt, or deuterated derivative according to any one of embodiments 94 to 107, selected from (substituted with 1 to 3 groups selected from aryl groups). 109. Two Rs F However, together with the atoms to which they are bonded, ■C6~C 10 Aryl, and ■3-11 member heterocyclils, independently, ○Oxo, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆Independent C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, C6-C6 alkyl groups are optionally substituted with 1-3 groups selected from hydroxy, cyano, and C1-C6 alkyl groups. 10 Ariel, ◆Independently, N(R) N)2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), and C1-C6 fluoroalkyl -(O) 0~1 -(C3~C 10 Cycloalkyl), ◆3-10 membered heterocyclines, independently and optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, and ◆Independently, N(R) N )2, C1~C6 alkyl, and -O-(C6~C 10 5-10 membered heteroaryls selected from aryls, C1-C9 alkyl ○C3-C6 fluoroalkyl groups are optionally substituted with 1-4 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Aryl, and ○ A compound, salt, or deuterated derivative according to any one of Embodiments 94 to 108, selected from 3 to 10-membered heterocyclils, which are optionally substituted with 1 to 3 groups, and which form a group, selected from 3 to 11-membered heterocyclils. 110. Compounds of formula IV: [ka] , its tautomer, compound or deuterated derivative of the tautomer, or any pharmaceutically acceptable salt of any of the above, Z, L 1 , L 2 , R 4 , R 5 , and R F However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in Embodiment 1. 111.Z is NR ZN and C(R ZC A compound, salt, or deuterated derivative according to Embodiment 110, selected from 2. 112.R 4 However, the compound, salt, or deuterated derivative according to Embodiment 110 or 111, selected from hydrogen and methyl. 113.R 4 The compound, salt, or deuterated derivative described in any one of Embodiments 110 to 112, wherein the compound is methyl. 114.R 4 However, the compound, salt, or deuterated derivative described in any one of embodiments 110 to 112 is hydrogen. 115.Each R 5 However, independently, a compound, salt, or deuterated derivative according to any one of embodiments 110 to 114, selected from C1-C6 alkyl and C1-C6 alkoxy. 116.Each R 5 However, independently, methyl, [ka] A compound, salt, or deuterated derivative according to any one of embodiments 110 to 115, selected from the above. 117.R ZN However, hydrogen and R F A compound, salt, or deuterated derivative according to any one of embodiments 110 to 116, selected from the above. 118.R ZN However, the compound, salt, or deuterated derivative described in any one of embodiments 110 to 117 is hydrogen. 119.R ZN However, R F The compound, salt, or deuterated derivative described in any one of embodiments 110 to 117. 120.R ZC However, it is either hydrogen or two R ZC A compound, salt, or deuterated derivative according to any one of embodiments 110 to 119, wherein these groups combine to form an oxo group. 121.Each R L1 However, independently, hydrogen, independently, C6~C 10 C1-C9 alkyl groups, and R, which are optionally substituted with 1-3 groups selected from aryl groups. FA compound, salt, or deuterated derivative according to any one of embodiments 110 to 120, selected from the above. 122.Each R L2 However, independently, hydrogen and R F Selected from, or two R on the same carbon atom L2 However, the compound, salt, or deuterated derivative described in any one of Embodiments 110 to 121, which together form an oxo group. 123.Each R N However, independently, hydrogen and C1-C8 alkyl (independently, oxo, C1-C6 alkoxy, C3-C 10 Cycloalkyl, and C6-C 10 A compound, salt, or deuterated derivative according to any one of embodiments 110 to 122, selected from (substituted with 1 to 3 groups selected from aryl groups). 124. Two R's F However, together with the atoms to which they are bonded, ■C6~C 10 Aryl, and ■3-11 member heterocyclils, independently, ○Oxo, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆Independent C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, C6-C6 alkyl groups are optionally substituted with 1-3 groups selected from hydroxy, cyano, and C1-C6 alkyl groups. 10 Ariel, ◆Independently, N(R) N )2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), and C1-C6 fluoroalkyl -(O) 0~1 -(C3~C 10Cycloalkyl), ◆3-10 membered heterocyclines, independently and optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, and ◆Independently, N(R) N )2, C1~C6 alkyl, and -O-(C6~C 10 5-10 membered heteroaryls selected from aryls, C1-C9 alkyl ○C3-C6 fluoroalkyl groups are optionally substituted with 1-4 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Aryl, and ○ A compound, salt, or deuterated derivative according to any one of embodiments 110 to 123, selected from 3 to 10-membered heterocyclines, which are optionally substituted with 1 to 3 groups, forming a group. 125. Compounds of formula V: [ka] , its tautomer, compound or deuterated derivative of the tautomer, or any pharmaceutically acceptable salt of any of the above, Z, L 1 , L 2 , R 4 , R 5 , and R F However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in Embodiment 1. 126.Z is NR ZN and C(R ZC A compound, salt, or deuterated derivative according to Embodiment 125, selected from 2. 127.R 4 However, the compound, salt, or deuterated derivative according to Embodiment 125 or 126, selected from hydrogen and methyl. 128.R 4The compound, salt, or deuterated derivative according to any one of embodiments 125 to 127, wherein the compound is methyl. 129.R 4 However, the compound, salt, or deuterated derivative described in any one of embodiments 125 to 127 is hydrogen. 130.Each R 5 However, independently, a compound, salt, or deuterated derivative according to any one of Embodiments 125 to 129, selected from C1-C6 alkyl and C1-C6 alkoxy. 131.Each R 5 However, independently, methyl, [ka] A compound, salt, or deuterated derivative according to any one of embodiments 125 to 131, selected from the above. 132.R ZN However, hydrogen and R F A compound, salt, or deuterated derivative according to any one of embodiments 125 to 131, selected from the above. 133.R ZN The compound, salt, or deuterated derivative described in any one of Embodiments 125 to 132, wherein the compound is hydrogen. 134.R ZN However, R F The compound, salt, or deuterated derivative described in any one of embodiments 125 to 132. 135.R ZC However, it is either hydrogen or two R ZC A compound, salt, or deuterated derivative according to any one of embodiments 125 to 134, wherein these groups combine to form an oxo group. 136.Each R L1 However, independently, hydrogen, independently, C6~C 10 C1-C9 alkyl groups, and R, which are optionally substituted with 1-3 groups selected from aryl groups. F A compound, salt, or deuterated derivative according to any one of embodiments 125 to 135, selected from the above. 137.Each R L2 However, independently, hydrogen and R FSelected from, or two R on the same carbon atom L2 However, the compound, salt, or deuterated derivative according to any one of embodiments 125 to 136, which together form an oxo group. 138.Each R N However, independently, hydrogen and C1-C8 alkyl (independently, oxo, C1-C6 alkoxy, C3-C 10 Cycloalkyl, and C6-C 10 A compound, salt, or deuterated derivative according to any one of embodiments 125 to 137, selected from (substituted with 1 to 3 groups selected from aryl groups). 139. Two R's F However, together with the atoms to which they are bonded, ■C6~C 10 Aryl, and ■3-11 member heterocyclils, independently, ○Oxo, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆Independent C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, C6-C6 alkyl groups are optionally substituted with 1-3 groups selected from hydroxy, cyano, and C1-C6 alkyl groups. 10 Ariel, ◆Independently, N(R) N )2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), and C1-C6 fluoroalkyl -(O) 0~1 -(C3~C 10 Cycloalkyl), ◆3-10 membered heterocyclines, independently and optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, and ◆Independently, N(R)N )2, C1~C6 alkyl, and -O-(C6~C 10 5-10 membered heteroaryls selected from aryls, C1-C9 alkyl ○C3-C6 fluoroalkyl groups are optionally substituted with 1-4 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Aryl, and ○ A compound, salt, or deuterated derivative according to any one of Embodiments 125 to 138, which is selected from 3 to 10-membered heterocyclines, or 3 to 11-membered heterocyclines that are optionally substituted with 1 to 3 groups, forming a group. 140. Compounds of formula VI: [ka] , its tautomer, compound or deuterated derivative of the tautomer, or any pharmaceutically acceptable salt of the above, L 1 , R 4 , R 5 , and R F However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in Embodiment 1. 141.R 4 However, the compound, salt, or deuterated derivative described in Embodiment 140, selected from hydrogen and methyl. 142.R 4 The compound, salt, or deuterated derivative described in Embodiment 140 or 141, wherein the compound is methyl. 143.R 4 The compound, salt, or deuterated derivative described in Embodiment 140 or 141, wherein the compound is hydrogen. 144.Each R 5 However, independently, a compound, salt, or deuterated derivative according to any one of Embodiments 140 to 143, selected from C1-C6 alkyl and C1-C6 alkoxy. 145.Each R 5 However, independently, methyl, [ka] A compound, salt, or deuterated derivative according to any one of embodiments 140 to 144, selected from the above. 146.Each R L1 However, independently, hydrogen, independently, C6~C 10 C1-C9 alkyl groups, and R, which are optionally substituted with 1-3 groups selected from aryl groups. F A compound, salt, or deuterated derivative according to any one of embodiments 140 to 145, selected from the above. 147.Each R N However, independently, hydrogen and C1-C8 alkyl (independently, oxo, C1-C6 alkoxy, C3-C 10 Cycloalkyl, and C6-C 10 A compound, salt, or deuterated derivative according to any one of embodiments 140 to 146, selected from (substituted with 1 to 3 groups selected from aryl groups). 148. Two R's F However, together with the atoms to which they are bonded, ■C6~C 10 Aryl, and ■3-11 member heterocyclils, independently, ○Oxo, ○C1-C9 alkyl groups, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R N )2, ◆Independent C6~C 10 C1-C6 alkoxys optionally substituted with 1-3 groups selected from aryl groups, ◆Independently, C6-C6 alkyl groups are optionally substituted with 1-3 groups selected from hydroxy, cyano, and C1-C6 alkyl groups. 10 Ariel, ◆Independently, N(R) N)2, C1-C6 alkyl (independently optionally substituted with 1-3 groups selected from oxo, hydroxyl, and C1-C6 alkoxy), and C1-C6 fluoroalkyl -(O) 0~1 -(C3~C 10 Cycloalkyl), ◆3-10 membered heterocyclines, independently and optionally substituted with 1-3 groups selected from oxo and C1-C6 alkyl groups, and ◆Independently, N(R) N )2, C1~C6 alkyl, and -O-(C6~C 10 5-10 membered heteroaryls selected from aryls, C1-C9 alkyl ○C3-C6 fluoroalkyl groups are optionally substituted with 1-4 groups independently selected from halogens and C1-C6 fluoroalkyl groups. 12 Cycloalkyl, ○C6~C 10 Aryl, and ○ A compound, salt, or deuterated derivative according to any one of Embodiments 140 to 147, selected from 3 to 10-membered heterocyclils, or 3 to 11-membered heterocyclils optionally substituted with 1 to 3 groups, forming a group. 149. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 148, selected from any one compound of formulas I, Ia, IIa, IIb, III, IV, V, Va, Vb, and VI, its tautomer, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing. 150. Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts according to any one of Embodiments 1 to 149, selected from Compounds 1 to 371 (Tables 13, 14, and 15), Compounds 372 to 385 (Table 12), Compounds 386 to 426 (Table 24), their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of any of the foregoing. 151. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 150, and a pharmaceutically acceptable carrier. 152. The pharmaceutical composition according to Embodiment 151, further comprising one or more additional therapeutic agents. 153. The pharmaceutical composition according to Embodiment 152, wherein one or more additional therapeutic agents are selected from mucolytics, bronchodilators, antibiotics, antiinfectives, and anti-inflammatorys. 154. The pharmaceutical composition according to Embodiment 152, wherein one or more additional therapeutic agents are tobramycin containing tobramycin inhalation powder (TIP), azithromycin, aztreonam containing an aerosolized form of aztreonam, amikacin containing a liposomal formulation of amikacin, ciprofloxacin containing a formulation of ciprofloxacin suitable for administration by inhalation, levoflaxacin containing an aerosolized formulation of levoflaxacin, and an antibiotic selected from two antibiotics, for example, a combination of fosfomycin and tobramycin. 155. The pharmaceutical composition according to Embodiment 152, wherein one or more additional therapeutic agents are CFTR modulators. 156. The pharmaceutical composition according to Embodiment 155, wherein the CFTR regulator is an enhancing factor. 157. The pharmaceutical composition according to Embodiment 155, wherein the CFTR modulator is a corrective factor. 158. The pharmaceutical composition according to Embodiment 156, comprising both a CFTR enhancing factor and a CFTR correcting factor. 159. The pharmaceutical composition according to Embodiment 155 or Embodiment 158, wherein the CFTR enhancer is selected from ibacaftol, dutivacaftol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and any of the deuterated derivatives and pharmaceutically acceptable salts thereof. 160. The pharmaceutical composition according to Embodiment 157 or Embodiment 158, wherein the CFTR correcting factor is selected from tezacaftol and lumakhatol. 161. The pharmaceutical composition according to Embodiment 152, wherein the composition comprises ibacaftol and tezacaftol. 162. The pharmaceutical composition according to Embodiment 152, wherein the composition comprises dutivacaftol and tezacaftol. 163. The pharmaceutical composition according to Embodiment 152, wherein the composition comprises (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and tezacaphthol. 164. The pharmaceutical composition according to Embodiment 152, wherein the composition comprises ibacaftol and lumacaftol. 165. The pharmaceutical composition according to Embodiment 152, wherein the composition comprises dutivacaftol and lumakhtol. 166. The pharmaceutical composition according to Embodiment 152, wherein the composition comprises (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and lumacafthol. 167. A method for treating cystic fibrosis, comprising administering to a patient in need of treatment a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 150, or a pharmaceutical composition described in any one of Embodiments 151 to 166. 168. The method according to Embodiment 167, further comprising administering to the patient one or more additional therapeutic agents before, simultaneously with, or after, any one of the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts described in any one of Embodiments 1 to 150, or the pharmaceutical composition described in Embodiment 151. 169. The method according to embodiment 168, wherein one or more additional therapeutic agents are selected from CFTR modulators. 170. The method according to Embodiment 169, wherein the CFTR regulator is an enhancing factor. 171. The method according to Embodiment 169, wherein the CFTR modulator is a correction factor. 172. The method according to Embodiment 169, comprising administration of both a CFTR enhancing factor and an additional CFTR correcting factor. 173. The method of Embodiment 170 or Embodiment 172, wherein the CFTR enhancing factor is selected from ibacaftol, dutivacaftol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and any of the deuterated derivatives and pharmaceutically acceptable salts thereof. 174. The method according to Embodiment 171 or Embodiment 172, wherein the CFTR correction factor is selected from tezacaftol and lumakhatol. 175. The method according to Embodiment 169, comprising the administration of ibacaftol and tezacaftol. 176. The method according to Embodiment 169, comprising the administration of dutivacaftol and tezacaftol. The method according to Embodiment 169, comprising the administration of (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18), 2,4,14,16-pentaen-6-ol and tezacaftol. 178. The method according to Embodiment 169, comprising the administration of ibacaftol and lumacaftol. 179. The method according to Embodiment 169, comprising the administration of dutivacaftol and lumacaftol. The method according to Embodiment 169, comprising the administration of 180.(6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18), 2,4,14,16-pentaen-6-ol and lumacafthol. 181. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 150, or a pharmaceutical composition according to any one of Embodiments 151 to 166, for use in the treatment of cystic fibrosis. 182. A compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 150, or a pharmaceutical composition according to any one of Embodiments 151 to 166, for use in the manufacture of a drug for the treatment of cystic fibrosis. 183. Compounds selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing. 184. Deuterated derivatives of compounds selected from compounds 1 to 426. 185. A pharmaceutically acceptable salt of a compound selected from compounds 1 to 426. 186. A compound selected from compounds 1 to 426. 187. A pharmaceutical composition comprising compounds selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. 188. A pharmaceutical composition comprising a deuterated derivative of a compound selected from compounds 1 to 426 and a pharmaceutically acceptable carrier. 189. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from compounds 1 to 426, and a pharmaceutically acceptable carrier. 190. A pharmaceutical composition comprising a compound selected from compounds 1 to 426 and a pharmaceutically acceptable carrier. 191. A pharmaceutical composition comprising (a) a compound selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier. 192. A pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from compounds 1 to 426, (b) a CFTR enhancer, and (c) a pharmaceutically acceptable carrier. 193. A pharmaceutical product comprising (a) a pharmaceutically acceptable salt of a compound selected from compounds 1 to 426, (b) a CFTR enhancer, and (c) a pharmaceutically acceptable carrier. 194. A pharmaceutical composition comprising (a) a compound selected from compounds 1 to 426, (b) a CFTR enhancer, and (c) a pharmaceutically acceptable carrier. 195. A pharmaceutical composition comprising (a) a compound selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing, (b) an additional CFTR correcting factor, and (c) a pharmaceutically acceptable carrier. 196. A pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, and (c) a pharmaceutically acceptable carrier. 197. A pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, and (c) a pharmaceutically acceptable carrier. 198. A pharmaceutical composition comprising (a) a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, and (c) a pharmaceutically acceptable carrier. 199. A pharmaceutical composition comprising (a) a compound selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing; (b) an additional CFTR correcting factor; (c) a CRTR enhancing factor; and (d) a pharmaceutically acceptable carrier. 200. A pharmaceutical composition comprising (a) a deuterated derivative of a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, (c) a CFTR enhancing factor, and (d) a pharmaceutically acceptable carrier. 201. A pharmaceutical composition comprising (a) a pharmaceutically acceptable salt of a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, (c) a CFTR enhancing factor, and (d) a pharmaceutically acceptable carrier. 202. A pharmaceutical composition comprising (a) a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, (c) a CFTR enhancing factor, and (d) a pharmaceutically acceptable carrier. 203. Compounds selected from compounds 1-426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts of the foregoing, for use in methods of treating cystic fibrosis. 204. Deuterated derivatives of compounds selected from compounds 1 to 426 for use in methods of treating cystic fibrosis. 205. pharmaceutically acceptable salts of compounds selected from compounds 1 to 426 for use in methods of treating cystic fibrosis. 206. Compounds selected from compounds 1 to 426 for use in methods of treating cystic fibrosis. 207. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising compounds selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. 208. A pharmaceutical composition comprising a deuterated derivative of a compound selected from compounds 1 to 426 and a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis. 209. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound selected from compounds 1 to 426 and a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis. 210. A pharmaceutical composition comprising a compound selected from compounds 1 to 426 and a pharmaceutically acceptable carrier, for use in a method of treating cystic fibrosis. 211. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a compound selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing; (b) a CFTR enhancer; and (c) a pharmaceutically acceptable carrier. 212. A pharmaceutical product for use in a method of treating cystic fibrosis, comprising (a) a deuterated derivative of a compound selected from compounds 1 to 426, (b) a CFTR enhancer, and (c) a pharmaceutically acceptable carrier. 213. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a pharmaceutically acceptable salt of a compound selected from compounds 1 to 426, (b) a CFTR enhancer, and (c) a pharmaceutically acceptable carrier. 214. A pharmaceutical composition comprising (a) a compound selected from compounds 1 to 426, (b) a CFTR enhancer, and (c) a pharmaceutically acceptable carrier. 215. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a compound selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing, (b) an additional CFTR correcting factor, and (c) a pharmaceutically acceptable carrier. 216. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a deuterated derivative of a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, and (c) a pharmaceutically acceptable carrier. 217. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a pharmaceutically acceptable salt of a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, and (c) a pharmaceutically acceptable carrier. 218. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, and (c) a pharmaceutically acceptable carrier. 219. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising: (a) a compound selected from compounds 1 to 426, their tautomers, deuterated derivatives of those compounds and tautomers, and any pharmaceutically acceptable salt of any of the foregoing; (b) an additional CFTR correcting factor; (c) a CRTR enhancing factor; and (d) a pharmaceutically acceptable carrier. 220. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a deuterated derivative of a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, (c) a CFTR enhancing factor, and (d) a pharmaceutically acceptable carrier. 221. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a pharmaceutically acceptable salt of a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, (c) a CFTR enhancing factor, and (d) a pharmaceutically acceptable carrier. 222. A pharmaceutical composition for use in a method of treating cystic fibrosis, comprising (a) a compound selected from compounds 1 to 426, (b) an additional CFTR correcting factor, (c) a CFTR enhancing factor, and (d) a pharmaceutically acceptable carrier. [Examples]

[0121] I. List of Abbreviations ACN: Acetonitrile Boc anhydrous ((Boc)2O): ditert-butyl dicarbonate CDCl3: Chloroform-d CDI: Carbonyldiimidazole CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine CH2Cl2: Dichloromethane CH3CN: Acetonitrile COMU: (1-Cyano-2-Ethoxy-2-Oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate Cmpd: Compound DABCO:1,4-Diazabicyclo[2.2.2]Octane DBU:1,8-Diazabicyclo(5.4.0)undeca-7-en DCE: 1,2-Dichloroethane DCM: Dichloromethane DI: Deionization DIAD: Diisopropyl azodicarboxylate DIEA (DIPEA): N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DMP: Des-Martin Periodinaan EA: Ethyl acetate EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ELSD: Evaporative Light Scattering Detector ESI-MS: Electrospray Ionization Mass Spectrometry æ:ethyl acetate EtOH: Ethanol GC: Gas chromatography First-generation Grubbs catalyst: Dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II) Second-generation Grubbs catalyst: [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-Performance Liquid Chromatography Second-generation Hoveyda-Grubbs catalyst: (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) IPA: Isopropanol KHSO4: Potassium sulfite LC: Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry LCMS Met.: LCMS method: LCMS Rt:LCMS retention time LDA: Lithium diisopropylamide LiOH: Lithium hydroxide MeCN: Acetonitrile MeOH: methanol MgSO4: Magnesium sulfate MTBE: Methyl tert-butyl ether MeTHF or 2-MeTHF:2-methyltetrahydrofuran NaHCO3: Sodium Bicarbonate NaOH: Sodium hydroxide NMP:N-methyl-2-pyrrolidone NMM: N-methylmorpholine Pd / C: Palladium Carbon Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2:[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) Pd(OAc)2: Palladium(II) acetate PTFE: Polytetrafluoroethylene rt, RT: room temperature RuPhos:2-Dicyclohexylphosphino-2′,6′-Diisopropoxybiphenyl SFC: Supercritical Fluid Chromatography TBAI: Tetrabutylammonium iodide TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin-layer chromatography TMS: Trimethylsilyl TMSCl: Trimethylsilyl chloride T3P: Propanephosphonic anhydride UPLC: Ultra-high-performance liquid chromatography Xanthophos:4,5-bis(diphenylphosphin)-9,9-dimethylxanthene XPhos:2-Dicyclohexylphosphino-2′,4′,6′-Triisopropylbiphenyl

[0122] II. General Methods Unless otherwise specified, reagents and starting materials were obtained from commercial sources and used without purification.

[0123] Proton and carbon NMR spectra were obtained at 400 MHz and 100 MHz, respectively. 1 H and 13 Spectroscopic maps were acquired using either a Bruker Biospin DRX 400MHz FTNMR spectrometer or a 300MHz NMR spectrometer operating at the ¹¹¹ C resonance frequency. One-dimensional proton and carbon spectra were acquired using a broadband observation (BBFO) probe with a 20Hz sample rotation and digital resolutions of 0.1834Hz / Pt and 0.9083Hz / Pt, respectively. All proton and carbon spectra were acquired under temperature control at 30°C using standard, previously published pulse sequences and routine processing parameters.

[0124] NMR (one-dimensional and two-dimensional) spectra were also recorded using a Bruker AVNEO 400MHz spectrometer operating at 400MHz and 100MHz, respectively, equipped with a 5mm multinuclear Iprobe.

[0125] The NMR spectrum was obtained using a pulse angle of 45 degrees, a spectral width of 4800 Hz, and 28860 acquisition points. 1 For H, recordings were also made using a 300 MHz Varian Mercury NMR instrument. The FID was zero-packed up to 32k points, and a 0.3 Hz linewidth expansion was applied before the Fourier transform. 19 The F NMR spectrum was recorded at 282 MHz using a pulse angle of 30 degrees, a spectral width of 100 kHz, and 59,202 acquisition points. The FID was zero-packed to 64 k points, and a linewidth expansion of 0.5 Hz was applied before the Fourier transform.

[0126] The NMR spectrum was obtained using a pulse angle of 30 degrees, a spectral width of 8000 Hz, and an acquisition point of 128 k. 1For H, the spectrum was also recorded using a 400 MHz Bruker Avance III HD NMR instrument. The FID was zero-packed to 32k points, and a 0.3 Hz linewidth expansion was applied before the Fourier transform. The 19F NMR spectrum was recorded at 377 MHz using a 30-degree pulse angle, a spectral width of 89286 Hz, and 128k acquisition points. The FID was zero-packed to 256k points, and a 0.3 Hz linewidth expansion was applied before the Fourier transform.

[0127] NMR spectra were also recorded using a Bruker AC 250MHz instrument equipped with a 5mm QNP(H1 / C13 / F19 / P31) probe (Type: 250-SB, s#23055 / 0020), or a Varian 500MHz instrument equipped with an ID PFG, 5mm, 50-202 / 500MHz probe (Model / Part Number 99337300).

[0128] The final purity of the compound is measured using Waters' Acquity UPLC BEH C 18 The purity was determined by reversed-phase ULC using a column (50 × 2.1 mm, 1.7 μm particle size) (product number: 186002350) and a double gradient run of 1–99% mobile phase B over 3.0 minutes. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60°C. Final purity was calculated by averaging the area under the curve (AUC) of two UV traces (220 nm, 254 nm). Low-resolution mass spectra were acquired using a single quadrupole mass spectrometer with an electrospray ionization (ESI) source capable of achieving a mass accuracy of 0.1 Da and a minimum resolution of 1000 (no resolution units) across the detection range [M+1]. +It was reported as a species. The optical purity of (2S)-2,4-dimethyl-4-nitropentanoate methyl was determined by chiral gas chromatography (GC) analysis using a Restek Rt-βDEXcst column (30 m × 0.25 mm × 0.25 μm df) on an Agilent 7890A / MSD 5975C instrument, with a flow rate of 2.0 mL / min (H2 carrier gas), an injection temperature of 220 °C and an oven temperature of 120 °C over 15 minutes.

[0129] III. Common UPLC / HPLC analysis methods LC Method A: Waters Acquity UPLC BEH C 18 Analytical reversed-phase ULC using a column (50 × 2.1 mm, particle size 1.7 μm) (product number: 186002350) and a dual gradient run of 1-99% mobile phase B over 3.0 minutes. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60°C.

[0130] LC method B: Kinetex C 18 Reverse-phase HPLC using a column (50 × 3.0 mm) and a dual gradient run of 5–100% mobile phase B over 6 minutes. Mobile phase A = H2O (0.1% CF3CO2H). Mobile phase B = CH3CN (0.1% CF3CO2H). Flow rate = 1.5 mL / min, injection volume = 2 μL, and column temperature = 60°C.

[0131] LC method C: Kinetex C 18 4.6 × 50 mm, 2.6 μm. Temperature: 45°C, Flow rate: 2.0 mL / min, Run time: 3 min. Mobile phase: Initial 95% water (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) linear gradient over 2.0 min ~ 95% acetonitrile (0.1% formic acid), then held in 95% acetonitrile (0.1% formic acid) for 1.0 min.

[0132] LC Method D: Waters Acquity UPLC BEH C 18A column (30 × 2.1 mm, particle size 1.7 μm) (product number: 186002349) and a dual gradient run of 1-99% mobile phase B over 1.0 min. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.5 mL / min, injection volume = 1.5 μL, and column temperature = 60°C.

[0133] LC method G: Symmetric, 4.6 × 75 mm, 3.5 μm. Temperature: 45°C, Flow rate: 2.0 mL / min, Run time: 8 min. Mobile phase: Initial 95% H2O (0.1% formic acid) and 5% CH3CN (0.1% FA) linear gradient over 6.0 mins to 95% CH3CN (0.1% formic acid), then held in 95% CH3CN (0.1% formic acid) for 2.0 mins.

[0134] LC method H:Kinetex C 18 4.6 × 50 mm, 2.6 μm. Temperature: 45°C, Flow rate: 2.0 mL / min, Run time: 6 min. Mobile phase: Initial 95% H2O (0.1% formic acid) and 5% CH3CN (0.1% FA) linear gradient over 4.0 mins ~ 95% CH3CN (0.1% FA), then held in 95% CH3CN (0.1% FA) for 2.0 mins.

[0135] LC Method I: Waters Acquity UPLC BEH C 18 A column (50 × 2.1 mm, particle size 1.7 μm) (product number: 186002350) and a dual gradient run of 1-99% mobile phase B over 5.0 minutes were used. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60°C.

[0136] LC method J:Waters Acquity UPLC BEH C 18 Reverse-phase ULC using a column (50 × 2.1 mm, particle size 1.7 μm) (product number: 186002350) and a double gradient run of 1-99% mobile phase B over 2.9 minutes. Mobile phase A = H2O (0.05% NH4HCO2). Mobile phase B = CH3CN. Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60°C.

[0137] LC method K:Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% ACN in H2O (0.1% formic acid), 1.2 mL / min.

[0138] LC method M: Poroshell 120 EC-C 18 3.0 × 50 mm 2.7 μM, temperature: 45°C, flow rate: 2.0 mL / min, run time: 6 min. Mobile phase conditions: initial 95% H2O (0.1% FA) and 5% CH3CN (0.1% FA) linear gradient to 95% CH3CN (0.1% FA) over 4.0 mins, then held in 95% CH3CN (0.1% FA) for 2.0 mins.

[0139] LC method N:Kinetex EVO C 18 4.6 × 50 mm, 2.6 μm, temperature: 45°C, flow rate: 2.0 mL / min, run time: 4 min. Mobile phase: initial 95% H2O (0.1% formic acid) and 5% CH3CN (0.1% FA) linear gradient over 2.0 mins ~ 95% CH3CN (0.1% FA), then held in 95% CH3CN (0.1% FA) for 2.0 mins.

[0140] LC method O: Zorbax C 18 4.6 × 50 mm, 3.5 μM, 2.0 mL / min, 95% H2O (0.1% formic acid) + 5% CH3CN (0.1% FA) - 95% CH3CN (0.1% FA) gradient (2.0 min), then held in 95% CH3CN (0.1% FA) for 1 min.

[0141] LC method P: Poroshell 120 EC-C18 3.0×50mm 2.7μM, temperature: 45℃, flow rate: 1.5mL / min, run time: 3min. Mobile phase conditions: Initial 95%H2O (0.1% formic acid) and 5%CH3CN (0.1% FA) linear gradient to 95%CH3CN (0.1% FA) over 1.5 minutes, then held in 95%CH3CN (0.1% FA) for 1.5 minutes.

[0142] LC method Q: Waters Acquity UPLC BEH C18 Reverse-phase ULC using a column (50 × 2.1 mm, particle size 1.7 μm) (product number: 186002350) and a double gradient run of 30-99% mobile phase B over 2.9 minutes. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60°C.

[0143] LC method S: Merckmillipore Chromolith SpeedROD C 18 A column (50 × 4.6 mm) and a dual gradient run of 5-100% mobile phase B over 12 minutes were used. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[0144] LC method T: Merckmillipore Chromolith SpeedROD C 18 A column (50 × 4.6 mm) and a dual gradient run of 5-100% mobile phase B over 6 minutes were used. Mobile phase A = water (0.1% CF3CO2H). Mobile phase B = acetonitrile (0.1% CF3CO2H).

[0145] LC method U:Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 6 min, 5-95% ACN in H2O (0.1% formic acid), 1.2 mL / min.

[0146] LC method W: Water Cortex 2.7μ C 18 (3.0 mm × 50 mm), Temperature: 55°C, Flow rate: 1.2 mL / min, Mobile phase: 100% water + 0.1% trifluoroacetic acid (TFA), followed by 100% acetonitrile + 0.1% TFA acid, Gradient: 5-100% B over 4 minutes, held at 100% B for 0.5 minutes, and equilibrated to 5% B over 1.5 minutes.

[0147] IV. Synthesis of Common Intermediates Example A: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]benzoic acid [ka] Step 1: N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidine-2-yl)carbamate tert-butyl [ka] To a solution of 4,6-dichloropyrimidine-2-amine (300 g, 1.829 mol) in DCM (2.1 L), (BOC)2O (838 g, 3.840 mol) was added, followed by DMAP (5.6 g, 45.84 mmol). The mixture was stirred at ambient temperature for 6 hours. Additional DMAP (5.6 g, 45.84 mmol) was added, and the reaction was continued to stir at ambient temperature for 24 hours. The mixture was diluted with water (2.1 L), and the organic phase was separated. The organic phase was washed with water (2.1 L) and 2.1 L of brine, dried on magnesium sulfate, filtered on Celite, and concentrated under vacuum to obtain a pale orange oil with slits in the slurry. The mixture was diluted with approximately 500 mL of heptane and filtered using an M filter. The precipitate (SM) was washed with 250 mL of heptane. The filtrate was concentrated in a vacuum to obtain a thick orange oil. A solid from the previous experiment was seeded into this oil, and it was allowed to stand and crystallize to obtain a pale orange, hard solid: N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidine-2-yl)carbamate tert-butyl (645g, 97%). 1 ¹H NMR (400MHz, DMSO-d6): δ 8.07 (s, 1H), 1.44 (s, 18H). ESI-MS m / z calculated value 363.07526, measured value 364.1 (M+1). + ; Retention time: 2.12 minutes (LC method A).

[0148] Step 2: N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]carbamate tert-butyl [ka] All solvents were degassed before use. To a slurry of tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidine-2-yl)carbamate (88 g, 241.6 mmol), solutions of (2,6-dimethylphenyl)boronic acid (approximately 36.24 g, 241.6 mmol) and Cs2CO3 (approximately 196.8 g, 604.0 mmol) in DME (704 mL) and water (176 mL) were added. Pd(dppf)Cl2 (approximately 8.839 g, 12.08 mmol) was added, and the mixture was vigorously stirred under nitrogen at 80°C (reflux) for 1 hour (no residual SM). The reaction product was cooled to ambient temperature and diluted with water (704 mL). The aqueous phase was separated and extracted with SiO2 (704 mL). The organic phase was washed with 700 mL of brine, dried on magnesium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to chromatography on a 1500 g silica gel column eluted with 0-30% siRNA / hexane. The product fractions (eluted with 15% siRNA) were combined and concentrated under vacuum to obtain the product as a clear oil, which was allowed to stand and crystallize. N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]carbamate tert-butyl (81.3 g, 78%). 1 H NMR (400MHz, DMSO-d6) δ7.88(s, 1H), 7.30(dd, J=8.2, 7.0Hz, 1H), 7.21~7.16(m, 2H), 2.03(s, 6H), 1.38(s, 18H). ESI-MS m / z calculated value 433.17682, measured value 434.1(M+1) + ; Retention time: 2.32 minutes (LC method A).

[0149] Step 3: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (hydrochloride) [ka] N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]carbamate tert-butyl (514.8 g, 915.9 mmol) was dissolved in dichloromethane (4 L). A solution of hydrogen chloride in p-dioxane (1 L, 4 mol) was added, and the mixture was stirred overnight at room temperature. The resulting precipitate was collected by vacuum filtration and dried under vacuum to obtain 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine hydrochloride (213.5 g, 82%) as a white solid. 1 H NMR (250MHz, DMSO-d6) δ7.45~6.91 (m, 3H), 6.73 (s, 1H), 2.08 (s, 6H). ESI-MS m / z calculated value 233.072, measured value 234.1(M+1) + ; Retention time: 2.1 minutes (LC method C).

[0150] Step 4: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine [ka] 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (hydrochloride) (166 g, 614.5 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (hydrochloride) (30 g, 111.0 mmol) were suspended in DCM (2.5 L) and treated with NaOH (725 mL, 1 M, 725.0 mmol), and stirred at room temperature for 1 hour. The mixture was transferred to a separatory funnel and allowed to stand overnight. The DCM phase was separated, and the aqueous phase containing insoluble substances was extracted twice more with DCM (2 × 500 mL). The combined brown DCM phase was stirred with magnesium sulfate and charcoal for 1 hour, filtered, and the yellow solution was concentrated to a volume of approximately 500 mL. The solution was diluted with heptane (750 mL), and the DCM was removed under reduced pressure at 60°C to obtain a cream-colored suspension. This was stirred at room temperature for 1 hour, filtered, washed with cold heptane, and dried to obtain 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (157 g, 91%) as a cream-colored solid. 1H NMR (400MHz, DMSO-d6) δ7.28~7.14 (m, 3H), 7.10 (d, J=7.5Hz, 2H), 6.63 (s, 1H), 2.06 (s, 6H). ESI-MS m / z calculated value 233.07198, measured value 234.0(M+1) + ; Retention time: 1.45 minutes (LC method A).

[0151] Step 5: 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]benzoic acid [ka] 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (235 g, 985.5 mmol) was dissolved in MeTHF (2.3 L) and cooled in an ice bath while stirring under nitrogen. Methyl 3-chlorosulfonylbenzoate (347 g, 1.479 mol) was added all at once to the cold solution (appearing slightly endothermic), and a solution of 2-methyl-butan-2-ol (lithium salt) (3.1 M, 2.712 mol in 875 mL of heptane) was added dropwise over 1.25 hours (exothermic, internal temperature 0-10°C). The ice bath was removed, and the greenish solution was stirred at room temperature for 4 hours. To the greenish solution, cold HCl (2 L, 1.5 M, 3,000 mol) was added to separate the phases. The organic phase was washed once with water (1 L) and once with brine (500 mL). The aqueous phase was extracted once with MeTHF (350 mL) and combined with the organic phase. This yellow 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]methyl benzoate MeTHF solution (ESI-MS m / z calculated value 431.07065, measured value 432.0 (M+1)) +The mixture (holding time: 1.81 min) was treated with NaOH (2.3 L, 2 M, 4.600 mol) and stirred at room temperature for 1 hour. The phases were separated, the NaOH phase was washed twice with MeTHF (2 × 500 mL), and the combined organic phase was extracted once with 2 M NaOH (1 × 250 mL). The combined NaOH phase was combined and stirred in an ice bath, slowly acidified by adding HCl (416 mL, 36% w / w, 4.929 mol) while maintaining the internal temperature at 10-20°C. At the end of the addition (pH approximately 5-6), the final pH was adjusted to 2-3 by adding solid citric acid. The resulting yellow, viscous suspension was stirred overnight at room temperature to obtain a creamy, crisp suspension. The solid was collected by filtration, washed with a large amount of water, and dried by suction for 3 hours. The solid was dried under reduced pressure with nitrogen leaked at 45-50°C for 120 hours to isolate 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]benzoic acid (395g, 96%) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6) δ13.44(s, 1H), 12.46(s, 1H), 8.48~8.39(m, 1H), 8.25~8.15(m, 1H), 8.15~8.0 8(m, 1H), 7.68(t, J=7.8Hz, 1H), 7.31(s, 1H), 7.28~7.18(m, 1H), 7.10(d,J=7.6Hz, 2H), 1.84(s, 6H). ESI-MS m / z calculated value 417.055, measured value 418.0 (M+1) + ;Retention time: 1.56 minutes. (LC method A).

[0152] Example B: Preparation of N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]-3-nitrobenzenesulfonamide Step 1: N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]-3-nitrobenzenesulfonamide [ka] A suspension of sodium hydride (60% in mineral oil) (4.87 g, 0.122 mol) in anhydrous tetrahydrofuran (30 mL) was added dropwise to a solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (8.13 g, 0.0348 mol) in anhydrous tetrahydrofuran (40 mL) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. A solution of 3-nitrobenzenesulfonyl chloride (11.57 g, 52.2 mmol) in anhydrous tetrahydrofuran (40 mL) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (100 mL). The reaction solution was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with water (100 mL), dried on anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography using 0-10% chloroform / ethyl acetate. The crude product was pulverized with a solvent mixture of diethyl ether and hexane (1:5) to obtain N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]-3-nitrobenzenesulfonamide (5.98 g, 41%) as a white solid. ESI-MS m / z calculated value: 418.1, measured value: 419.0 (M+1). Retention time: 5.73 min. 1 H NMR (250MHz, CDCl3)δ(ppm): 9.01(s, 1H); 8.43(t, J=10.5Hz, 2H); 7.682(t, J=7.8Hz, 1H); 7.23(m, 1H); 7.12(d, J=7.5Hz, 2H); 6.95(s, 1H); 1.99(s, 6H).

[0153] Example C: Preparation of N-[4-(2,6-dimethylphenyl)-6-methylsulfonylpyrimidine-2-yl]-3-nitrobenzenesulfonamide Step 1: N-[4-(2,6-dimethylphenyl)-6-methylsulfonylpyrimidine-2-yl]-3-nitrobenzenesulfonamide [ka] Step 1: N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]-3-nitrobenzenesulfonamide (14.14 g, 33.76 mmol), sodium thiomethoxide (5.86 g, 83.61 mmol), and NMP (130 mL) were added to a 250 mL round-bottom flask. This solution was stirred at 100 °C for 3 hours. The reaction mixture was then cooled to room temperature, quenched with 1 N HCl (300 mL), and extracted with ethyl acetate (3 × 300 mL). The combined organic extract was washed with water (300 mL), 3% hydrogen peroxide solution (300 mL), water (300 mL), and saturated sodium chloride solution (300 mL), then dried over sodium sulfate, filtered, and evaporated under vacuum. This produced orange foam (16.71 g, 115% crude product yield), which was then used to proceed to the next reaction.

[0154] Step 2: To a 250 mL round-bottom flask containing the product from Step 1, 120 mL of DCM was added, followed by m-CPBA (77% pure, 27.22 g, 121.5 mmol). This solution was stirred at room temperature for 90 minutes. The reaction mixture was quenched by transferring it to a 1 L Erlenmeyer flask containing 400 mL of DCM and solid Na₂S₂O₃ (41.15 g, 260.3 mmol). This mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 300 mL of DCM and then washed with 3 × 400 mL of water and 300 mL of saturated sodium chloride aqueous solution. The organic layer was then dried over sodium sulfate, filtered, and evaporated under vacuum. The solid was then partially dissolved in 100 mL of DCM and filtered under vacuum over a Buchner funnel to remove m-chlorobenzoic acid waste (this was repeated three times). Next, the remaining solution was purified by silica gel chromatography (330 g silica, 0-60% gradient of ethyl acetate / hexane) to obtain N-[4-(2,6-dimethylphenyl)-6-methylsulfonylpyrimidine-2-yl]-3-nitrobenzenesulfonamide (5.881 g, 36%). ESI-MS m / z calculated value: 462.06677, measured value: 463.1 (M+1). + ; Retention time: 1.6 minutes, LC method A.

[0155] Example D: Preparation of dispiro[2.0.24.13]heptane-7-carbaldehyde Step 1: 1-Cyclopropylcyclopropanol [ka] To a solution of methyl cyclopropanecarboxylate (75 g, 749.1 mmol) in ether (450 mL), titanium(IV) isopropoxide (55.3 mL, 187.4 mmol) was added. Ethyl magnesium bromide (1.6 L, 1 M, 1.60 mol) was slowly added to the mixture over 2 hours. The addition was exothermic and the rate of addition was monitored and controlled using a cooling bath. The reaction temperature was maintained at 21°C to 26°C during the addition. After the addition, the mixture was stirred at ambient temperature for a further 2 hours. Next, the mixture was cooled to -5°C using an acetone / dry ice bath and slowly quenched with sulfuric acid (970 g, 10% w / w, 990 mmol). The reaction mixture was cooled in a dry ice / acetone bath to keep the reaction vessel below 0°C during the quench. As the quenching progressed, a gray / purple solid was formed. After the complete addition of aqueous sulfuric acid, the mixture was stirred at 0°C for 1 hour. The precipitate was filtered through Celite using a culture medium frit, and the precipitate was washed with diethyl ether (900 mL). The filtrate was transferred to a separatory funnel, and the organic phase was washed with brine (1 L), saturated sodium bicarbonate (1 L), and brine (1 L). The organic phase was dried on magnesium sulfate, filtered on Celite, and the solvent was evaporated by rotary evaporation at 100 Torre, with the water bath set to 20°C. The crude product was stored overnight at -23°C and used without further purification. The product, 1-cyclopropylcyclopropanol (61 g, 83%), contained approximately 50% solvent (tetrahydrofuran and i It was found to contain PrOH and was used in that manner in the next step. 1 ¹H NMR (400MHz, chloroform-d) δ 1.32 (tt, J=8.2, 5.1Hz, 1H), 0.71~0.61 (m, 2H), 0.51~0.43 (m, 2H), 0.43~0.33 (m, 2H), 0.23~0.14 (m, 2H).

[0156] Step 2: 1-Bromo-1-cyclopropyl-cyclopropane [ka] A solution of triphenylphosphine (56.1 g, 213.9 mmol) in dichloromethane (200 mL) was cooled to -10°C. A solution of bromine (11.0 mL, 214 mmol) in dichloromethane (40 mL) was added, and the reaction mixture was stirred at -10°C for a further 15 minutes. The reaction mixture was then cooled to -30°C, and pyridine (3.3 mL, 41 mmol) was added. A solution of 1-cyclopropylcyclopropanol (20.0 g, 204 mmol), pyridine (17.3 mL, 214 mmol), and dichloromethane (100 mL) was added dropwise while maintaining a temperature of -15°C to -20°C. After 30 minutes, the addition was complete, and the reaction mixture was gradually warmed to room temperature. The reaction mixture was then stirred at 40°C overnight. The reaction mixture was cooled to room temperature and quenched with water (100 mL). Next, the reaction mixture was stirred for 10 minutes, and the phases were separated. The organic phase was successively washed with 1M hydrochloric acid (102 mL), then saturated sodium bicarbonate (50 mL), dried over sodium sulfate, filtered, and concentrated (30°C / approximately 300 Torre house vacuum) to remove most of the dichloromethane. The crude reaction mixture was flash-distilled (40°C / 20 Torre) to remove further dichloromethane. The solid residue (Ph3PO and product) was reheated and distilled (50-60°C / 20 Torre) to obtain 21.5 g (65% yield) of 1-bromo-1-cyclopropyl-cyclopropane as a turbid, colorless liquid. 1 ¹H NMR (400MHz, chloroform-d) δ 1.61 (tt, J=8.2, 5.0Hz, 1H), 1.07~1.02 (m, 2H), 0.78~0.66 (m, 2H), 0.67~0.51 (m, 2H), 0.35~0.21 (m, 2H).

[0157] Step 3: Cyclopropylidenecyclopropane [ka] A solution of tert-butoxide potassium (16.7 g, 148.8 mmol) in dimethyl sulfoxide (100 mL) was stirred at room temperature in a 250 mL three-necked round-bottom flask. 1-bromo-1-cyclopropyl-cyclopropane (20.0 g, 124.2 mmol) was added dropwise, and the reaction mixture immediately turned dark, then brown. The reaction mixture was mildly exothermic (maintaining a temperature of 18°C–22°C using an ice bath). After 10 minutes, the addition was complete. The ice bath was removed, and the reaction mixture was stirred at room temperature. After 90 minutes, the reaction mixture was vacuum-distilled using valve-to-valve distillation. Distillation was carried out at 60°C–80°C at 40–100 Torr. The distillate was slowly collected in a receiver to obtain 18.2 g (7.3 g of product as a 42 wt% solution in t-BuOH) of colorless liquid. The distillate was further washed with water (5 × 10 mL). Dichloromethane (4 g) was added, and the mixture was dried over magnesium sulfate and filtered (washed with two additional portions of 3 g each of dichloromethane) to obtain 17.30 g of colorless liquid (6.9 g of product as a 39.6 wt% solution in dichloromethane, 69% yield). 1 ¹H NMR (400 MHz, chloroform-d) δ 1.19 (s, 8H). ¹H NMR confirms the presence of dichloromethane and small amounts of tert-butanol.

[0158] Step 4: Dispiro[2.0.2.1]heptane-7-carboxylate ethyl dispiro[2.0.2.1]heptane-7-carboxylate [ka] Under a nitrogen atmosphere, rhodium(II) acetate (4.2 g, 9.503 mmol) was added to a solution of cyclopropylidenecyclopropane (49.5 g, 617.8 mmol) in dichloromethane (110 mL) at 0°C. To the mixture at 0°C, 2-ethyl diazoacetate (106.8 mL, 1.016 mol) was added using a syringe pump set to an addition rate of 0.02 mL / min (1.2 mL / hour). The addition was continued for 89 hours. The crude reaction mixture was filtered through a silica stopper and washed three times with 150 mL of dichloromethane. The volatile substances were removed under vacuum to obtain a crude dark yellow oil, dispiro[2.0.2.1]heptane-7-carboxylate ethyl (100 g, 97%, containing approximately 20% dichloromethane, diethyl(E)-buto-2-enediote, and diethyl(Z)-buto-2-enediote as contaminants), which was used directly in the next step. 1 ¹H NMR (400MHz, chloroform-d): 4.13 (q, J=7.1Hz, 2H), 2.23 (s, 1H), 1.24 (t, J=7.1Hz, 3H), 1.08~0.93 (m, 4H), 0.90~0.82 (m, 2H), 0.77 (ddd, J=8.2, 5.0, 3.5Hz, 2H).

[0159] Step 5: Dispiro[2.0.2.1]heptan-7-ylmethanol [ka] To a slurry of lithium aluminum hydride (7.8 g, 200.2 mmol) in diethyl ether (300 mL) cooled in an ice bath, ethyl dispiroethyl[2.0.2.1]heptane-7-carboxylate (10.77 g, 64.79 mmol) was gradually added. The mixture was gently heated under reflux during the addition and stirred at ambient temperature for 1 hour. The reaction mixture was cooled in an ice bath and slowly quenched by adding water (8.0 mL, 440 mmol), followed by sodium hydroxide (8.0 mL, 2 M, 16 mmol), and then water (24.0 mL, 1.33 mol). The pale yellow slurry was filtered on Celite and washed three times with 150 mL of methyl tert-butyl ether. The filtrate was concentrated under vacuum to obtain 8.87 g of a clear oil, dispiro[2.0.2.1]heptan-7-ylmethanol (8.87 g, quantitative yield). 1 H NMR (400MHz, chloroform-d) δ3.71 (dd, J=6.7, 5.5Hz, 2H), 1.76~1.65 (m, 1H), 1.46 (t, J=5.6Hz, 1H), 0.87(q, J=1.9Hz, 4H), 0.72~0.61(m, 2H), 0.60~0.50(m, 2H).

[0160] Step 6: Dispiro[2.0.24.13]heptane-7-carbaldehyde [ka] To a 20 mL vial, {dispiro[2.0.2.1]heptan-7-yl}methanol (381 mg, 3.068 mmol), dichloromethane (4 mL), potassium bicarbonate (620 mg, 6.193 mmol), and pyridinium chlorochromate (728 mg, 3.377 mmol) (PCC) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered over Celite and evaporated (300 Torrell, minimal heating in a 40°C water bath). The reaction mixture was dissolved in diethyl ether, filtered over Celite, and evaporated at 300 Torrell (minimal heating in a 40°C water bath) to provide dispiro[2.0.24.13]heptan-7-carbaldehyde (433 mg, 58%) as a light brown oil. The purity was estimated to be approximately 50%. The crude product was used in the next step without further purification.

[0161] Example E: Preparation of 2-dispiro[2.0.24.13]heptan-7-ylacetaldehyde Step 1: 7-(bromomethyl)dispiro[2.0.2.1]heptane [ka] A 1000 mL three-necked round-bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, a J-Kem temperature probe, and a nitrogen inlet / outlet. Under a nitrogen atmosphere, triphenylphosphine (102.7 mL, 443.2 mmol) and dichloromethane (1 L) were added to this container to obtain a clear, colorless solution. Stirring was started, and acetone was added to the cooling bath. Dry ice was added to the cooling bath in small amounts until a pot temperature of -15°C was achieved. A solution of bromine (22.82 mL, 443.0 mmol) in dichloromethane (220 mL, 10 mL / g) was added to the addition funnel, and this was then added dropwise over 1 hour. During the addition, dry ice was added to the cooling bath in small amounts to maintain the pot temperature at -15°C. After the addition of bromine was complete, the pale yellow suspension was stirred at -15°C for 15 minutes, at which point the suspension was cooled to -30°C. A solution of dispiro[2.0.2.1]heptane-7-ylmethanol (50 g, 402.6 mmol), pyridine (35.82 mL, 442.9 mmol), and dichloromethane (250 mL, 5 mL / g) was loaded into the addition funnel. The clear pale yellow solution was then added dropwise over 1.5 hours, maintaining the pot temperature at -30°C. The resulting clear pale yellow reaction mixture was gradually heated to a pot temperature of -5°C, and then stirred at -5°C for 1 hour. The reaction mixture was then poured into hexane (2000 mL), which allowed a precipitate to form. The suspension was stirred at room temperature for 30 minutes, and then filtered through a glass frit-Buchner funnel with a 20 mm Celite layer. The clear filtrate was concentrated under reduced pressure (water bath temperature 20°C) to provide a yellow oil with some precipitate present. The oil was diluted with some hexane and allowed to stand at room temperature for 15 minutes, then filtered through a glass frit-Buchner funnel with a 20 mm Celite layer. The clear filtrate was concentrated under reduced pressure (water bath temperature 20°C) to provide 7-(bromomethyl)dispiro[2.0.2.1]heptane (70 g, 93%) as a clear yellow oil. 1H NMR (400MHz, chloroform-d) δ3.49(d, J=7.5Hz, 2H), 1.90(t, J=7.5Hz, 1H), 1.06~0.84( m, 4H), 0.71 (ddd, J=9.1, 5.1, 4.0Hz, 2H), 0.54 (dddd, J=8.6, 4.8, 3.8, 1.0Hz, 2H).

[0162] Step 2: 2-Dispiro[2.0.2.1]heptane-7-ylacetonitrile [ka] A 1000 mL three-necked round-bottom flask was fitted with a mechanical stirrer, a cooling bath used as a secondary containment vessel, a J-Kem temperature probe, and nitrogen inlet / outlet ports. Under a nitrogen atmosphere, 7-(bromomethyl)dispiro[2.0.2.1]heptane (35 g, 187.1 mmol) and dimethyl sulfoxide (245 mL) were packed into the flask, yielding a clear amber-colored solution. Stirring was initiated, and the pot temperature was recorded at 19°C. Sodium cyanide (11.46 g, 233.8 mmol) was then added to the flask as a solid in one go, resulting in a dark-colored solution that gradually heated to 49°C over 15 minutes. After a few minutes, the pot temperature began to decrease, and the mixture was stirred at room temperature overnight (approximately 15 hours). The dark-colored reaction mixture was quenched with ice-cold saturated sodium carbonate solution (500 mL), then transferred to a separatory funnel, and partitioned with diethyl ether (500 mL). The organic matter was removed, and the remaining aqueous solution was extracted with diethyl ether (2 × 250 mL). The combined organic matter was washed with water (500 mL), dried on sodium sulfate (200 g), and then filtered through a glass frit-Buchner funnel. The clear amber filtrate was concentrated under reduced pressure (water bath temperature of 20°C) to obtain 2-dispiro[2.0.2.1]heptane-7-ylacetonitrile (21 g, 84%) as a clear, dark amber oil. 1 ¹H NMR (400MHz, chloroform-d): δ 2.42 (d, J=6.6Hz, 2H), 1.69 (t, J=6.6Hz, 1H), 1.02~0.88 (m, 4H), 0.79~0.70 (m, 2H), 0.66~0.55 (m, 2H).

[0163] Step 3: 2-Dispiro[2.0.2.1]heptan-7-ylacetate [ka] To a solution of 2-dispiro[2.0.2.1]heptane-7-ylacetonitrile (2.1 g, 14.19 mmol) in EtOH (32 mL), sodium hydroxide (5.12 g, 128.0 mmol), followed by water (13 mL), was added. The resulting solution was stirred and heated to 70°C overnight. The mixture was then cooled to room temperature, diluted with water, and extracted with diethyl ether. The aqueous phase was adjusted to pH=1 by adding 6N hydrochloric acid (a turbid precipitate was formed), and extracted with diethyl ether (three times). The organic phase was dried (with magnesium sulfate), filtered, and concentrated to obtain 2-dispiro[2.0.2.1]heptane-7-ylacetic acid (2.19 g, 99% yield, 98% purity) as an orange solid, which was used in the next step without further purification. 1 H NMR (400MHz, chloroform-d) δ2.44(d, J=6.9Hz, 2H), 1.67(t, J=6.9Hz, 1H), 0.91(ddd, J=9.0, 5.2, 3.9Hz , 2H), 0.81(dddd, J=8.9, 5.2, 3.9, 0.5Hz, 2H), 0.69(ddd, J=8.9, 5.2, 3.9Hz, 2H), 0.56~0.44(m, 2H).

[0164] Step 4: 2-Dispiro[2.0.2.1]heptan-7-ylethanol [ka] Lithium aluminum hydride (827.4 mg, 902.3 μL, 21.80 mmol) was dissolved in tetrahydrofuran (33.71 mL) cooled in an ice / water bath. 2-dispiro[2.0.2.1]heptane-7-ylacetic acid (2.552 g, 16.77 mmol) from tetrahydrofuran (7.470 mL) was added dropwise over 15 minutes, maintaining the reaction temperature below 20°C. The mixture was stirred for a total of 18 hours and gradually warmed to ambient temperature. The mixture was cooled in an ice / water bath, and water (838.4 mg, 838.4 μL, 46.54 mmol), followed by sodium hydroxide (1.006 mL of 5 M, 5.031 mmol), and then water (2.493 g, 2.493 mL, 138.4 mmol) was slowly added and quenched sequentially to obtain a white granular slurry, which was filtered through Celite. The filtered solid was washed with diethyl ether. The filtrate was concentrated in a vacuum of approximately 300 millibars and in a water bath at 30°C. The residue was diluted with diethyl ether, dried (magnesium sulfate), filtered, concentrated in a vacuum of approximately 300 millibars and in a water bath at 30°C, and then concentrated under vacuum for approximately 30 seconds to obtain 2-dispiro[2.0.2.1]heptan-7-ylethanol (2.318 g, 100%), which was used directly in subsequent steps without further purification. 1 H NMR (400MHz, chloroform-d) δ3.64(s, 2H), 1.68(d, J=6.7Hz, 2H), 1.39(s, 1H), 1.31(s, 1H), 0.82(d, J=14.0Hz, 4H), 0.65(s, 2H), 0.50(d, J=3.6Hz, 2H).

[0165] Step 5: 2-Dispiro[2.0.24.13]heptan-7-ylacetaldehyde [ka] To a 20 mL vial, 2-dispiro[2.0.24.13]heptan-7-ylethanol (506 mg, 65% w / w, 2.380 mmol), dichloromethane (3 mL), potassium bicarbonate (500 mg, 4.994 mmol), and pyridinium chlorochromate (640 mg, 2.969 mmol) (PCC) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered on Celite and evaporated. The reaction mixture was dissolved in ether, filtered on Celite, and evaporated at 300 Torre (with minimal heating) to provide 2-dispiro[2.0.24.13]heptan-7-ylacetaldehyde (492 mg, 61%).

[0166] Example F: Preparation of 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol Step 1: 2-[1-(trifluoromethyl)cyclopropyl]ethyl methanesulfonic acid [ka] A 1000 mL three-necked round-bottom flask was fitted with a mechanical stirrer, a cooling bath, a J-Kem temperature probe, an addition funnel, and a nitrogen inlet / outlet. Under a nitrogen atmosphere, 2-[1-(trifluoromethyl)cyclopropyl]ethanol (125 g, 811.0 mmol) and 2-methyltetrahydrofuran (625 mL) were added to the flask, providing a clear, colorless solution. Stirring was initiated, and the pot temperature was recorded at 19°C. Then, triethylamine (124.3 mL, 891.8 mmol) was added undiluted in a single addition. Next, crushed ice / water was added to the cooling bath, and the pot temperature was reduced to 0°C. A solution of methanesulfonyl chloride (62.77 mL, 811.0 mmol) in 2-methyltetrahydrofuran (125 mL, 2 mL / g) was packed into an additive funnel, and then added dropwise over 90 minutes, resulting in a white suspension and exothermic reaction up to 1°C. The mixture was slowly warmed to room temperature and stirred continuously for 1 hour. At this point, the mixture was poured into ice-cold water (250 mL) and then transferred to a separatory funnel. Organic matter was removed, the mixture was washed with 20% by weight potassium bicarbonate solution (250 mL), dried over sodium sulfate (200 g), and then filtered through a glass frit-Buchner funnel. The clear filtrate was concentrated under reduced pressure to obtain 2-[1-(trifluoromethyl)cyclopropyl]ethyl methanesulfonic acid (185 g, 98%) as a clear, pale yellow oil. 1 ¹H NMR (400 MHz, chloroform-d): δ 4.36 (ddt, J=7.1, 6.4, 0.7 Hz, 2H), 3.02 (s, 3H), 2.03 (t, J=7.1 Hz, 2H), 1.11~0.98 (m, 2H), 0.81~0.66 (m, 2H).

[0167] Step 2: 3-[1-(trifluoromethyl)cyclopropyl]propanenitrile [ka] A 1000 mL three-necked round-bottom flask was fitted with a mechanical stirrer, heating mantle, J-Kem temperature probe / controller, water-cooled reflux condenser, and nitrogen inlet / outlet. Under a nitrogen atmosphere, 2-[1-(trifluoromethyl)cyclopropyl]ethyl methanesulfonic acid (50 g, 215.3 mmol) and dimethyl sulfoxide (250 mL) were added to this vessel, yielding a clear, pale yellow solution. Stirring was initiated, and the pot temperature was recorded at 19°C. Sodium cyanide (13.19 g, 269.1 mmol) was added to the vessel as a solid in a single addition. The mixture was heated to a pot temperature of 70°C and maintained at this temperature for 24 hours. During heating, all the sodium cyanide dissolved, and the reaction mixture became a pale amber suspension. After cooling to room temperature, the reaction mixture was poured into water (500 mL), then transferred to a separatory funnel, and partitioned with methyl tert-butyl ether (500 mL). Organic matter was removed, and the residual aqueous solution was extracted with methyl tert-butyl ether (3 × 250 mL). The combined organic layers were washed with water (2 × 250 mL), dried over sodium sulfate (200 g), and then filtered through a glass frit-Buchner funnel. The clear filtrate was concentrated under reduced pressure to obtain 3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (30 g, 85%) as a clear amber oil. 1 ¹H NMR (400MHz, chloroform-d): δ 2.55 (t, J=7.6Hz, 2H), 1.93 (t, J=7.7Hz, 2H), 1.11~1.04 (m, 2H), 0.78~0.70 (m, 2H).

[0168] Step 3: 3-[1-(trifluoromethyl)cyclopropyl]propanoic acid [ka] A 1000 mL three-necked round-bottom flask was fitted with a mechanical stirrer, heating mantle, J-Kem temperature probe / controller, water-cooled reflux condenser, and nitrogen inlet / outlet. Then, under a nitrogen atmosphere, 3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (25 g, 153.2 mmol) and ethyl alcohol (375 mL) were added to the flask, yielding a clear amber solution. Stirring was initiated, and the pot temperature was recorded at 19°C. Next, sodium hydroxide (102.1 mL of 6 M, 612.6 mmol) was added to the flask in a single addition. The resulting clear amber solution was heated to a pot temperature of 70°C and maintained at this temperature for 24 hours. After cooling to room temperature, the reaction mixture was concentrated to remove the ethyl alcohol. The residual aqueous layer was diluted with water (150 mL), then transferred to a separatory funnel, and partitioned with methyl tert-butyl ether (50 mL). The aqueous components were removed, and the pH was adjusted to approximately 1 with a 6M hydrochloric acid solution. The resulting aqueous solution was transferred to a separatory funnel and partitioned with methyl tert-butyl ether (250 mL). The organic components were removed, and the residual aqueous components were extracted with methyl tert-butyl ether (2 × 150 mL). The combined organic components were dried over sodium sulfate (150 g) and then filtered through a glass frit-Buchner funnel. The clear filtrate was concentrated under reduced pressure to provide 3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (26 g, 93%) as a clear amber-colored oil. 1 ¹H NMR (400 MHz, chloroform-d): δ 2.63~2.50 (m, 2H), 1.96~1.84 (m, 2H), 1.03~0.95 (m, 2H), 0.66~0.58 (m, J=1.7 Hz, 2H).

[0169] Step 4: 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol [ka] A 1000 mL three-necked round-bottom flask was fitted with a mechanical stirrer, cooling bath, addition funnel, J-Kem temperature probe, and nitrogen inlet / outlet. This vessel was filled with lithium aluminum hydride pellets (6.775 g, 178.5 mmol) under a nitrogen atmosphere. Then, tetrahydrofuran (250 mL) was added to the same flask under a nitrogen atmosphere. Stirring was initiated, and the pot temperature was recorded at 20°C. The mixture was stirred at room temperature for 0.5 hours to dissolve the pellets. The resulting gray suspension was recorded at 24°C. Next, crushed ice / water was added to the cooling bath, and the pot temperature was reduced to 0°C. A solution of 3-[1-(trifluoromethyl)cyclopropyl]propanoic acid (25 g, 137.3 mmol) in tetrahydrofuran (75 mL, 3 mL / g) was added to the addition funnel, and the clear, pale yellow solution was added dropwise over 1 hour. After the addition was complete, the pot temperature of the resulting grayish-brown suspension was recorded at 5°C. The mixture was slowly warmed to room temperature and stirred continuously at room temperature for 24 hours. The suspension was cooled to 0°C in a crushed ice / water cooling bath, then quenched by very slowly adding water (6.775 mL), followed by 15 wt% sodium hydroxide solution (6.775 mL), and finally quenched with water (20.32 mL). The pot temperature of the resulting white suspension was recorded at 5°C. The suspension was stirred continuously at approximately 5°C for 30 minutes and then filtered through a glass frit-Buchner funnel with a 20 mm Celite layer. The filter cake was washed by displacement with tetrahydrofuran (2 × 150 mL) and then dried under vacuum for 15 minutes. The filtrate was dried over sodium sulfate (250 g) and then filtered through a glass frit-Buchner funnel. The filtrate was concentrated under reduced pressure to provide the desired product, 3-[1-(trifluoromethyl)cyclopropyl]propan-1-ol (21.2 g, 92%), as a clear, pale amber oil. 1 ¹H NMR (400 MHz, chloroform-d): δ 3.65 (t, J=6.0 Hz, 2H), 1.78~1.59 (m, 4H), 0.99~0.91 (m, 2H), 0.59 (dp, J=4.7, 1.7 Hz, 2H).

[0170] Example G: Preparation of 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-4-carboxylic acid Step 1: 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-4-carboxylate methyl [ka] 2-Chlorosulfonylpyridine-4-carboxylate methyl (5 g, 21.218 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (5 g, 21.395 mmol) were dissolved in anhydrous THF (150 mL) under nitrogen, and the solution was cooled to -78°C. A 1 M solution of LiHMDS in THF (43 mL of 1 M, 43.000 mmol) was added dropwise, and the mixture was gradually warmed to 0°C. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with chloroform (3 × 50 mL). The organic fractions were combined, dried over sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography using 0-100% hexane-ethyl acetate to obtain 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-4-carboxylate methyl (8.3 g, 80.6%) as a white solid. ESI-MS m / z calculation value: 432.06592, measured value: 432.8 (M+1). + ; Retention time: 5.5 min; LC method S.

[0171] Step 2: 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-4-carboxylic acid [ka] A 1M aqueous solution of NaOH (95 mL, 95.000 mmol) was added to a solution of 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-4-carboxylic acid methyl (8.1 g, 18.712 mmol) in THF (95 mL), and the mixture was stirred at room temperature for 1 hour. A 1M aqueous solution of HCl was added to bring the pH down to approximately 8, and the mixture was extracted with 2-MeTHF (2 × 100 mL). The aqueous phase was separated and acidified to approximately 2 pH with a 1M aqueous solution of HCl. The formed precipitate was collected by filtration to obtain 2-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-4-carboxylic acid (5.17 g, 71%) as a white solid. 1 H NMR(250MHz, DMSO(d6)) δ8.87(d, J=5.0Hz, 1H), 8.32(d, J=1.1Hz, 1H), 8.04( dt, J=4.9, 1.5Hz, 1H), 7.32~7.16(m, 2H), 7.04(d, J=7.5Hz, 2H), 1.76(s, 6H). ESI-MS m / z calculated value 418.05026, measured value 419.3(M+1) + ; Retention time: 4.62 min; LC method S.

[0172] V. Synthesis of Novel Compounds Example 1: Preparation of Compound 1 and Compound 2 Step 1: N-(2-aminoethyl)-2-nitrobenzenesulfonamide [ka] To a solution of ethane-1,2-diamine (600.00 mL, 8.89 mol) in tetrahydrofuran (500 mL), a solution of 2-nitrobenzenesulfonyl chloride (205 g, 897.26 mmol) in tetrahydrofuran (700 mL) was added dropwise under a nitrogen atmosphere with stirring. After the addition, the reaction mixture was stirred for a further 30 minutes, then heated to room temperature and concentrated under vacuum. The oily residue was taken into DCM (500 mL) and washed with water (500 mL). The organic layer was separated, and the product was extracted from the aqueous layer (pH=11, 3 × 300 mL). The organic layers were combined, dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain an orange gel (161 g, purity 90%). The aqueous layer was treated with 6M HCl to adjust the pH to 8-7, and then extracted with a chloroform:isopropanol mixture (3:1, v:v, 4 × 300 mL). After evaporation, more of the substance was isolated (57.2 g, purity 98%). The total amount of N-(2-aminoethyl)-2-nitrobenzenesulfonamide was 218.2 g (89%). ESI-MS m / z calculated value: 245.04703, measured value: 246.4 (M+1). + ; Retention time: 1.69 min; LC method T.

[0173] Step 2: N-[2-[[(2R)-3-chloro-2-hydroxypropyl]amino]ethyl]-2-nitrobenzenesulfonamide [ka] A 250 mL flask equipped with a magnetic stirring bar was packed with N-(2-aminoethyl)-2-nitrobenzenesulfonamide (75 g, 275.22 mmol), anhydrous methanol (80 mL), and anhydrous magnesium sulfate (18 g, 149.54 mmol). Solvent-free (2R)-2-(chloromethyl)oxirane (12 mL, 147.35 mmol) was rapidly added via syringe. The orange suspension was stirred under nitrogen at room temperature for 7 hours. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was taken up in DCM (500 mL) and water (200 mL), and the two phases were separated. After drying over sodium sulfate, the solvent was evaporated. The residue was purified by flash chromatography on silica gel (2 × 330 g column) using a methanol gradient (0-10%) in dichloromethane. The pure fractions were combined, and the solvent was removed under vacuum to obtain N-[2-[[(2R)-3-chloro-2-hydroxypropyl]amino]ethyl]-2-nitrobenzenesulfonamide (40.2 g, 78%) as a yellow gel. ESI-MS m / z calculation: 337.04993, measured value: 338.4 (M+1). + ; Retention time: 1.91 min; LC method T.

[0174] Step 3: (6R)-1-(2-nitrophenyl)sulfonyl-1,4-diazepan-6-ol [ka] A suspension of N-[2-[[(2R)-3-chloro-2-hydroxypropyl]amino]ethyl]-2-nitrobenzenesulfonamide (58.3 g, 167.42 mmol) and cesium carbonate (205 g, 629.19 mmol) in anhydrous acetonitrile (1500 mL) was stirred under nitrogen in an oil bath at 65 °C for 2.5 hours. After cooling, the solid was filtered and the solvent was removed by evaporation. The residue was partitioned between DCM (800 mL) and water (200 mL) and the two phases were decanted. The organic phase was dried over sodium sulfate and the solvent was evaporated. The crude residue was dissolved in DCM and purified by flash chromatography (330 g column) on silica gel using 0-15% methanol in dichloromethane. The pure fractions were combined, and the solvent was evaporated to obtain (6R)-1-(2-nitrophenyl)sulfonyl-1,4-diazepan-6-ol (18.1 g, 34%) as an orange gel. 1 H NMR (250MHz, DMSO) δ8.06~7.93(m, 2H), 7.93~7.77(m, 2H), 5.01(s, 1H), 3. 85~3.65(m, 2H), 3.62~3.50(m, 2H), 3.25~3.09(m, 3H), 2.96~2.64(m, 4H). ESI-MS m / z calculated value 301.07324, measured value 302.1(M+1) + ; Retention time: 0.88 min; LC method W.

[0175] Step 4: (6R)-6-hydroxy-4-(2-nitrophenyl)sulfonyl-1,4-diazepane-1-carboxylate tert-butyl [ka] In a 500 mL flask, (6R)-1-(2-nitrophenyl)sulfonyl-1,4-diazepan-6-ol (12.14 g, 40.29 mmol) was dissolved in anhydrous methanol (130 mL) under nitrogen. Triethylamine (8 mL, 57.40 mmol) was added, and the mixture was cooled in an ice bath. Di-tert-butyl dicarbonate (11 mL, 47.88 mmol) was added, and the ice bath was removed after 5 minutes. The reaction mixture was stirred at room temperature for 20 hours. The reaction product was concentrated, and the residue was taken up in DCM (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The two phases were decanted, and the aqueous phase was further extracted with DCM (25 mL). The combined extract was dried over sodium sulfate, and the solvent was evaporated to obtain the residue, which was purified by flash chromatography on silica gel (330 g column) using a methanol gradient (0-10% over 40 minutes) in dichloromethane. The product eluted approximately 2-3% methanol. The pure fractions were combined, and the solvent was evaporated to obtain (6R)-6-hydroxy-4-(2-nitrophenyl)sulfonyl-1,4-diazepane-1-carboxylate tert-butyl (13.93 g, 86%) as a yellow foamy solid. 1 ¹H NMR (400 MHz, chloroform-d) revealed the presence of several conformational isomers: δ 8.09~7.99 (m, 1H), 7.77~7.62 (m, 3H), 4.33~4.12 (m, 1H), 3.96~3.66 (m, 4H), 3.58~3.42 (m, 2H), 3.36~3.17 (m, 2H), 3.01~2.85 (m, 1H), 1.51~1.42 (m, 9H). ESI-MS m / z calculated value: 401.12567, measured value: 402.28 (M+1). + ; Retention time: 1.3 min; LC method A.

[0176] Step 5: (6S)-6-hydroxy-1,4-diazepan-1-carboxylate tert-butyl [ka] (6R)-6-hydroxy-4-(2-nitrophenyl)sulfonyl-1,4-diazepane-1-carboxylate tert-butyl (52 g, 116.58 mmol) was dissolved in acetonitrile (500 mL) at room temperature. Potassium carbonate (97 g, 694.83 mmol) was added, followed by thiophenol (40.071 g, 38.5 mL, 352.79 mmol). The mixture was then heated under nitrogen in an oil bath at 55°C for 4 hours. It was cooled to room temperature and concentrated to remove most of the acetonitrile. The residue was partitioned between DCM (500 mL) and HCl (400 mL, 1N aqueous). The layers were separated, and the aqueous layer was washed two more times with DCM (200 mL x 2). The aqueous solution (containing the desired product) was cooled in ice water. NaOH (3N aqueous) was added to reach pH=12. DCM was added, and the free base product was extracted. The layers were separated again, and the aqueous product was further extracted with DCM (200 mL x 2). The combined DCM solution was washed with brine (3200 mL), dried on anhydrous sodium sulfate, filtered, and concentrated to obtain (6S)-6-hydroxy-1,4-diazepane-1-carboxylate tert-butyl (15.6 g, 59%). ESI-MS m / z calculated value: 216.1474, measured value: 217.4 (M+1) + Retention time: 2.27 minutes. ESI-MS m / z calculated value: 216.1474, measured value: 217.4 (M+1) + ; Retention time: 2.27 min; LC method T.

[0177] Step 6: (6S)-4-[3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]benzoyl]6-hydroxy-1,4-diazepan-1-carboxylate tert-butyl [ka] A 100 mL flask was packed under nitrogen with (6S)-6-hydroxy-1,4-diazepane-1-carboxylate tert-butyl (1.195 g, 5.525 mmol), anhydrous DMF (35 mL), and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]benzoic acid (1.828 g, 4.375 mmol). After dissolving the reagents, the mixture was cooled in an ice bath. DIEA (5 mL, 28.71 mmol) and HATU (2.013 g, 5.294 mmol) were added, and the mixture was stirred at 0°C for 14 minutes. The mixture was then quenched by pouring it into citric acid (150 mL of 10% w / v, 78.07 mmol) (10% aqueous solution) cooled in ice. The resulting white solid was filtered and washed with water. The wet solid was dissolved in DCM, and the solution was dried over sodium sulfate. After evaporation of the solvent, the residue (2.76 g) was purified by flash chromatography on silica gel (120 g column) using a methanol gradient (0-10% over 30 minutes) in dichloromethane. The product eluted approximately 4% methanol. By evaporation of the solvent, (6S)-4-[3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]benzoyl]-6-hydroxy-1,4-diazepane-1-carboxylate tert-butyl (1.672 g, 62%) was obtained as a white foamy solid. 1 1H NMR (400 MHz, DMSO-d6): Complex spectrum likely due to the presence of rotational isomers, unclear signal assignment, and apparent proton excess. δ12.40(s, 1H), 8.05~7.84(m, 2H), 7.72~7.53(m, 2H), 7.38-7.30(m, 1H), 7.24(t, J=7.3Hz, 1H ), 7.16~7.01(m, 2H), 5.27(d, J=13.5Hz, 0.5H), 4.98(s, 0.5H), 4.13~3.36(m, 7H), 3.19(broad s, 1H), 3.13~2.95(m, 2H), 1.90(d, J=9.2Hz, 6H), 1.39(d, J=17.4Hz, 6H), 1.11(s, 3H). ESI-MS m / z calculated value: 615.19183, measured value: 616.41 (M+1) + ; Retention time: 1.69 min; LC method A.

[0178] Step 7: (16S)-12-(2,6-dimethylphenyl)-2,8,8-trioxo-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-18-carboxylate tert-butyl [ka] A 250 mL flask was packed under nitrogen with (6S)-4-[3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]benzoyl]-6-hydroxy-1,4-diazepane-1-carboxylate tert-butyl (1.426 g, 2.314 mmol) and anhydrous DMF (70 mL). The mixture was cooled on ice. NaH (783 mg, 60% w / w, 19.58 mmol) (60% mineral oil dispersion) was added in two portions. The mixture was stirred under nitrogen at 0°C for 3.5 hours. The mixture was slowly poured into ice-cold citric acid (300 mL, 10% w / v, 156.1 mmol) (10% aqueous solution) while stirring. The resulting solid suspension was extracted with siRNA (4 × 60 mL). After drying on sodium sulfate, the solvent evaporated, leaving a residue (3.97 g), which was purified by flash chromatography on silica gel (120 g column) using a methanol gradient (0-10% over 30 minutes) in dichloromethane. The product eluted approximately 4-5% methanol. The evaporation of the solvent yielded (16S)-12-(2,6-dimethylphenyl)-2,8,8-trioxo-15-oxa-8λ as a colorless resin. 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-18-carboxylate tert-butyl (858 mg, 64%) was produced. 11H NMR (400 MHz, DMSO-d6) shows that residual DMF is visible. Two conformational isomers (55:45) were observed: δ 12.59 (two broad s, 1H), 8.33 (2 s, 1H), 7.95 (s, 2H overlapping with the residual DMF signal), 7.67 (br s, 2H), 7.26 (t, J=7.6Hz, 1H), 7.12 (d, J=7.6Hz, 2H), 6.34 (br s, 1H), 5.42 (two br m, 1H), 4.61~4.38 (m, 1H), 4.23~3.84 (m, 2H), 3.64~3.36 (m, 2H), 3.32~3.09 (m, 2H), 2.04 (br s, 6H), 1.44 (two s, 9H). ESI-MS m / z calculated value: 579.21515, measured value: 580.45 (M+1) + ; Retention time: 1.51 min; LC method A.

[0179] Step 8: (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (compound 2) [ka] (16S)-12-(2,6-dimethylphenyl)-2,8,8-trioxo-15-oxa-8λ in DCM (200 mL, cooled in an ice bath) 6-Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-18-carboxylate tert-butyl (21.68 g, 33.661 mmol) was treated with HCl (80 mL of 4 M, 320.00 mmol). The solution was then stirred at room temperature for 2 hours. The mixture was concentrated to dryness. The residue was pulverized with DCM / ether / hexane (1 / 1 / 2, v:v, 40 mL). The supernatant was decanted. The residue was treated three times in this manner. The resulting solid was dried under high vacuum for 48 hours to obtain a white solid (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (11.88g, 66%) was obtained. 1 H NMR (250MHz, DMSO-d6) δ10.36(s, 1H), 9.42(s, 1H), 8.76(s, 1H), 7.99~7.89(m, 1H), 7.76~7.62(m, 2H), 7.33~7.21 (m, 1H), 7.16~7.10(m, 2H), 6.39(d, J=0.9Hz, 1H), 5.75(m, 1H), 4.62~4.41(m, 1H), 3.74~3.15(m, 7H), 2.05(s, 6H). ESI-MS m / z calculated value 479.16272, measured value 480.1(M+1) + ; Retention time: 1.42 min; LC method W.

[0180] Step 9: (16R)-18-(3,3-dimethylbutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (compound 1) [ka] (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (4.7 g, 9.108 mmol) was added to DCM (47 mL) with stirring, and the suspension was treated with 3,3-dimethylbutanal (4.6 mL, 36.65 mmol), followed by acetic acid (3.1 mL, 54.51 mmol). The resulting fine gelatinous suspension was stirred at room temperature for 50 minutes. The suspension was cooled in an ice bath, and sodium borohydride (3.4 g, 54.10 mmol) was slowly added over approximately 30 seconds to induce an exothermic reaction. The suspension was stirred in an ice bath for 15 minutes, then the ice bath was removed and the suspension was stirred for another 15 minutes. The reaction mixture was added to a stirred saturated solution of ammonium chloride (250 mL) and extracted with ethyl acetate (250 mL). The organic phase was washed once with a saturated solution of ammonium chloride (200 mL) and once with brine (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL), and the combined organic phase was dried, filtered, and evaporated. The crude product was subjected to reverse-phase chromatography with a linear gradient of 5% acetonitrile to 100% acetonitrile in water containing 5 mM HCl (435 g C). 18 The material was purified by liquid loading with DMSO and a few drops of 6M HCl. The impurity fraction was re-purified by the same method. The pure materials were combined and obtained as a grayish-white solid (16R)-18-(3,3-dimethylbutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (3.56 g, 64%) was obtained. 1H NMR (400MHz, DMSO-d6) δ10.59(s, 1H), 8.82(s, 1H), 7.95(t, J=4.6Hz, 1H), 7. 69(d, J=4.7Hz, 2H), 7.27(t, J=7.6Hz, 1H), 7.13(d, J=7.6Hz, 2H), 6.40(s, 1H) , 5.82(tt, J=10.5, 4.5Hz, 1H), 4.51(dt, J=14.8, 5.4Hz, 1H), 3.95~3.61(m, 4H ), 3.55~3.21(m, 5H), 2.05(s, 6H), 1.71(dp, J=17.3, 5.9Hz, 2H), 0.95(s, 9H). ESI-MS m / z calculated value: 563.25665, measured value: 564.0 (M+1) + ; Holding time 4.75 minutes; LC method A using a 1-99% gradient over 13.5 minutes in phase B.

[0181] Example 2: Preparation of Compound 3 Step 1: (16R)-12-(2,6-dimethylphenyl)-18-{spiro[3.5]nonan-2-yl}-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 3) [ka] In a 20 mL vial, a stirred solution of spiro[3.5]nonan-2-one (600 mg, 4.341 mmol) in anhydrous dichloromethane (40 mL) is prepared by adding (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (2.0 g, 3.876 mmol), N,N-diisopropylethylamine (1.1 mL, 6.315 mmol), and glacial acetic acid (450 μL, 7.913 mmol) were added in that order. The resulting pale yellow solution was stirred at ambient temperature for 25 minutes, and then sodium triacetoxyborohydride (1.743 g, 8.224 mmol) was added all at once, and stirring continued for another hour. Then saturated hydrated sodium bicarbonate (5 mL) was added to the reaction mixture, and it was stirred for 20 minutes. The heterogeneous mixture was diluted with dichloromethane (10 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic matter was washed with brine (15 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5% methanol in methylene chloride over 80 g of silica gel for 30 minutes). The desired product was (16R)-12-(2,6-dimethylphenyl)-18-{spiro[3.5]nonan-2-yl}-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (1.649g, 70%) was obtained as a white solid. 1H NMR (499MHz, DMSO-d6) δ12.75(s, 1H), 8.44(s, 1H), 7.95~7.85(m, 1H), 7.66(d, J=5.6Hz, 2H), 7.25(t, J=7.6Hz, 1 H), 7.12(d, J=7.6Hz, 2H), 6.27(s, 1H), 5.43(t, J=9.2Hz, 1H), 4.14(dt, J=13.9, 6.8Hz, 1H), 3.56(dd, J=14.5, 4. 0Hz, 1H), 3.27(dd, J=14.4, 10.8Hz, 1H), 3.21~3.08(m, 3H), 2.94(dd, J=13.4, 7.0Hz, 1H), 2.73~2.60(m, 2H), 2.0 5(s, 6H), 1.97(t, J=9.3Hz, 2H), 1.52(t, J=9.6Hz, 2H), 1.44(d, J=6.0Hz, 2H), 1.40(d, J=5.5Hz, 4H), 1.32(s, 4H). ESI-MS m / z calculated value 601.2723, measured value 602.5(M+1) + ; Retention time: 1.29 min; LC method A.

[0182] Example 3: Preparation of Compound 4 Step 1: (16R)-18-(4,4-difluorocyclohexyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 4) [ka] (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ in the vial. 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (65 mg, 0.1260 mmol), 4,4-difluorocyclohexanone (102 mg, 0.7605 mmol), 5-ethyl-2-methylpyridineborane complex (75 μL, 0.5038 mmol), and acetic acid (250 μL, 4.396 mmol) were added. The reaction mixture was gently heated at 35°C for 4 hours. The reaction product was quenched with methanol, filtered, and purified by reverse-phase HPLC (1%-60% ACN:0.1% HCl water modifier) ​​to obtain (16R)-18-(4,4-difluorocyclohexyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ as a solid. 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (40.1 mg, 53%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ8.71(t, J=1.2Hz, 1H), 8.01~7.92(m, 1H), 7.78~7.68(m, 2H), 7.31( t, J=7.6Hz, 1H), 7.16(d, J=7.6Hz, 2H), 6.30(s, 1H), 5.80(d, J=7.1Hz, 1H), 4.48(dt, J=15. 0, 5.8Hz, 1H), 3.91~3.77(m, 3H), 3.65(ddt, J=19.5, 13.7, 6.8Hz, 3H), 3.58~3.43(m, 1H), 3 .30(dd, J=14.5, 10.9Hz, 1H), 2.31~2.14(m, 4H), 2.06(d, J=7.5Hz, 6H), 1.98~1.79(m, 3H). ESI-MS m / z calculated value 597.2221, measured value 598.5 (M+1) + ; Retention time: 1.13 minutes (LC method A).

[0183] Example 4: Preparation of Compound 5 Step 1: (16R)-18-(4,4-dimethylcyclohexyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione (compound 5) [ka] (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ in anhydrous dichloromethane (0.50 mL) 6 To a solution of -thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (10 mg, 0.01938 mmol), 4,4-dimethylcyclohexanone (5 mg, 0.03962 mmol), triethylamine (5 μL, 0.03587 mmol), and glacial acetic acid (2 mg, 0.03330 mmol) were added in that order under nitrogen at room temperature. The pale yellow solution was stirred for 20 minutes, and then solid sodium triacetoxyborohydride (9 mg, 0.04246 mmol) was added at ambient temperature. After stirring for 12 hours (overnight), hydrated sodium bicarbonate (1 mL) and dichloromethane (2 mL) were added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 2 mL). The combined organic extract was successively washed with water (2 mL) and brine (2 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was taken up in DMSO (0.8 mL), microfiltered, and purified by preparative reverse-phase HPLC with elution in 0-99% acetonitrile (HCl as a modifier) ​​in water over 15 minutes. The desired product was (16R)-18-(4,4-dimethylcyclohexyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (8 mg, 65%) was obtained as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.27(s, 1H), 8.78(s, 1H), 7.94(s, 1H), 7.69(s, 2H), 7.27(t, J=7.6Hz, 1H), 7.13( d, J=7.6Hz, 2H), 6.36(s, 1H), 5.84(s, 1H), 4.50~4.32(m, 1H), 3.99~3.83(m, 2H), 3.80(dd, J=14.7, 4.1Hz, 1 H), 3.66(d, J=6.0Hz, 2H), 3.56~3.43(m, 2H), 3.30(dd, J=14.3, 10.8Hz, 1H), 2.05(s, 6H), 1.89(d, J=12.7Hz) , 2H), 1.74(two t, J=12.2Hz, 2H), 1.52(d, J=13.1Hz, 2H), 1.31(t, J=13.4Hz, 2H), 0.96(s, 3H), 0.93(s, 3H). ESI-MS m / z calculated value 589.2723, measured value 590.5 (M+1) + ; Retention time: 1.2 minutes; LC method A.

[0184] Example 5: Preparation of Compound 6 Step 1: (16R)-18-cyclopentyl-12-(2,6-dimethylphenyl)-8,8-dioxo-15-oxa-8λ 6 -Thi-1,9,11,18,22-Pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-Hexaen-2-one (Compound 6) [ka] In a test tube, (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (12 mg, 0.02502 mmol), DCE (0.5 mL), and DIEA (approximately 4.204 mg, 5.666 μL, 0.03253 mmol) were added. After 5 minutes, cyclopentanone (approximately 10.52 mg, 11.06 μL, 0.1251 mmol) and acetic acid (approximately 7.513 mg, 7.115 μL, 0.1251 mmol) were added, and the reaction mixture was stirred for 1 hour. Sodium cyanoborohydride (approximately 7.862 mg, 0.1251 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DMF (0.5 mL), filtered, and purified by reverse-phase HPLC using a 1% to 70% gradient of CAN in water containing an HCl modifier. (16R)-18-cyclopentyl-12-(2,6-dimethylphenyl)-8,8-dioxo-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaen-2-one (hydrochloride) was isolated as a solid (5.3 mg, 36.3%). ESI-MS m / z calculated value: 547.22534, measured value: 548.1 (M+1). + ; Retention time: 0.94 min; LC method A).

[0185] Example 6: Preparation of Compound 7 Step 1: (16R)-18-(3-tert-butylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexene-2,8,8-trione (compound 7) [ka] (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ in the vial. 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (100 mg, 0.1938 mmol), 3-tert-butylcyclobutanone (147 mg, 1.165 mmol), acetic acid (400 μL, 7.034 mmol), and 5-ethyl-2-methylpyridineborane complex (115 μL, 0.7725 mmol) were added. The reaction mixture was stirred overnight at 35°C. The reaction product was diluted with methanol, filtered, and purified by HPLC (1%-60% ACN:0.1% HCl water modifier) ​​to obtain a white solid (16R)-18-(3-tert-butylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (90.1 mg, 74%) was obtained. ESI-MS m / z calculated value: 589.2723, measured value: 590.5 (M+1) + ; Retention time: 1.27 min; LC method A.

[0186] Example 7: Preparation of Compound 8 Step 1: (16R)-12-(2,6-dimethylphenyl)-18-{spiro[3,4]octan-2-yl}-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 8) [ka] Place the 4 mL vial into (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6The vial was filled with -thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (55 mg, 0.1066 mmol), spiro[3.4]octan-2-one (73 mg, 0.5879 mmol), anhydrous DCM (1 mL), DIEA (28 μL, 0.1608 mmol), and acetic acid (40 μL, 0.7034 mmol). The vial was briefly purged with nitrogen, capped, and stirred at room temperature for approximately 10 minutes. Sodium triacetoxyborohydride (66 mg, 0.3114 mmol) was added. The vial was purged with nitrogen, capped, and the reaction mixture was stirred at room temperature for 16 hours. Methanol (100 μL) was added. DCM was evaporated, and the residue was taken up in DMSO (1 mL). The solution was microfiltered through a PTFE syringe filter disc and subjected to reverse-phase preparative HPLC (C) using an acetonitrile gradient in water (1-99% over 15 minutes) and HCl as a modifier. 18 It was purified by [method]. Evaporation yielded a solid dissolved in DCM / MeOH for transfer to a vial. After evaporation of the solvent, grinding and evaporation in DCM / hexane yielded a grayish-white solid of (16R)-12-(2,6-dimethylphenyl)-18-{spiro[3.4]octan-2-yl}-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (44 mg, 65%) was obtained. 1H NMR (500MHz, DMSO-d6) δ11.37(broad s, 1H), 8.83(broad s, 1H), 7.95(s, 1H), 7.69(s, 2H), 7.27(t, J=7.6Hz, 1H), 7.13(d, J=7.7Hz, 2H), 6.35(br s, 1H), 5.99~5.82(m, 1H), 4.47~4.42(m, 1H), 3.98(h, J=8.5Hz, 1H), 3.79(dd, J=14.6, 4.0Hz, 1H), 3.71~3.59(m, 2H), 3.52~3.38(m, probably 3H, overlapping with water signal), 2.40(dq, J=26.8, 10.1, 8.9Hz, 2H), 2.22(q, J=8.4Hz, 2H), 2.05(br s, 6H), 1.72~1.45(m, 10H). ESI-MS m / z calculated value 587.25665, measured value 588.6(M+1) + ; Retention time: 1.16 min; LC method A.

[0187] Example 8: Preparation of Compound 9 and Compound 10 Step 1: (16R)-18-(2,2-dimethylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione, diastereomer 1 (compound 9), and (16R)-18-(2,2-dimethylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione, diastereomer 2 (compound 10) [ka] (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ in the vial. 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (20 mg, 0.03876 mmol), 2,2-dimethylcyclobutanone (23 mg, 0.2344 mmol), 5-ethyl-2-methylpyridineborane complex (18 μL, 0.1209 mmol), and acetic acid (45 μL, 0.7913 mmol) were added. The reaction mixture was stirred overnight at 30°C. The reaction mixture was quenched with methanol, filtered, and purified by preparative HPLC (1% to 50% MeCN, HCl modifier over 30 minutes). The first diastereomer to be eluted is (16R)-18-(2,2-dimethylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (0.8 mg, 7%) ESI-MS m / z calculated value 561.24097, measured value 562.3 (M+1) + Retention time: 1.11 minutes (diastereomer 1). The second diastereomer that eluted was (16R)-18-(2,2-dimethylcyclobutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (0.8 mg, 7%) ESI-MS m / z calculated value 561.24097, measured value 562.5 (M+1) + Retention time: 1.14 minutes (diastereomer 2), LC method A.

[0188] Example 9: Preparation of Compound 11 Step 1: (16R)-12-(2,6-dimethylphenyl)-18-(1-ethylpropyl)-8,8-dioxo-15-oxa-8λ 6-Thi-1,9,11,18,22-Pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-Hexaen-2-one (Compound 11) [ka] In a test tube, (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (12 mg, 0.02502 mmol), DIEA (approximately 4.204 mg, 5.666 μL, 0.03253 mmol), and 1,2-dichloroethane (0.5 mL) were added. After stirring for 5 minutes, pentane-3-one (approximately 10.78 mg, 13.26 μL, 0.1251 mmol), acetic acid (approximately 7.513 mg, 7.115 μL, 0.1251 mmol), and sodium triacetoxyborohydride (approximately 26.51 mg, 0.1251 mmol) were added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with methanol, filtered, and purified by reverse-phase HPLC to (16R)-12-(2,6-dimethylphenyl)-18-(1-ethylpropyl)-8,8-dioxo-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaen-2-one (hydrochloride) (14.9 mg, 100%) was obtained. ESI-MS m / z calculated value: 549.24097, measured value: 550.4 (M+1) + ; Retention time: 1.12 min; LC method A.

[0189] Example 10: Characterization of compounds 12-34 The compounds listed in the following table were prepared using commercially available reagents and intermediates as described herein, in a manner similar to that described above. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 4-1] [Table 4-2]

[0190] Example 11: Preparation of Compound 35 Step 1: (16R)-18-(cyclopropylmethyl)-12-(2,6-dimethylphenyl)-8,8-dioxo-15-oxa-8λ 6 -Thi-1,9,11,18,22-Pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-Hexaen-2-one (Compound 35) [ka] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6A vial containing -thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (10.5 mg, 0.02035 mmol) was mixed with dichloroethane (700 μL), cyclopropane carbaldehyde (7.7 μL, 0.1030 mmol), and acetic acid (6 μL, 0.1055 mmol). The reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (7 mg, 0.1114 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by LC-MS analysis. The reaction product was quenched with methanol, filtered, and purified by preparative HPLC using water containing 1%-99% ACN:0.1% HCl modifier. (16R)-18-(cyclopropylmethyl)-12-(2,6-dimethylphenyl)-8,8-dioxo-15-oxa-8λ 6 -Thi-1,9,11,18,22-Pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-Hexaen-2-one (6.8 mg, 63%) ESI-MS m / z calculated value 533.20966, measured value 534.4 (M+1) + The sample with a retention time of 0.93 minutes was isolated as a white solid. ESI-MS m / z calculated value: 533.20966, measured value: 534.4 (M+1). + ; Retention time: 0.93 min; LC method A.

[0191] Example 12: Preparation of Compound 36 and Compound 37 Step 1: (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaene-2,8,8-trione (a mixture of diastereomers) [ka] (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ in the vial. 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (20 mg, 0.03876 mmol), 3,3-dimethylcyclopentanone (approximately 21.74 mg, 0.1938 mmol), 5-ethyl-2-methylpyridineborane complex (approximately 15.70 mg, 17.31 μL, 0.1163 mmol), and acetic acid (approximately 46.55 mg, 44.08 μL, 0.7752 mmol) were added. The reaction mixture was heated at 30°C and stirred overnight. The reaction product was quenched with methanol, filtered, and purified by preparative HPLC to obtain (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaene-2,8,8-trione (11.0 mg, 49%) was obtained as a mixture of diastereomers.

[0192] Step 2: (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaene-2,8,8-trione, diastereomer 1 (compound 36), and (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaene-2,8,8-trione, diastereomer 2 (compound 37) [ka] (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaene-2,8,8-trione (11 mg, 0.01911 mmol) was subjected to chiral SFC separation (ChiralCel OD (250 × 10 mm) 5 μm column, 35 °C, mobile phase: 22% MeOH, 78% CO2 (no modifier), flow rate: 10 mL / min, injection volume: 70 μL, pressure: 10 bar, wavelength: 210 nm), and the first diastereomer eluted was (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 We provided -thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (2.9 mg, 50%). ESI-MS m / z calculated value: 575.25665, measured value: 576.3 (M+1). + Retention time: 1.19 minutes; The second diastereomer to be eluted is (16R)-18-(3,3-dimethylcyclopentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 We provided -thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (3.4 mg, 58%). ESI-MS m / z calculated value: 575.25665, measured value: 576.5 (M+1). + ; Retention time: 1.2 minutes; (LC method A).

[0193] Example 13: Preparation of Compound 38, Compound 39, and Compound 40 Step 1: (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione, 2:1 diastereomer mixture (compound 40), (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione, diastereomer 1 (compound 38), and (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione, diastereomer 2 (compound 39) [ka] In a 4 mL vial, a stirring solution of 4-fluorocyclohexanone (35 mg, 0.3014 mmol) in anhydrous 1,2-dichloroethane (1.5 mL) is prepared by adding (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (40 mg, 0.07752 mmol), triethylamine (20 μL, 0.1435 mmol), and glacial acetic acid (10 μL, 0.1758 mmol) were added in that order. The resulting pale yellow solution was stirred at ambient temperature for 30 minutes, then sodium borohydride (40 mg, 0.6365 mmol) was added, and stirring continued for 13 hours. The crude substance was diluted with DMSO (0.8 mL), microfiltered, and purified by preparative reverse-phase HPLC with elution in 1-99% acetonitrile (HCl as a modifier) ​​in water over 15 minutes. Desired product: (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (33 mg, 69%) was obtained as a diastereomer mixture in the form of a white solid. ESI-MS m / z calculation value: 579.23157, measured value: 580.5 (M+1) + ; Retention time: 1.01 min (LC method A).

[0194] The two diastereomers were separated by preparative SFC (column: ChiralCel OD (250 × 10 mm), 5 μm; 35C; mobile phase: 30% MeOH (unmodified), 70% CO2; flow rate: 10 mL / min; concentration: approximately 23 mg / mL in MeOH (unmodified); injection volume: 70 μL; pressure: 179 bar; wavelength: 210 nm), and the following was obtained: Peak 1, diastereomer 1, (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione (17.5 mg, 39%).1 H NMR (500MHz, methanol-d4) δ8.63(t, J=1.7Hz, 1H), 7.99(dt, J=7.2, 1.8Hz, 1H), 7.74~7.60(m, 2H), 7.27(t, J=7.7Hz, 1H), 7.1 4(d, J=7.7Hz, 2H), 6.18(s, 1H), 5.61(tt, J=9.4, 4.7Hz, 1H), 4.82~4.67(m, 1H), 4.27(ddd, J=14.3, 8.7, 5.9Hz, 1H), 3.66( dd, J=14.5, 4.0Hz, 1H), 3.38(dd, J=13.1, 5.2Hz, 1H), 3.30~3.25(m, 2H), 3.25~3.18(m, 1H), 3.00(dd, J=13.1, 9.3Hz, 1H), 2.95(ddd, J=13.5, 8.7, 4.6Hz, 1H), 2.76(dt, J=10.9, 6.4Hz, 1H), 2.39~1.93(m, 8H), 1.83~1.72(m, 3H), 1.72~1.51(m, 3H). ESI-MS m / z calculated value 579.23157, measured value 580.4 (M+1) + Retention time: 0.97 min (LC method A); and peak 2, diastereomer 2, (16R)-12-(2,6-dimethylphenyl)-18-(4-fluorocyclohexyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione (9mg, 20%) 1H NMR (500MHz, methanol-d4) δ8.61(d, J=1.8Hz, 1H), 7.99(dt, J=7.0, 1.9Hz, 1H), 7.71~7.62(m, 2H), 7.27(t , J=7.7Hz, 1H), 7.14(d, J=7.7Hz, 2H), 6.17(s,1H), 5.59(tt, J=9.6, 4.7Hz, 1H), 4.56~4.37(m, 1H), 4.31 ~4.23(m, 1H), 3.65(dd, J=14.4, 4.0Hz, 1H), 3.35(dd, J=13.3, 5.3Hz, 1H), 3.29~3.23(m, 2H), 3.22~3.16 (m, 1H), 3.01~2.87(m, 2H), 2.77~2.69(m, 1H), 2.33~2.00(m, 8H), 1.99~1.90(m, 2H), 1.61~1.42(m, 4H). ESI-MS m / z calculated value 579.23157, measured value 580.4 (M+1) + ; Retention time: 0.98 minutes (LC method A).

[0195] Example 14: Preparation of Compound 41 Step 1: (16R)-12-(2,6-dimethylphenyl)-18-{2-oxaspiro[3.5]nonan-7-yl}-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione (compound 41) [ka] (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6-thia-1,9,11,18,22-pentaazatetracyclo[14.4.1.13,7.110,14]tricos-3,5,7(23),10,12,14(22)-hexaen-2,8,8-trione (hydrochloride) (15 mg, 0.02907 mmol), anhydrous DCM (1 mL), N,N-diisopropylethylamine (10 μL, 0.05741 mmol), 2-oxaspiro[3.5]nonan-7-one (22 mg, 0.1569 mmol), and glacial acetic acid (10 μL, 0.1758 mmol) were charged. The vial was briefly purged with nitrogen, capped, and stirred at room temperature for about 10 minutes. Sodium triacetoxyborohydride (25 mg, 0.1180 mmol) was added. The vial was purged with nitrogen, capped, and the reaction was stirred at room temperature for 13 hours (overnight). Methanol (0.25 mL) was added. The volatiles were evaporated under reduced pressure, and the residue was taken up in DMSO (1 mL). The solution was microfiltered (0.45 uM) and purified by reverse phase preparative HPLC (C 18 ) using a gradient of acetonitrile in water (1 - 99% over 15 minutes, HCl as modifier) to afford the following as a white solid. (16R)-12-(2,6-dimethylphenyl)-18-{2-oxaspiro[3.5]nonan-7-yl}-15-oxa-8λ 6 -thia-1,9,11,18,22-pentaazatetracyclo[14.4.1.13,7.110,14]tricos-3(23),4,6,10,12,14(22)-hexaen-2,8,8-trione (hydrochloride) (4.4 mg, 23%) 1H NMR (499MHz, methanol-d4) δ8.91(s, 1H), 8.06(dt, J=7.7, 1.5Hz, 1H), 7.76(dt, J=7.7, 1.5Hz, 1H), 7.71(t, J=7.7Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.15(d, J=7.7Hz, 2H), 6.29(s, 1H), 6.14~6.04(m, 1H), 4.73~4.55(m, 1H), 4.07~3.98(m, 1H), 3. 93(d, J=7.7Hz, 2H), 3.85(dt, J=13.4, 6.6Hz, 1H), 3.75~3.66(m, 1H), 3.63(s, 2H), 3.60~3.48(m, 2H), 3.41(s, 2H), 3.3 8~3.32(m, 1H), 2.11(s, 6H), 2.03(d, J=10.3Hz, 2H), 1.94~1.73(m, 4H), 1.37(t, J=13.3Hz, 1H), 1.11(t, J=16.7Hz, 1H). ESI-MS m / z calculated value 603.2515, measured value 604.4 (M+1) + ; Retention time: 0.92 minutes; (LC method A).

[0196] Example 15: Preparation of Compound 42 and Compound 43 Step 1: 1,4-Dibenzyl-1,4-Diazepane-6-ol [ka] To a solution of N,N'-dibenzylethan-1,2-diamine (49.97 g, 48.990 mL, 205.83 mmol) in toluene (1.2 L), 1,3-dibromopropan-2-ol (45.3 g, 21.268 mL, 197.51 mmol) and triethylamine (59.95 g, 82.576 mL, 592.45 mmol) were slowly added. The solution was refluxed for 2 days. The solvent was removed, and the residue was dissolved in water (400 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient method with ethyl acetate / hexane 0-100% to obtain 1,4-dibenzyl-1,4-diazepan-6-ol (27 g, 42%) as a yellow oil.1 H NMR (250MHz, CDCl3) δ7.40~7.18 (m, 10H), 3.81 (p, J=3.7Hz, 1H), 3.72~3.64 (s, 4H), 2.90~2.66 (m, 6H), 2.47 (tdd, J=8.1, 6.7, 5.0Hz, 2H). ESI-MS m / z calculated value 296.18887, measured value 297.2(M+1) + ; Retention time: 1.53 min; LC method T.

[0197] Step 2: 6-hydroxy-1,4-diazepan-1-carboxylate tert-butyl [ka] A solution of 1,4-dibenzyl-1,4-diazepan-6-ol (13.36 g, 45.07 mmol) in methanol (500 mL) was purged under nitrogen gas. Palladium hydroxide (3.03 g, 20% carbon, 50% wet, 2.16 mmol) was added, and the reaction mixture was purged under hydrogen gas and then stirred under 1 atmosphere of hydrogen for 24 hours. The mixture was purged again under nitrogen gas, then filtered on Celite and washed with methanol (approximately 500 mL). It was concentrated under reduced pressure to obtain crude diamine as a yellow oil. The crude diamine was dissolved in methanol (200 mL) and cooled in an ice bath. Triethylamine (7.6 mL, 54.5 mmol) was added, followed by di-tert-butyl dicarbonate (9.85 g, 45.1 mmol), and the reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and then suspended in dichloromethane (approximately 150 mL) and heptane (approximately 100 mL). A white, fluffy solid was crushed. The solid was filtered, and the filtrate was absorbed onto silica gel. The filtrate was purified by silica gel chromatography on a 220 g column that elutes 0-10% methanol from the dichloromethane to obtain 6-hydroxy-1,4-diazepane-1-carboxylate tert-butyl (3.265 g, 32%) as a concentrated amber oil. 1H NMR (300MHz, CDCl3) δ1.47 (s, 9H), 2.69~3.12 (m, 6H), 3.14~3.80 (m, 4H), 3.91~4.05 (m, 1H). ESI-MS m / z calculated value 216.1474, measured value 217.2 (M+1) + ; Retention time: 0.93 minutes (LC method M).

[0198] Step 3: 4-{3-[4-chloro-6-(2,6-dimethylphenyl)-pyrimidine-2-ylsulfamoyl]-benzoyl}6-hydroxy-[1,4]diazepane-1-carboxylate tert-butyl ester [ka] To a solution of 3-[4-chloro-6-(2,6-dimethylphenyl)-pyrimidine-2-ylsulfamoyl]benzoic acid (9.82 g, 23.5 mmol) in dichloromethane (150 mL), N,N'-diisopropylcarbodiimide (3.68 mL, 23.5 mmol) was added at room temperature. The reaction mixture was stirred for 10 minutes. A solution of 6-hydroxy-[1,4]diazepane-1-carboxylic acid tert-butyl ester (4.53 g, 20.95 mmol) in dichloromethane (75 mL) was added dropwise at room temperature within 1 hour. The reaction mixture was stirred for a further 30 minutes, and then quenched with 10% citric acid aqueous solution (75 mL). The two layers were separated. The aqueous layer was extracted with dichloromethane (2 × 150 mL), and the combined organic layers were washed with brine (100 mL), dried on anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography using 0-80% hexane-acetone, and 4-{3-[4-chloro-6-(2,6-dimethylphenyl)-pyrimidine-2-ylsulfamoyl]-benzoyl}-6-hydroxy-[1,4]diazepane-1-carboxylate tert-butyl ester (7.62 g, 59%) was supplied as a pink solid. ESI-MS m / z: calculated 615.19, measured 616.0 (M1). Retention time: 5.24 min.

[0199] Step 4: 12-(2,6-Dimethylphenyl)-2,8,8-TrioXO-15-Oxa-8λ 6 -Thia-1,9,11,18,22-Pentaazatetracyclo[14.4.1.13,7.110,14]Tricos-3(23),4,6,10(22),11,13-Hexaene-18-Carboxylic Acid tert-Butyl (Compound 43) [Chemical Structure Diagram] To a solution of tert-Butyl 4-{3-[4-Chloro-6-(2,6-Dimethyl-Phenyl)-Pyrimidin-2-Ylsulfamoyl]-Benzoyl}-6-Hydroxy-[1,4]Diazepane-1-Carboxylate (7.62 g, 12.37 mmol) in anhydrous Dimethylformamide (800 mL) was added portionwise 60% Suspended Sodium Hydride in Mineral Oil (4.95 g, 123.7 mmol). The reaction mixture was stirred at room temperature for 16 hours and then quenched with 10% Aqueous Citric Acid (500 mL). The mixture was extracted with Ethyl Acetate (3 × 500 mL), and the combined organic phases were washed with brine (thrice with 500 mL each), dried over anhydrous Sodium Sulfate, and concentrated. The residue was purified by silica gel column chromatography using 0-70% Hexane-Acetone to afford tert-Butyl 16-(2,6-Dimethylphenyl)-4-Oxo-2-Oxa-6-Thia-7-Aza-3(6,1)-Diazepana-1(,2)-Pyrimidina-5(1,3)-Benzanacycloheptafan-34-Carboxylate 6,6-Dioxide (4.404 g, 56%) as a white solid. 1H-NMR (250 MHz, DMSO-d6) δ (ppm): 8.30 (d, J = 15.1 Hz, 1H), 7.92 (s, 1H), 7.67 (s, 2H), 7.27 (m, 1H), 7.14 (m, 2H), 6.35 (s, 1H), 5.50 (m, 1H), 4.48 (m, 1H), 3.99 (m, 2H), 3.56 (m, 1H), 3.24 (m, 5H), 2.05 (s, 6H), 1.42 (d, J = 10.5 Hz, 9H). ESI-MS m / z calculated value 579.21515, measured value 580.2 (M + 1) + ; Retention Time: 4.66 minutes.

[0200] Step 5: 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 42) [ka] TFA (12 mL, 155.8 mmol) was added to 16-(2,6-dimethylphenyl)-2-oxa-6-thia-7-aza-3(6,1)-diazepana-1(4,2)-pyrimidina-5(1,3)-benzenacycloheptaphan-4-one 6,6-dioxide (3 g, 5.175 mmol) in DCM (50 mL). The mixture was stirred at room temperature. The solvent was removed, and the crude product was resuspended in DCM / toluene. The mixture was concentrated to dryness under reduced pressure (this step was repeated three times) to obtain 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (2.3g, 93%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ10.42(s, 1H), 9.46(s, 1H), 8.76(s, 1H), 7.95(s, 1H), 7.67(s, 2H), 7.28(s, 1H), 7.14(s , 2H), 6.38(s, 1H), 5.75(s, 1H), 4.49(s, 1H), 3.76(s, 2H), 3.62(s, 1H), 3.43(s, 3H), 3.25(s, 1H), 2.05(s, 6H). ESI-MS m / z calculated value 479.16272, measured value 480.0(M+1) + ; Retention time: 0.69 min; LC method A.

[0201] Example 16: Preparation of Compound 44 Step 1: 12-(2,6-dimethylphenyl)-18-isobutyl-8,8-dioxo-15-oxa-8λ 6-Thi-1,9,11,18,22-Pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-Hexaen-2-one (Compound 44) [ka] 2-methylpropanal (approximately 22.53 mg, 0.3125 mmol) is added to 12-(2,6-dimethylphenyl)-15-oxa-8λ in acetic acid (0.5 mL) in a 3 ml vial. 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (30 mg, 0.06250 mmol), followed by the addition of sodium triacetoxyborohydride (approximately 132.5 mg, 0.6250 mmol). The reaction mixture was stirred at room temperature for 1 hour, then at 60°C for 16 hours. The mixture was then cooled to room temperature, filtered, and purified by reverse-phase HPLC to 12-(2,6-dimethylphenyl)-18-isobutyl-8,8-dioxo-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10(22),11,13-hexaen-2-one (4.3 mg, 13%) was obtained. ESI-MS m / z calculated value: 535.22534, measured value: 536.0 (M+1) + ; Retention time: 1.0 min; LC method A.

[0202] Example 17: Characterization of compounds 45-63 The compounds listed in the following table were prepared using commercially available reagents and intermediates as described herein, in a manner similar to that described above. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 6]

[0203] Example 18: Preparation of Compound 64 Step 1: 12-(2,6-dimethylphenyl)-18-[(pyridine-2-yl)methyl]-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 64) and 12-(2,6-dimethylphenyl)-18-[(pyridine-4-yl)methyl]-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione [ka] The two reactions were carried out in separate vials: 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (20 mg, 0.04166 mmol), 2-(bromomethyl)pyridine (hydrobromide) (15 mg, 0.05930 mmol), TEA (35 μL, 0.2511 mmol), and DMF (0.5 mL) were combined and stirred at 90°C for 16 hours. The reaction mixture was filtered and purified on reverse-phase HPLC (Waters, HCl, 10-60% ACN-water) to 12-(2,6-dimethylphenyl)-18-[(pyridine-2-yl)methyl]-15-oxa-8λ 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene 2,8,8-trione (8.5 mg, 36%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ8.77 (d, J=9.7Hz, 2H), 8.10~8.03 (m, 1H), 7.94 (s, 1H), 7.70(d, J=11.8Hz, 3H), 7.63~7.56(m, 1H), 7.26(t, J=7.6Hz, 1H), 7.13(d, J=7.6 Hz, 2H), 6.37(s, 1H), 5.89(s, 1H), 4.72(s, 2H), 4.40(s, 1H), 3.95~3.91(m, 3H) , 3.42(s, 3H), 3.30(s, 1H), 2.70(s, 1H), 2.20(s, 1H), 2.05(s, 6H), 1.90(s, 1H). ESI-MS m / z calculated value 570.2049, measured value 571.0 (M+1) + ; Retention time: 0.96 minutes (LC method A).

[0204] In the second vial, 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (20 mg, 0.04166 mmol), 4-(bromomethyl)pyridine (hydrobromide) (15 mg, 0.05930 mmol), TEA (35 μL, 0.2511 mmol), and DMF (0.5 mL) were combined and stirred at 90°C for 16 hours. The reaction mixture was filtered and purified on reverse-phase HPLC (water, HCl, 10-60% ACN-water) to 12-(2,6-dimethylphenyl)-18-[(pyridine-4-yl)methyl]-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-2,8,8-trione, ESI-MS m / z calculated value 570.2049, measured value 571.0 (M+1) +A retention time of 0.99 minutes (LC method A) was obtained.

[0205] Example 19: Preparation of Compound 65 Step 1: 18-(4,4-dimethylpentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 65) [ka] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (30 mg, 0.06250 mmol), 1-bromo-4,4-dimethylpentane (16 mg, 0.08934 mmol), triethylamine (25 mg, 0.2471 mmol), and DMF (0.5 mL) were combined and stirred at 110°C for 16 hours. The reaction mixture was filtered and purified on reverse-phase HPLC (water, HCl, 25-75% ACN-water) to 18-(4,4-dimethylpentyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (2 mg, 6%) ESI-MS m / z calculated value 577.2723, measured value 578.0 (M+1) + A retention time of 1.26 minutes (LC method A) was obtained.

[0206] Example 20: Preparation of Compound 66 Step 1: (36R)-16-(2,6-dimethylphenyl)-34-(pyridine-3-ylmethyl)-2-oxa-6-thia-7-aza-3(6,1)-diazepana-1(4,2)-pyrimidinea-5(1,3)-benzenacycloheptaphan-4-one 6,6-dioxide (compound 66) [ka] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (20 mg, 0.04166 mmol), 3-(bromomethyl)pyridine (hydrobromide) (approximately 15.81 mg, 0.06249 mmol), TEA (approximately 16.86 mg, 23.22 μL, 0.1666 mmol), and DMF (1 mL) were combined and stirred at 120°C for 16 hours. The reaction mixture was filtered and purified on reverse-phase HPLC (water, HCl, 25-75% ACN-water) to obtain (36R)-16-(2,6-dimethylphenyl)-34-(pyridine-3-ylmethyl)-2-oxa-6-thia-7-aza-3(6,1)-diazepana-1(4,2)-pyrimidina-5(1,3)-benzenacycloheptaphan-4-one 6,6-dioxide (2.6 mg, 11%). ESI-MS m / z calculated value: 570.2049, measured value: 571.0 (M+1). + A retention time of 0.97 minutes (LC method A) was obtained.

[0207] Example 21: Preparation of Compound 67 and Compound 68 Step 1: (16R)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 67) [ka] Place the 4 mL vial into (16R)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 The vial was filled with -thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (hydrochloride) (25 mg, 0.04845 mmol), anhydrous DCM (500 μL), DIEA (15 μL, 0.08612 mmol) (all solids dissolved), benzaldehyde (10 μL, 0.09838 mmol), and acetic acid (10 μL, 0.1758 mmol). The vial was briefly purged with nitrogen, capped, and stirred at room temperature for approximately 20 minutes. Sodium triacetoxyborohydride (20 mg, 0.09437 mmol) was added. The vial was purged with nitrogen, capped, and the reaction mixture was stirred at room temperature for 1 hour. A small amount of methanol was added. The DCM was evaporated, and the residue was taken up in DMSO (1 mL). The solution was microfiltered and purified by reverse-phase preparative HPLC using an acetonitrile gradient in water (1-99% over 15 minutes) and HCl as a modifier to obtain a white solid (16R)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (17 mg, 57%) was obtained. ESI-MS m / z calculated value: 569.20966, measured value: 570.44 (M+1) + ; Retention time: 1.07 minutes (LC method A). 1¹H NMR (400MHz, DMSO-d6 + 10%D2O (broad signal in the absence of D2O) δ 8.67 (s, 1H), 7.96 (d, J=7.8Hz, 1H), 7.76~7.65 (m, 2H), 7.67~7.51 (m, 5H), 7.31 (t, J=7.9Hz, 1H), 7.16 (d, J=7.6Hz, 2H), 6.28 (s, 1H), 5.75 (broad s, 1H), 4.66~4.35 (m, 3H), 3.86~3.51 (m, 5H), 3.51~3.40 (m, 1H), 3.38~3.24 (m, 1H), 2.06 (br s, 6H).

[0208] Step 2: (16R)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 67), and (16S)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione (compound 68) [ka] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (25 mg, 0.05208 mmol) and benzaldehyde (25 μL, 0.2459 mmol) were combined with acetic acid (15 μL, 0.2638 mmol) in dichloroethane (0.5 mL). After 45 minutes, sodium triacetoxyborohydride (45 mg, 0.2123 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. At this point, the conversion was thought to have stalled, so additional benzaldehyde (25 μL, 0.2459 mmol) and acetic acid (15 μL, 0.2638 mmol) were added. After stirring the reaction mixture for a further 1 hour, sodium cyanoborate (16 mg, 0.2546 mmol) was added, and the reaction mixture was stirred at room temperature for a further 16 hours. After this time, the reaction mixture was diluted with methanol, filtered, and purified by reverse-phase HPLC (1-70% ACN in water, HCl modifier, run for 15 minutes) to 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (hydrochloride) (22 mg, 70%) ESI-MS m / z calculated value 569.20966, measured value 570.4 (M+1) + ; Retention time: 0.48 min (LC method D).

[0209] Next, this material was submitted for chiral SFC separation (ChiralCel OJ-H (250 × 10 mm, 5 μm column, mobile phase: 28% MeCN / MeOH (90:10, 20 mM NH3, 72% CO2, MeCN / MeOH / DMSO (81:9:10) at a concentration of 14 mg / mL, injection volume 70 μL, 100 bar, 220 nm)), and each enantiomer was obtained as a white solid. The first eluted substance, peak 1, (16R)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ) 6-Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexen-2,8,8-trione (4 mg, 13%) ESI-MS m / z calculated value 569.20966, measured value 570.5 (M+1) + Retention time: 1.16 min (LC method A), and the second eluted substance, peak 2, (16S)-18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10,12,14(22)-hexaene-2,8,8-trione (4.4 mg, 15%). ESI-MS m / z calculated value 569.20966, measured value 570.5 (M+1) + ; Retention time: 1.16 minutes (LC method A).

[0210] Example 22: Preparation of Compound 69 Step 1: 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione, enantiomer 1, and 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione, enantiomer 2 [ka] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6-Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (660 mg, 1.375 mmol) and benzaldehyde (approximately 689.0 mg, 660.0 μL, 6.493 mmol) were combined with acetic acid (approximately 418.2 mg, 396.0 μL, 6.964 mmol) in dichloromethane (13.20 mL). After 45 minutes, sodium borocyanohydride (approximately 422.4 mg, 6.722 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was diluted with methanol, filtered, and purified by reverse-phase HPLC (1-70% ACN in water, HCl modifier, run for 15 minutes) to obtain 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-Pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-Hexaene-2,8,8-Trion (hydrochloride) (750 mg, 96%) ESI-MS m / z calculated value 569.20966, measured value 570.5 (M+1) + Retention time: 1.14 min (LC method A). Next, the substance was submitted for chiral SFC separation (ChiralCel OJ-H (250 × 21.2 mm, 5 μm column, mobile phase: MeCN / MeOH (90:10, 20 mM NH3, 72% CO2, flow rate 70 mL / min, 24 mg / mL in MeCN / MeOH / DMSO (81 / 9 / 10), injection volume 500 μL, 100 bar, 220 nm)), and the substance that eluted first as peak 1 was 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (121 mg, 31%) ESI-MS m / z calculated value 569.20966, measured value 570.5 (M+1) + Retention time: 1.14 minutes; LC method A was obtained as a white solid. The second isomer was discarded.

[0211] Step 2: 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione [ka] 18-benzyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (121 mg, 0.2124 mmol) (peak 1 from separation in step 1) was dissolved in methanol (22 mL) in a nitrogen-purged flask, and short sonication was used to aid in the dissolution of the starting material. Dihydroxypalladium (45 mg, 0.06409 mmol) was added, and the reaction mixture was purged with hydrogen gas by foaming through a balloon for 15 minutes, and then stirred under hydrogen for 3 hours. The reaction vessel was then purged with nitrogen, and the reaction mixture was filtered through Celite and washed with 100 mL of methanol. The filtrate was concentrated to obtain a white solid, 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexen-2,8,8-trione (97 mg, 95%) ESI-MS m / z calculated value 479.16272, measured value 480.3 (M+1) + Retention time: 0.79 minutes; LC method A was obtained.

[0212] Step 3: 12-(2,6-dimethylphenyl)-18-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-15-oxa-8λ 6-Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 69) [ka] 12-(2,6-dimethylphenyl)-15-oxa-8λ 6 A vial containing -thia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (28 mg, 0.05839 mmol) was mixed with dichloromethane (1 mL), 2-[1-(trifluoromethyl)cyclopropyl]acetaldehyde (44 mg, 0.2893 mmol), and acetic acid (17 μL, 0.2989 mmol). The reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (19 mg, 0.3023 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction product was quenched with methanol, filtered, and purified by preparative HPLC (1%-99% ACN:0.1% water with HCl modifier) ​​to obtain a white solid: 12-(2,6-dimethylphenyl)-18-{2-[1-(trifluoromethyl)cyclopropyl]ethyl}-15-oxa-8λ 6 -Tia-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (17.4 mg, 48%) was provided. ESI-MS m / z calculated value: 615.2127, measured value: 616.3 (M+1) + ; Retention time: 1.18 min; LC method A.

[0213] Example 23: Preparation of Compound 70 Step 1: 6-Benzylsulfanylpyridine-2-carboxylate methyl [ka] To a solution of phenylmethanethiol (28.408 g, 26.800 mL, 228.72 mmol) in THF (600 mL), NaH (11.200 g, 60% w / w, 280.03 mmol) was added in several portions at 0°C. The slurry was heated to room temperature and stirred for 30 minutes, after which methyl 6-bromopyridine-2-carboxylate (50 g, 231.45 mmol) was added as a single part. After 3 hours, the reaction mixture was diluted with ether (800 mL) and quenched with water (400 mL) and saturated sodium bicarbonate (50 mL). The layers were separated, the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to produce methyl 6-benzylsulfanylpyridine-2-carboxylate (56.35 g, 89%) as a yellow oil. 1 H NMR (500MHz, DMSO-d6) δ7.84~7.77(m, 1H), 7.77~7.73(m, 1H), 7.52(m, 1H), 7.48(d, J=7.8 Hz, 2H), 7.28 (t, J=7.2, 7.2Hz, 2H), 7.24~7.18 (m, 1H), 4.44 (s, 2H), 3.90 (d, J=1.2Hz, 3H). ESI-MS m / z calculated value 259.0667, measured value 260.1(M+1) + ; Retention time: 3.2 minutes; LC method T.

[0214] Step 2: Methyl 6-chlorosulfonylpyridine-2-carboxylate [ka] A solution of methyl 6-benzylsulfanylpyridine-2-carboxylate (121.62 g, 431.47 mmol) in DCM (950 mL) and DI water (300 mL) was cooled in an ice bath at -1 to 0°C, and sulfuryl chloride (228.14 g, 140 mL, 1.6396 mol) was added dropwise with vigorous stirring while maintaining the temperature below 5°C. After addition, the organic phase was separated, washed with deionized water (2 × 500 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in DCM (500 mL). Hexaene (1000 mL) was added, and the DCM was slowly evaporated. The white precipitate was filtered under vacuum, and the solid was washed with hexane (2 × 500 mL). The filtered solid was collected. The residual solid in the filtrate was filtered and dissolved in DCM (500 mL). The DCM solution was transferred to a 1 L round-bottom flask and concentrated under vacuum. The residue was dissolved in 200 mL of DCM. 600 mL of hexane was added, and the DCM was slowly evaporated. The white precipitate was filtered under vacuum, and the solid was washed with 2 × 500 mL of hexane. After drying, methyl 6-chlorosulfonylpyridine-2-carboxylate (56.898 g, 55%) was isolated. 1 H NMR (500MHz, chloroform-d) δ8.48 (dd, J=7.8, 1.1Hz, 1H), 8.31 (dd, J=7.9, 1.1Hz, 1H), 8.25 (t, J=7.8Hz, 1H), 4.08 (s, 3H). ESI-MS m / z calculated value 234.97061, measured value 236.1(M+1) + ; Retention time: 1.74 min; LC method T.

[0215] Step 3: 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylate methyl [ka] A solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-amine (16.63 g, 71.161 mmol) and methyl 6-chlorosulfonylpyridine-2-carboxylate (16.8 g, 71.294 mmol), dissolved in anhydrous THF (680 mL), was cooled to -78°C. Lithium bis(trimethylsilyl)amide (143 mL of 1 M, 143.00 mmol) in the THF solution was then added dropwise. The mixture was slowly warmed to 0°C, followed by the addition of 1 M aqueous HCl (146 mL), and then deionized water (680 mL). The THF was evaporated, and the aqueous phase was extracted with chloroform (3 × 250 mL). The combined organic layers were washed with saturated aqueous NaCl (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was recrystallized in 10% acetone (500 mL) in hexane. The white precipitate was filtered and rinsed with acetone (2 × 100 mL) to obtain methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylate (15.79 g, 50%). ESI-MS m / z calculated value: 432.06592, measured value: 433.3 (M+1). + ; Retention time: 5.5 min; LC method S.

[0216] Step 4: 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylic acid [ka] To a solution of methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylic acid (15.79 g, 36.477 mmol) in THF (180 mL), aqueous sodium hydroxide (182.00 mmol in 182 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The THF was evaporated, and the aqueous layer was washed with diethyl ether (2 × 200 mL). The aqueous layer was acidified to pH 2 with 1 M aqueous HCl (250 mL). The precipitate was filtered, and the white solid was rinsed with deionized water (2 × 250 mL). The solid was dried under vacuum to obtain 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylic acid (14.3444 g, 93%). 1 H NMR (250MHz, DMSO-d6) δ8.14~7.99 (m, 3H), 7.21~7.11 (m, 1H), 7.03 (d, J=7.7Hz, 2H), 6.92 (s, 1H), 1.78 (s, 6H). ESI-MS m / z calculated value 418.05026, measured value 419.1(M+1) + ; Retention time: 2.61 min; LC method T.

[0217] Step 5: 1,4-Diazepane-6-ol [ka] Pd(OH)2 (6 g, 8.5 mmol, 20 wt%) on carbon was added to a solution of 1,4-dibenzyl-1,4-diazepan-6-ol (54 g, 182 mmol) in MeOH (1400 mL). The mixture was hydrogenated under a hydrogen atmosphere for 16 hours. The reaction product was filtered on Celite and concentrated to obtain 1,4-diazepan-6-ol (20.6 g, 92%) as a colorless oil. ESI-MS m / z calculated value: 116.09496, measured value: 117.3 (M+1) + ; Retention time: 0.78 min; LC method T.

[0218] Step 6: 6-Hydroxy-1,4-Diazepan-1-carboxylate benzyl [ka] A solution of 1,4-diazepan-6-ol (7.17 g, 58.6 mmol) in MeOH (100 mL) was slowly added with ethyl trifluoroacetate (7.2 mL, 59.9 mmol) at 0 °C. The solution was stirred at room temperature for 1 hour. Then, the reaction mixture was cooled to 0 °C, and TEA (10.0 mL, 69.6 mmol) and benzyl chloroformate (22 mL of 2.7 M, 59.4 mmol) were slowly added. The reaction mixture was stirred at room temperature for 1 hour. Potassium carbonate (13 g, 94.1 mmol) in water (5 mL) was added. The reaction mixture was stirred at 40 °C for 14 hours. After filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using a gradient of MeOH / ethyl acetate from 0 to 60% to obtain benzyl 6-hydroxy-1,4-diazepane-1-carboxylate (3.6 g, 23%) as a colorless oil. 1 1H NMR (250 MHz, CD3OD) δ 7.66 - 7.08 (m, 5H), 5.14 (s, 2H), 4.14 - 3.87 (m, 1H), 3.84 - 3.61 (m, 2H), 3.59 - 3.36 (m, 2H), 3.16 - 2.76 (m, 4H). ESI-MS m / z calculated value 250.13174, measured value 251.3 (M + 1) + Retention time: 1.81 minutes; LC method T.

[0219] Step 7: Benzyl 4-(3,3-dimethylbutyl)-6-hydroxy-1,4-diazepane-1-carboxylate

Chemical formula

[0220] Step 8: 18-(3,3-dimethylbutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22,23-Hexaazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-Hexaene-2,8,8-Trion (Compound 70) [ka] Step 1: 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylic acid (170 mg, 0.4059 mmol) and 4-(3,3-dimethylbutyl)-6-hydroxy-1,4-diazepane-1-carboxylate benzyl (135 mg, 0.4036 mmol) were combined and dissolved in tetrahydrofuran (1.5 mL). Sodium tert-butoxide (97 mg, 1.009 mmol) was added. The reaction mixture was stirred at 50°C for 3 hours. More sodium tert-butoxide (97 mg, 1.009 mmol) and tetrahydrofuran (1.5 mL) were added, and the reaction was continued at room temperature for 18 hours. The reaction mixture was cooled to room temperature, filtered, and C 18The 6-[[4-[[1-benzyloxycarbonyl-4-(3,3-dimethylbutyl)-1,4-diazepan-6-yl]oxy]-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylic acid (29.8 mg, 10%) was purified by reverse-phase preparative chromatography using a 15-minute gradient elution of 10-60% acetonitrile in water containing 5 mM hydrochloric acid. The ESI-MS m / z calculation value was 716.2992, and the measured value was 716.0 (M+1). + The retention time was 1.3 minutes (LC method A), and 6-[[4-[[1-(3,3-dimethylbutyl)-1,4-diazepan-6-yl]oxy]-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylic acid (45.5 mg, 18%) was obtained. 1 H NMR (400MHz, DMSO-d6) δ8.31~8.20(m, 2H), 8.18~8.11(m, 1H), 7.29(t, J=7.6Hz, 1H), 7.16(d, J=7.6Hz, 2H), 6.30(d, J=20.3Hz, 1H), 3.85~3.74( m, 2H), 3.57(ddd, J=21.9, 10.1, 6.1Hz, 2H), 3.46~3.23(m, 3H), 3.22~2. 80(m, 4H), 2.24~2.08(m, 6H), 1.73~1.43(m, 2H), 0.91(d, J=16.9Hz, 9H). ESI-MS m / z calculated value: 582.26245, measured value: 583.0 (M+1) + ; Retention time: 0.92 minutes (LC method A).

[0221] Step 2: 6-[[4-[[1-(3,3-dimethylbutyl)-1,4-diazepan-6-yl]oxy]-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]pyridine-2-carboxylic acid (45.5 mg, 18%), HATU (100 mg, 0.2630 mmol), DIEA (300 μL, 1.722 mmol), and DMF (1 mL) were stirred at room temperature for 30 minutes. The crude product was filtered and C 18The solution was purified by reverse-phase preparative chromatography using a column and a 15-minute gradient elution of 1-50% acetonitrile in water containing 5 mM hydrochloric acid, and then 18-(3,3-dimethylbutyl)-12-(2,6-dimethylphenyl)-15-oxa-8λ was obtained. 6 -Tia-1,9,11,18,22,23-hexaazatetracyclo[14.4.1.13,7.110,14]tricosa-3,5,7(23),10,12,14(22)-hexaene-2,8,8-trione (1.8 mg, 1%) was obtained. ESI-MS m / z calculated value: 564.2519, measured value: 565.0 (M+1) + ; Retention time: 1.03 minutes (LC method A).

[0222] Example 24: Preparation of Compound 71 Step 1: 2-[(2R)-3-(tert-butylamino)-2-hydroxypropyl]isoindoline-1,3-dione [ka] A pressure vessel was packed with a solution of 2-methylpropan-2-amine (2.16 g, 29.534 mmol) and 2-[[(2S)-oxiran-2-yl]methyl]isoindorin-1,3-dione (5 g, 24.607 mmol) in isopropanol (160 mL). The reaction mixture was stirred overnight at 85°C. The isopropanol was evaporated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH = 100 / 0~90 / 10) to obtain 2-[(2R)-3-(tert-butylamino)-2-hydroxy-propyl]isoindorin-1,3-dione (5.65 g, 78%) as a white solid. ESI-MS m / z calculated value: 276.1474, measured value: 277.2 (M+1) + ; Retention time: 1.78 min; LC method T.

[0223] Step 2: 2-[(2R)-3-(tert-butylamino)-2-[tert-butyl(dimethyl)silyl]oxypropyl]isoindoline-1,3-dione [ka] To a solution of 2-[(2R)-3-(tert-butylamino)-2-hydroxypropyl]isoindoline-1,3-dione (4.8 g, 16.328 mmol) and imidazole (2.223 g, 32.654 mmol) in DMF (60 mL), tert-butyl-chloro-dimethyl-silane (4.925 g, 32.676 mmol) was added. The reaction mixture was stirred at room temperature for 36 hours. Imidazole (0.74 g, 10.87 mmol) and tert-butyl-chloro-dimethyl-silane (1.64 g, 10.87 mmol) were added to the reaction mixture and stirred for 60 hours. The reaction mixture was quenched with brine (150 mL), and the aqueous layer was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (3 × 150 mL), dried on anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography using 0-10% MeOH in DCM to obtain 2-[(2R)-3-(tert-butylamino)-2-[tert-butyl(dimethyl)silyl]oxypropyl]isoindoline-1,3-dione (4.47 g, 68%) as a pale yellow liquid. ESI-MS m / z calculation value: 390.23386, measured value: 391.7 (M+1) + ; Retention time: 3.25 min; LC method T.

[0224] Step 3: 2-[tert-butyl-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-3-(1,3-dioxoisoindolin-2-yl)propyl]amino]ethyl acetate [ka] To a solution of 2-[(2R)-3-(tert-butylamino)-2-(1-methyl-1-trimethylsilyl-ethoxy)propyl]isoindoline-1,3-dione (4.85 g, 12.045 mmol) in DCM (150 mL), 2-ethyl oxoethyl (2.459 g, 50% w / w, 12.043 mmol) was added, followed by the addition of sodium triacetoxyborohydride (2.553 g, 12.046 mmol). The reaction mixture was stirred at room temperature. Ethyl oxoethyl (2.459 g, 50% w / w, 12.043 mmol) and sodium triacetoxyborohydride (2.553 g, 12.046 mmol) were added to the reaction mixture every 2 hours for a total of 10 times over 2 days. The reaction mixture was quenched with saturated sodium bicarbonate (150 mL) and stirred for 0.5 hours. The two layers were separated, and the aqueous layer was extracted with dichloromethane (3 × 120 mL). The combined dichloromethane layer was washed with brine (250 mL), dried on anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (hexane / siRNA = 100 / 0~60 / 40) to obtain 2-[tert-butyl-[(2R)-3-(1,3-dioxoisoindolin-2-yl)-2-(1-methyl-1-trimethylsilyl-ethoxy)propyl]amino]ethyl acetate (5.22 g, 91%) as a clear oil. ESI-MS m / z calculation: 476.27066, measured value: 477.5 (M+1). + ; Retention time: 3.61 min; LC method T.

[0225] Step 4: (6S)-4-tert-butyl-6-[tert-butyl(dimethyl)silyl]oxy-1,4-diazepan-2-one [ka] To a solution of 2-[tert-butyl-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-3-(1,3-dioxoisoindolin-2-yl)propyl]amino]ethyl acetate (5.22 g, 11.283 mmol) in ethanol (150 mL), hydrazine hydrate (2.8244 g, 3.76 mL, 41.186 mmol) was added. The reaction mixture was stirred at 85 °C for 18 hours. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The residue was diluted with 10% NaOH (hydrated) (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layer was washed with brine (100 mL), dried on anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography using 0-40% acetone in hexane to obtain (6S)-4-tert-butyl-6-[tert-butyl(dimethyl)silyl]oxy-1,4-diazepan-2-one (2.6 g, 77%) as a pale yellow solid. ESI-MS m / z calculation: 300.2233, measured value: 301.5 (M+1). + ; Retention time: 2.67 min; LC method T.

[0226] Step 5: (6R)-4-tert-butyl-6-hydroxy-1,4-diazepan-1-carboxylate tert-butyl [ka] Step 1: To a solution of (6S)-4-tert-butyl-6-[tert-butyl(dimethyl)silyl]oxy-1,4-diazepan-2-one (2.6 g, 8.6519 mmol) in anhydrous THF (55 mL), LAH (1.97 g, 51.905 mmol) was slowly added at 0°C. The reaction mixture was stirred at 40°C for 9 hours. The reaction mixture was cooled to 0°C in a batch of ice and diluted with diethyl ether (50 mL). The reaction mixture was quenched with water (2.1 mL), 15% NaOH (2.1 mL), and water (6.3 mL) and stirred at room temperature for 30 minutes. The white precipitate was removed by filtration through a Celite pad and washed with THF (3 × 25 mL). The combined filtrate was concentrated under vacuum.

[0227] Step 2: The residue was dissolved in THF (20 mL), and an aqueous solution of NaOH (17.3 g, 10% w / w, 43.253 mmol) was added, followed by the addition of anhydrous Boc (1.98 g, 9.0723 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (50 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using 0-50% ethyl acetate in hexane to obtain (6R)-4-tert-butyl-6-hydroxy-1,4-diazepane-1-carboxylic acid tert-butyl (1.86 g, 78%) as a white solid. 1 H NMR (250MHz, DMSO-d6) δ4.61 (t, J=5.4Hz, 1H), 3.80~3.64 (m, 1H), 3.64~3. 43(m, 2H), 3.13~2.60(m, 4H), 2.47~2.25(m, 2H), 1.39(s, 9H), 1.01(s, 9H). ESI-MS m / z calculated value 272.21, measured value 273.3(M+1) + ; Retention time: 1.13 min; LC method W.

[0228] Step 6: (6S)-1-tert-butyl-1,4-diazepane-6-ol [ka] A 100 mL round-bottom flask was packed with (6R)-4-tert-butyl-6-hydroxy-1,4-diazepan-1-carboxylic acid tert-butyl (1.04 g, 3.818 mmol) and dioxane (3 mL). After dissolving the solid, HCl (12 mL of 4 M, 48.00 mmol) (4 M dioxane solution) was added, and the mixture was stirred at room temperature for 3 hours. Volatiles were removed under reduced pressure. The solid was treated with DCM / MeOH and hexane, and the solvent was evaporated. The procedure was repeated three times. After drying in vacuum, (6S)-1-tert-butyl-1,4-diazepan-6-ol (dihydrochloride) (1.018 g, 100%) was provided as a white, foamy solid. ESI-MS m / z calculation: 172.15756, measured value: 173.09 (M+1). + ; Retention time: 0.15 min; LC method A.

[0229] Step 7: 3-[(6R)-4-tert-butyl-6-hydroxy-1,4-diazepan-1-carbonyl]-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]benzenesulfonamide [ka] A 100 mL flask was packed under nitrogen with (6S)-1-tert-butyl-1,4-diazepan-6-ol (dihydrochloride) (384 mg, 1.441 mmol), anhydrous DMF (6 mL), and 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]sulfamoyl]benzoic acid (504 mg, 1.206 mmol). After dissolving the reagents, the mixture was cooled in an ice bath. DIEA (1.4 mL, 8.038 mmol) and HATU (580 mg, 1.525 mmol) were added, and the mixture was stirred at 0°C for 19 minutes (completion after 10 minutes by LC-MS). The reaction was quenched by pouring the mixture into citric acid (50 mL of 10% w / v, 26.02 mmol) (10% water) with vigorous stirring, and cooled in ice. The resulting white solid was filtered and washed with water. The wet solid was dissolved in DCM, and the solution was dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in DCM and purified by flash chromatography on silica gel (80 g column) using a methanol gradient (0-10% over 60 minutes) in dichloromethane. The product eluted approximately 5-6% methanol. By evaporation of the solvent, 3-[(6R)-4-tert-butyl-6-hydroxy-1,4-diazepan-1-carbonyl]-N-4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]benzenesulfonamide (158 mg, 23%) was obtained as a white solid. ESI-MS m / z calculation: 571.202, measured value: 572.28 (M+1) + ; Retention time: 1.27 minutes (LC method A).

[0230] Step 8: (16R)-18-tert-butyl-12-(2,6-dimethylphenyl)-15-oxa-8λ 6 -Thi-1,9,11,18,22-pentazatetracyclo[14.4.1.13,7.110,14]tricosa-3(23),4,6,10(22),11,13-hexaene-2,8,8-trione (compound 71) [ka] A 100 mL flask was packed under nitrogen with 3-[(6R)-4-tert-butyl-6-hydroxy-1,4-diazepan-1-carbonyl]-N-4-chloro-6-(2,6-dimethylphenyl)pyrimidine-2-yl]benzenesulfonamide (155 mg, 0.2709 mmol) and anhydrous DMF (8 mL). The mixture was cooled on ice. NaH (93 mg, 60% w / w, 2.325 mmol) (60% mineral oil dispersion) was added all at once. The mixture was stirred under nitrogen at 0°C for 10 minutes. The ice bath was removed and the reaction mixture was vigorously stirred under nitrogen for 4 hours. The mixture was slowly poured into an ice-cold citric acid aqueous solution (40 mL, 10% w / v, 20.82 mmol) while stirring. The resulting solid suspension was extracted with siRNA (3 × 40 mL). A considerable amount of product was detected in the aqueous phase (pH=2). The aqueous phase was neutralized to pH=6 using saturated sodium carbonate, and the remaining product was extracted with ¼ (50 mL). The combined extract was dried over sodium sulfate, and the solvent was evaporated. After evaporation of the solvent, the residue was dissolved in DMSO (4 mL). The solution was subjected to reverse-phase preparative HPLC (C) using an acetonitrile gradient in water (1–99% over 15 minutes) and HCl as a modifier. 18 The product was purified by ( ) to obtain 89 mg of the product containing a large amount of impurities. The product was dissolved in DMSO (2...

Claims

1. Compound of formula I: 【Chemistry 1】 , its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, in the formula, Ring A is ■C ６ ~C １０ Aryl, and ■ Selected from 5- to 10-membered heteroaryls, Ring B is ■C ６ ~C １０ Selected from Ariel, V is selected from O and NH, W １ However, N is, W ２ However, N is, Z is O, NR ＺＮ , and C(R ＺＣ ), ２ selected from, provided that when L ２ is absent, Z is C(R ＺＣ ), ２ on the condition that Each L １ However, independently, C(R) Ｌ１ ) ２ Selected from, Each L ２ However, independently, C(R) Ｌ２ ) ２ Selected from, Each R ３ However, they became independent, ■Halogen, ■C １ ~C ６ Alkyl, ■C １ ~C ６ Alkoxy, ■C ３ ~C １０ Cycloalkyl, ■ Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ Aryl, and ■Selected from 3- to 10-membered heterocyclines, R ４ However, hydrogen and C １ ~C ６ Selected from alkyl groups, Each R ５ However, they became independent, ■ Hydrogen, ■Halogen, ■ Hydroxyl, ■N(R Ｎ ) ２ 、 ■-SO-Me, ■Both R ＬＣ Together, C ３ ~C １０ -CH=C(R) ＬＣ ) ２ , ■C １ ~C ６ Alkyl, independently, ○ Hydroxyl, ○ Independent CC １ ~C ６ Alkoxy and C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ○C ３ ~C １０ Cycloalkyl, ○ Independent CC １ ~C ６ Alkyl and C １ ~C ６ -(O) is optionally substituted with 1 to 3 groups selected from alkoxy groups. ０～１ - (C ６ ~C １０ Ariel), ○3-10 membered heterocyclils, and ○N(R) Ｎ ) ２ C, which is optionally substituted with 1 to 3 groups selected from , １ ~C ６ Alkyl, ■C １ ~C ６ It is an alkoxy, and independently, ○Halogen, ○C ６ ~C １０ Aryl, and ○ Independent CC １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ C, which is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ６ Alkoxy, ■C １ ~C ６ Fluoroalkyl, ■C ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ Ariel, and ■Selected from 3- to 10-membered heterocyclines, R ＺＮ but, ■ Hydrogen, ■C １ ~C ９ Alkyl, independently, ○ Hydroxyl, ○Oxo, ○Cyano, ○ Independently halogen and C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkoxy groups. １ ~C ６ Alkoxy, ○N(R Ｎ ) ２ 、 ○SO ２ Me、 ○C ３ ~C １０ Cycloalkyl, independently, ◆Hydroxyl, ◆ Independently, hydroxyl, oxo, C １ -C ６ -alkoxy, C ６ -C １０ -aryl, and N(R Ｎ ) ２ optionally substituted with 1 to 3 groups selected from C １ -C ６ -alkyl, ◆C １ ~C ６ Fluoroalkyl, ◆C １ ~C ６ Alkoxy, and ◆COOH, ◆N(R Ｎ ) ２ 、 ◆C ６ ~C １０ Ariel, and ◆Independently, oxo and C １ ~C ６ A C selected from 3- to 10-membered heterocyclyls, which are optionally substituted with 1 to 3 groups selected from alkyl groups, and which are optionally substituted with 1 to 3 groups. ３ ~C １０ Cycloalkyl, ○C ６ ~C １０ It is an army, and independently, ◆Halogen, ◆Hydroxyl, ◆Cyano, ◆SiMe ３ 、 ◆SO ２ Me、 ◆SF ５ 、 ◆N(R Ｎ ) ２ 、 ◆P(O)Me ２ 、 ◆Independent C １ ~C ６ -(O) ０～１ - (C ３ ~C １０ Cycloalkyl), ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkyl, 5-10 membered heteroaryl, SO ２ Me, and N(R Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ◆Independently, hydroxyl, oxo, N(R) Ｎ ) ２ , and C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ◆C １ ~C ６ Fluoroalkyl, ◆Independent C １ ~C ６ 3-10 membered heterocyclines optionally substituted with 1-3 groups selected from alkyl groups, ◆-(O) ０～１ - (C ６ ~C １０ Aryl), and ◆Hydroxyl, oxo, N(R) Ｎ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Fluoroalkyl and C ３ ~C １０ -(O) optionally substituted with cycloalkyl groups ０～１ -C is optionally substituted with 1 to 3 groups selected from (5 to 10-membered heteroaryl groups). ６ ~C １０ Ariel, ○3- to 10-membered heterocyclines, independently, ◆Hydroxyl, ◆Oxo, ◆N(R Ｎ ) ２ 、 ◆C １ ~C ６ Alkyl (independently oxo and C) １ ~C ６ (Optionally substituted with 1 to 3 groups selected from alkoxys) ◆C １ ~C ６ Alkoxy, ◆C １ ~C ６ Fluoroalkyl, ◆C is optionally substituted with 1 to 3 groups independently selected from halogens. ６ ~C １０ Aryl, and ◆ 3-10 membered heterocyclils, optionally substituted with 1-4 groups, selected from 5-10 membered heteroaryls. ○A 5- to 10-membered heteroaryl, independently, ◆Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆B(OH) ２ 、 ◆N(R Ｎ ) ２ 、 ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkoxy (1-3 -SiMe ３ (Optionally replaced by), and N (R Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkoxy, N(R Ｎ ) ２ , and C ３ ~C １０ C is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ６ Alkoxy, ◆C １ ~C ６ Fluoroalkyl, ◆Independent C １ ~C ６ -(O) ０～１ - (C ３ ~C １０ Cycloalkyl), ◆-(O) ０～１ - (C ６ ~C １０ Ariel), ◆Independently, hydroxyl, oxo, halogen, cyano, N(R) Ｎ ) ２ , C １ ~C ６ Alkyl (hydroxyl, oxo, N(R) Ｎ ) ２ , and C １ ~C ６ C １ ~C ６ Alkoxy, C １ ~C ６ Fluoroalkyl, 3-10 membered heterocyclyl (independently C) １ ~C ６ (Optionally substituted with 1 to 4 groups selected from fluoroalkyl groups) ０～１ - (3-10 membered heterocyclyl), and ◆Independent C １ ~C ６ Alkyl and C ３ ~C １０ A 5-10 membered heteroaryl selected from a cycloalkyl group, optionally substituted with 1-4 groups selected from a cycloalkyl group, a 5-10 membered heteroaryl selected from a cycloalkyl group, optionally substituted with 1-3 groups selected from a cycloalkyl group, C １ ~C ９ Alkyl, ■C １ ~C ６ Fluoroalkyl, ■C ３ ~C １０ Cycloalkyl, independently, ○ Hydroxyl, ○Oxo, ○Halogen, ○Cyano, ○N(R Ｎ ) ２ 、 ○C １ ~C ６ Alkyl, independently, ◆Hydroxyl, ◆Oxo, ◆N(R Ｎ ) ２ 、 ◆C １ ~C ６ Alkoxy, and ◆C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkyl, ○ Independently, halogen, oxo, C ６ ~C １０ Aryl, and N(R Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkoxy, ○Halogen, ○C ３ ~C １０ Cycloalkyl, ○ Independent CC １ ~C ６ 3- to 10-membered heterocyclines optionally substituted with 1 to 3 groups selected from alkyl groups, and ○A 5- to 10-membered heteroaryl, independently, ◆Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆N(R Ｎ ) ２ 、 ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkoxy, and N(R) Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ◆Independently, hydroxyl, C １ ~C ６ Alkoxy, N(R Ｎ ) ２ , and C ３ ~C １０ C is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ６ Alkoxy, ◆C １ ~C ６ Fluoroalkyl, ◆Independent C １ ~C ６ -(O) ０～１ - (C ３ ~C １０ Cycloalkyl), ◆C ６ ~C １０ Aryl, and ◆Independent C １ ~C ６ A 3-10 membered heterocyclyl selected from alkyl groups, a 5-10 membered heteroaryl selected from alkyl groups, and a C selected from alkyl groups, which are optionally substituted with 1-3 groups. ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ Ariel, ■3- to 10-membered heterocyclines, independently, ○Oxo, ○C １ ~C ６ Alkyl, independently, ◆Oxo, ◆Hydroxyl, ◆N(R Ｎ ) ２ 、 ◆Independently, halogen and C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, and ◆-(O) ０～１ - (C ３ ~C １０ C (Cycloalkyl) is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ○C １ ~C ６ Fluoroalkyl, ○C is optionally substituted with 1 to 3 groups independently selected from halogens. ３ ~C １０ Cycloalkyl, and ○ 3- to 10-membered heterocyclines, selected from 3- to 10-membered heterocyclines, which are arbitrarily substituted with 1 to 3 groups. ■ 5- to 10-membered heteroaryls, independently, ○Halogen, ○ Independently, Oxo, C １ ~C ６ Alkoxy, and N(R) Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, and ○ Independent CC １ ~C ６ Alkyl (oxo, C １ ~C ６ Alkoxy and C ６ ~C １０ 3- to 10-membered heterocyclyls, which are optionally substituted with 1 to 3 groups selected from aryls, 5- to 10-membered heteroaryls, which are optionally substituted with 1 to 3 groups selected from aryls, and ■R Ｆ , selected from, Each R ＺＣ However, they became independent, ■ Hydrogen, ■ Independent C ６ ~C １０ Aryl (independently C １ ~C ６ C (optionally substituted with 1 to 3 groups selected from alkyl groups) １ ~C ６ Alkyl, ■ Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ Aryl, and ■R Ｆ , can be selected from, or two R ＺＣ They come together to form an oxo group, Each R Ｌ１ However, they became independent, ■ Hydrogen, ■Two Ns (R Ｎ ) ２ The condition is that they are not bonded to the same carbon, N(R Ｎ ) ２ , ■C １ ~C ９ Alkyl, independently, ○Halogen, ○ Hydroxyl, ○Oxo, ○N(R Ｎ ) ２ 、 ○ Independent CC ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ○ Independently halogen and C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ Cycloalkyl, ○ Independent CC １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ Aryl, and ○ Independent CC １ ~C ６ A C12C that is selected from a 3- to 10-membered heterocycline that is selectively substituted with 1 to 3 groups selected from alkyl groups (selectively substituted with 1 to 3 groups independently selected from hydroxyl and oxo groups), which is selectively substituted with 1 to 3 groups. １ ~C ９ Alkyl, ■C ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ It is an army, and independently, ○Halogen, ○Cyano, ○SiMe ３ 、 ○POMe ２ 、 ○C １ ~C ７ Alkyl, independently, ◆Hydroxyl, ◆Oxo, ◆Cyano, ◆SiMe ３ 、 ◆N(R) Ｎ ) ２ , and ◆Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ C is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ７ Alkyl, ○C １ ~C ６ It is an alkoxy, ◆Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ Cycloalkyl, and ◆C １ ~C ６ C, which is optionally substituted with 1 to 3 groups selected from alkoxy groups. １ ~C ６ Alkoxy, ○C １ ~C ６ Fluoroalkyl, ○ Independent CC １ ~C ６ Alkyl and C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ Cycloalkyl, ○C ６ ~C １０ Ariel, ○ Independent CC １ ~C ６ 3- to 10-membered heterocyclines optionally substituted with 1 to 3 groups selected from alkyl groups, and ○C13 ６ ~C １０ Ariel, ■3- to 10-membered heterocyclines, independently, ○C １ ~C ６ Alkyl, independently, ◆Oxo, and ◆C １ ~C ６ C, which is optionally substituted with 1 to 3 groups selected from alkoxy groups. １ ~C ６ 3-10 membered heterocyclines optionally substituted with 1-3 groups selected from alkyl groups, ■ 5- to 10-membered heteroaryls, independently, ○C １ ~C ６ Alkyl, independently, ◆Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ C is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ６ Alkyl, and ○ Independent CC １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ aryls, 5-10 membered heteroaryls optionally substituted with 1-3 groups selected from, and ■R Ｆ , can be selected from, or two R on the same carbon atom Ｌ１ They come together to form an oxo group, Each R Ｌ２ However, hydrogen and R are independent Ｆ Selected from, or two R on the same carbon atom Ｌ２ These combine to form an oxo group, however, at least one R Ｌ１ or R Ｌ２ R Ｆ The condition is that, Each R Ｎ However, they became independent, ■ Hydrogen, ■C １ ~C ８ Alkyl, independently, ○Oxo, ○Halogen, ○ Hydroxyl, ○NH ２ 、 ○NHMe, ○NMe ２ 、 ○ Independent CC ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ○-(O) ０～１ - (C ３ ~C １０ Cycloalkyl), ○ Independently halogen and C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ Ariel, ○ Independently oxo and C １ ~C ６ 3- to 14-membered heterocyclines optionally substituted with 1 to 4 groups selected from alkyl groups, and ○ Independently oxo and C １ ~C ６ A 5- to 14-membered heteroaryl molecule, selected from alkyl groups, which is optionally substituted with 1 to 4 groups selected from alkyl groups, and a C molecule, which is optionally substituted with 1 to 3 groups selected from alkyl groups. １ ~C ８ Alkyl, ■C ３ ~C １０ Cycloalkyl, independently, ○ Hydroxyl, ○NH ２ , and ○NHMe, and ○C13 C １ ~C ６ C, optionally substituted with 1 to 3 groups selected from alkyl groups. ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ Ariel, and ■Selected from 3- to 10-membered heterocyclines, or two R on the same nitrogen atom Ｎ However, together with the nitrogen atoms to which they are bound, they form 3- to 10-membered heterocyclines, and these 3- to 10-membered heterocyclines can independently... ■ Hydroxyl, ■Oxo, ■Cyano, ■ Independently, oxo, hydroxyl, C １ ~C ６ Alkoxy, and N(R) Ｎ２ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, each R Ｎ２ However, independently, hydrogen and C １ ~C ６ Selected from alkyl groups, C １ ~C ６ Alkyl, ■C １ ~C ６ Alkoxy, and ■C １ ~C ６ Fluoroalkyl groups, optionally substituted with 1 to 3 groups selected from the fluoroalkyl group, or one R ４ and one R Ｌ１ Together, C ６ ~C ８ Forming alkylenes, Two R's Ｆ However, together with the atoms to which they are bonded, ■ Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ It is an army, and independently, ○Halogen, ○C １ ~C ６ Alkyl, ○N(R) Ｎ ) ２ , and ○C selected from 3- to 10-membered heterocyclines, which are arbitrarily substituted with 1 to 3 groups independently selected from hydroxyls, and which are arbitrarily substituted with 1 to 3 groups. ６ ~C １０ Ariel, ■3- to 11-membered heterocyclines, independently, ○Oxo, ○N(R Ｎ ) ２ 、 ○C １ ~C ９ Alkyl, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R Ｎ ) ２ 、 ◆-SO ２ - (C １ ~C ６ Alkyl), ◆Independently, halogen, C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ◆Independently, hydroxyl, halogen, cyano, C １ ~C ６ Alkyl (independently oxo and C) １ ~C ６ C １ ~C ６ Alkoxy (independently C) ６ ~C １０ (Optionally substituted with 1 to 3 groups selected from aryl groups), -(O) ０～１ - (C １ ~C ６ Fluoroalkyl), and C ６ ~C １０ Aryl (independently C １ ~C ６ C (optionally substituted with 1 to 3 groups selected from alkoxy) ６ ~C １０ Ariel, ◆Independently, hydroxyl, halogen, N(R) Ｎ ) ２ , C １ ~C ６ Alkyl (independently oxo, hydroxyl, and C) １ ~C ６ C １ ~C ６ Fluoroalkyl and C ６ ~C １０ -(O) - ( ０～１ - (C ３ ~C １０ Cycloalkyl), ◆Independently, Oxo, C １ ~C ６ Alkyl (independently C ６ ~C １０ Aryl (optionally substituted with 1 to 3 groups selected independently from halogens), C １ ~C ６ Alkoxy, C ３ ~C １０ Cycloalkyl, and R Ｎ A 3-10 membered heterocycline, optionally substituted with 1-3 groups selected from the following: ◆Independent, C ６ ~C １０ Aryl (optionally substituted with 1 to 3 groups independently selected from halogens) and C １ ~C ６ -O- (5-12 member heteroaryl) groups optionally substituted with 1-3 groups selected from alkyl groups, and ◆Independently, hydroxyl, oxo, N(R) Ｎ ) ２ , C １ ~C ６ Alkyl (optionally substituted with 1 to 3 groups independently selected from cyano), C １ ~C ６ Alkoxy, -(O) ０～１ - (C １ ~C ６ Fluoroalkyl), -O-(C ６ ~C １０ Aryl), and C ３ ~C １０ A 5-10 membered heteroaryl selected from cycloalkyl groups, optionally substituted with 1-4 groups, and optionally substituted with 1-4 groups. １ ~C ９ Alkyl, ○ Independently, halogen, C １ ~C ６ Alkyl and C １ ~C ６ C is optionally substituted with 1 to 4 groups selected from fluoroalkyl groups. ３ ~C １２ Cycloalkyl, ○C ６ ~C １０ Ariel, ○3-10 membered heterocyclils, and ○ Independently, C １ ~C ６ Alkoxy, C １ ~C ６ Fluoroalkyl, and N(R Ｎ ) ２ 5-10 member heteroaryls optionally substituted with 1-3 groups selected from, 3-11 member heterocyclines optionally substituted with 1-3 groups selected from, and ■ Independent, C １ ~C ６ Alkyl (C ６ ~C １０ (Optionally replaced with aryl) and C １ ~C ６ Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts forming groups selected from 5- to 12-membered heteroaryls, which are optionally substituted with 1 to 3 groups selected from fluoroalkyls.

2. Compounds of formula Ia: 【Chemistry 2】 , its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, wherein ring A, ring B, W １ , W ２ Z, L １ , L ２ , R ３ , R ４ , R ５ , and R Ｆ However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in claim 1.

3. Compounds of formula IIa: 【Transformation 3】 , its tautomer, a deuterated derivative of the compound or its tautomer, or a pharmaceutically acceptable salt of any of the above, wherein rings B, W １ , W ２ Z, L １ , L ２ , R ３ , R ４ , R ５ , and R Ｆ However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in claim 1.

4. Compounds of formula IIb: 【Chemistry 4】 , its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, wherein rings A, W １ , W ２ Z, L １ , L ２ , R ３ , R ４ , R ５ , and R Ｆ However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in claim 1.

5. Compounds of formula III: 【Transformation 5】 , its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, W １ , W ２ Z, L １ , L ２ , R ４ , R ５ , and R Ｆ However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in claim 1.

6. Compound of formula V: 【Transformation 7】 , its tautomer, the compound or a deuterated derivative of the tautomer, or any pharmaceutically acceptable salt of any of the above, Z, L １ , L ２ , R ４ , R ５ , and R Ｆ However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in claim 1.

7. Compounds of formula VI: 【Transformation 8】 , its tautomer, the compound or a deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, L １ , R ４ , R ５ , and R Ｆ However, a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as defined in claim 1. 【Request Item 8】 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 [Chemistry 10-4] [Transformation 10-5] 【Chemistry 10-6】 【Chemistry 10-7】 [Transformation 10-8] 【Chemistry 10-9】 【Chemistry 10-10】 【Chemistry 10-11】 [Chemistry 10-12] [Chemistry 10-13] [Chemistry 10-14] [Chemistry 10-15] [Chemistry 10-16] 【Chemistry 10-17】 [Chemistry 10-18] [Chemistry 10-19] [Chemistry 10-20] [Chemistry 10-21] 【Chemistry 10-22】 [Chemistry 10-23] [Chemistry 10-24] [Chemistry 10-25] [Chemistry 10-26] [Chemistry 10-27] [Chemistry 10-28] [Chemistry 10-29] [Chemistry 10-30] 【Chemistry 10-31】 【Chemistry 10-32】 【Chemistry 10-33】 【Chemistry 10-34】 [Chemistry 10-35] 【Chemistry 10-36】 【Chemistry 10-37】 [Chemistry 10-38] [Chemistry 10-39] [Chemistry 10-40] 【Chemistry 10-41】 The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from the tautomer, the compound and the tautomer, and any pharmaceutically acceptable salt of the foregoing.

9. Compound of formula I: 【Chemistry 9】 , its tautomer, compound or deuterated derivative of the tautomer, or a pharmaceutically acceptable salt of any of the above, in the formula, Ring A is ■C ６ ~C １０ Aryl, and ■ Selected from 5- to 10-membered heteroaryls, Ring B is ■C ６ ~C １０ Selected from the alphabet, V is selected from O and NH, W １ However, N is, W ２ However, N is, Z is O, NR ＺＮ , and C(R ＺＣ ) ２ It is selected from, however, L ２ If Z is absent, C(R ＺＣ ) ２ The condition is that, Each L １ However, independently, C(R) Ｌ１ ) ２ Selected from, Each L ２ However, independently, C(R) Ｌ２ ) ２ Selected from, Each R ３ However, they became independent, ■Halogen, ■C １ ~C ６ Alkyl, ■C １ ~C ６ Alkoxy, ■C ３ ~C １０ Cycloalkyl, ■ Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ Aryl, and ■Selected from 3- to 10-membered heterocyclines, R ４ However, hydrogen and C １ ~C ６ Selected from alkyl groups, Each R ５ However, they became independent, ■ Hydrogen, ■Halogen, ■ Hydroxyl, ■N(R Ｎ ) ２ 、 ■-SO-Me, ■Both R ＬＣ Together, C ３ ~C １０ -CH=C(R) ＬＣ ) ２ , ■C １ ~C ６ Alkyl, independently, ○ Hydroxyl, ○ Independent CC １ ~C ６ Alkoxy and C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ○C ３ ~C １０ Cycloalkyl, ○ Independent CC １ ~C ６ Alkyl and C １ ~C ６ -(O) is optionally substituted with 1 to 3 groups selected from alkoxy groups. ０～１ - (C ６ ~C １０ Ariel), ○3-10 membered heterocyclils, and ○N(R) Ｎ ) ２ C, which is optionally substituted with 1 to 3 groups selected from , １ ~C ６ Alkyl, ■C １ ~C ６ It is an alkoxy, and independently, ○Halogen, ○C ６ ~C １０ Aryl, and ○ Independent CC １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ C, which is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ６ Alkoxy, ■C １ ~C ６ Fluoroalkyl, ■C ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ Ariel, and ■Selected from 3- to 10-membered heterocyclines, R ＺＮ but, ■ Hydrogen, ■C １ ~C ９ Alkyl, independently, ○ Hydroxyl, ○Oxo, ○Cyano, ○ Independently halogen and C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkoxy groups. １ ~C ６ Alkoxy, ○N(R Ｎ ) ２ 、 ○SO ２ Me、 ○C ３ ~C １０ Cycloalkyl, independently, ◆Hydroxyl, ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkoxy, C ６ ~C １０ Aryl, and N(R Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ◆C １ ~C ６ Fluoroalkyl, ◆C １ ~C ６ Alkoxy, and ◆COOH, ◆N(R Ｎ ) ２ 、 ◆C ６ ~C １０ Ariel, and ◆Independently, oxo and C １ ~C ６ A C selected from 3- to 10-membered heterocyclyls, which are optionally substituted with 1 to 3 groups selected from alkyl groups, and which are optionally substituted with 1 to 3 groups. ３ ~C １０ Cycloalkyl, ○C ６ ~C １０ It is an army, and independently, ◆Halogen, ◆Hydroxyl, ◆Cyano, ◆SiMe ３ 、 ◆SO ２ Me、 ◆SF ５ 、 ◆N(R Ｎ ) ２ 、 ◆P(O)Me ２ 、 ◆Independent C １ ~C ６ -(O) ０～１ - (C ３ ~C １０ Cycloalkyl), ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkyl, 5-10 membered heteroaryl, SO ２ Me, and N(R Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ◆Independently, hydroxyl, oxo, N(R) Ｎ ) ２ , and C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ◆C １ ~C ６ Fluoroalkyl, ◆Independent C １ ~C ６ 3-10 membered heterocyclines optionally substituted with 1-3 groups selected from alkyl groups, ◆-(O) ０～１ - (C ６ ~C １０ Aryl), and ◆Hydroxyl, oxo, N(R) Ｎ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Fluoroalkyl and C ３ ~C １０ -(O) optionally substituted with cycloalkyl groups ０～１ -C is optionally substituted with 1 to 3 groups selected from (5 to 10-membered heteroaryl groups). ６ ~C １０ Ariel, ○3- to 10-membered heterocyclines, independently, ◆Hydroxyl, ◆Oxo, ◆N(R Ｎ ) ２ 、 ◆C １ ~C ６ Alkyl (independently oxo and C) １ ~C ６ (Optionally substituted with 1 to 3 groups selected from alkoxys) ◆C １ ~C ６ Alkoxy, ◆C １ ~C ６ Fluoroalkyl, ◆C is optionally substituted with 1 to 3 groups independently selected from halogens. ６ ~C １０ Aryl, and ◆ 3-10 membered heterocyclyls, optionally substituted with 1-4 groups, selected from 5-10 membered heteroaryls, and ○A 5- to 10-membered heteroaryl, independently, ◆Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆B(OH) ２ 、 ◆N(R Ｎ ) ２ 、 ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkoxy (1-3 -SiMe ３ (Optionally replaced by), and N (R Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkoxy, N(R Ｎ ) ２ , and C ３ ~C １０ C is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ６ Alkoxy, ◆C １ ~C ６ Fluoroalkyl, ◆Independent C １ ~C ６ -(O) ０～１ - (C ３ ~C １０ Cycloalkyl), ◆-(O) ０～１ - (C ６ ~C １０ Ariel), ◆Independently, hydroxyl, oxo, halogen, cyano, N(R) Ｎ ) ２ , C １ ~C ６ Alkyl (hydroxyl, oxo, N(R) Ｎ ) ２ , and C １ ~C ６ C １ ~C ６ Alkoxy, C １ ~C ６ Fluoroalkyl, 3-10 membered heterocyclyl (independently C) １ ~C ６ (Optionally substituted with 1 to 4 groups selected from fluoroalkyl groups) ０～１ - (3-10 membered heterocyclyl), and ◆Independent C １ ~C ６ Alkyl and C ３ ~C １０ A 5-10 membered heteroaryl selected from cycloalkyl groups, a 3-10 membered heterocyclyl selected from 1-3 groups, a C １ ~C ９ Alkyl, ■C １ ~C ６ Fluoroalkyl, ■C ３ ~C １０ Cycloalkyl, independently, ○ Hydroxyl, ○Oxo, ○Halogen, ○Cyano, ○N(R Ｎ ) ２ 、 ○C １ ~C ６ Alkyl, independently, ◆Hydroxyl, ◆Oxo, ◆N(R Ｎ ) ２ 、 ◆C １ ~C ６ Alkoxy, and ◆C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkyl, ○ Independently, halogen, oxo, C ６ ~C １０ Aryl, and N(R Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkoxy, ○Halogen, ○C ３ ~C １０ Cycloalkyl, ○ Independent CC １ ~C ６ 3- to 10-membered heterocyclines optionally substituted with 1 to 3 groups selected from alkyl groups, and ○A 5- to 10-membered heteroaryl, independently, ◆Hydroxyl, ◆Cyano, ◆Oxo, ◆Halogen, ◆N(R Ｎ ) ２ 、 ◆Independently, hydroxyl, oxo, C １ ~C ６ Alkoxy, and N(R) Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ◆Independently, hydroxyl, C １ ~C ６ Alkoxy, N(R Ｎ ) ２ , and C ３ ~C １０ C is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ６ Alkoxy, ◆C １ ~C ６ Fluoroalkyl, ◆Independent C １ ~C ６ -(O) ０～１ - (C ３ ~C １０ Cycloalkyl), ◆C ６ ~C １０ Aryl, and ◆Independent C １ ~C ６ A 3-10 membered heterocyclyl selected from alkyl groups, a 5-10 membered heteroaryl selected from alkyl groups, a C 3-10 membered heterocyclyl selected from alkyl groups, a 5-10 membered heteroaryl selected from alkyl groups, a C selected from alkyl groups, a C selected from alkyl groups, ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ Ariel, ■3- to 10-membered heterocyclines, independently, ○Oxo, ○C １ ~C ６ Alkyl, independently, ◆Oxo, ◆Hydroxyl, ◆N(R Ｎ ) ２ 、 ◆Independently, halogen and C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, and ◆-(O) ０～１ - (C ３ ~C １０ C (Cycloalkyl) is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, ○C １ ~C ６ Fluoroalkyl, ○C is optionally substituted with 1 to 3 groups independently selected from halogens. ３ ~C １０ Cycloalkyl, and ○ 3- to 10-membered heterocyclines, selected from 3- to 10-membered heterocyclines, which are arbitrarily substituted with 1 to 3 groups. ■ 5- to 10-membered heteroaryls, independently, ○Halogen, ○ Independently, Oxo, C １ ~C ６ Alkoxy, and N(R) Ｎ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, and ○ Independently C １ ~C ６ alkyl (oxo, C １ ~C ６ alkoxy, and C ６ ~C １０ aryl optionally substituted with 1 to 3 groups selected from), optionally substituted with 1 to 3 groups selected from a 3- to 10-member heterocyclyl, optionally substituted with 1 to 3 groups selected from a 5- to 10-member heteroaryl, and ■R Ｆ , selected from, Each R ＺＣ is independently ■ Hydrogen, ■ Independent C ６ ~C １０ Aryl (independently C １ ~C ６ C (optionally substituted with 1 to 3 groups selected from alkyl groups) １ ~C ６ Alkyl, ■ Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ Aryl, and ■R Ｆ , can be selected from, or two R ＺＣ They come together to form an oxo group, Each R Ｌ１ However, they became independent, ■ Hydrogen, ■Two N(R) Ｎ ) ２ The condition is that they are not bonded to the same carbon, N(R Ｎ ) ２ , ■C １ ~C ９ Alkyl, independently, ○Halogen, ○ Hydroxyl, ○Oxo, ○N(R Ｎ ) ２ 、 ○ Independent CC ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ○ Independently halogen and C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ Cycloalkyl, ○ Independent CC １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ Aryl, and ○ Independent CC １ ~C ６ A C12C １ ~C ９ Alkyl, ■C ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ It is an army, and independently, ○Halogen, ○Cyano, ○SiMe ３ 、 ○POMe ２ 、 ○C １ ~C ７ Alkyl, independently, ◆Hydroxyl, ◆Oxo, ◆Cyano, ◆SiMe ３ 、 ◆N(R) Ｎ ) ２ , and ◆Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ C is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ７ Alkyl, ○C １ ~C ６ It is an alkoxy, and independently, ◆Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ Cycloalkyl, and ◆ C １ ~C ６ C optionally substituted with 1 to 3 groups selected from alkoxy １ ~C ６ alkoxy ○C １ ~C ６ Fluoroalkyl, ○ Independent CC １ ~C ６ Alkyl and C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ Cycloalkyl, ○C ６ ~C １０ Ariel, ○ Independent CC １ ~C ６ 3- to 10-membered heterocyclines optionally substituted with 1 to 3 groups selected from alkyl groups, and ○C13 ６ ~C １０ Ariel, ■3- to 10-membered heterocyclines, independently, ○C １ ~C ６ Alkyl, independently, ◆Oxo, and ◆C １ ~C ６ C, which is optionally substituted with 1 to 3 groups selected from alkoxy groups. １ ~C ６ Alcochyl, 3-10 membered heterocyclyls optionally substituted with 1-3 groups selected from ■ 5- to 10-membered heteroaryls, independently, ○C １ ~C ６ Alkyl, independently, ◆Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from fluoroalkyl groups. ３ ~C １０ C, which is optionally substituted with 1 to 3 groups selected from cycloalkyl groups. １ ~C ６ Alkyl, and ○ Independent CC １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ aryls, 5-10 membered heteroaryls optionally substituted with 1-3 groups selected from, and ■R Ｆ , can be selected from, or two R on the same carbon atom Ｌ１ They come together to form an oxo group, Each R Ｌ２ However, hydrogen and R are independent Ｆ Selected from, or two R on the same carbon atom Ｌ２ These combine to form an oxo group, however, at least one R Ｌ１ or R Ｌ２ R Ｆ The condition is that, Each R Ｎ However, they became independent, ■ Hydrogen, ■C １ ~C ８ Alkyl, independently, ○Oxo, ○Halogen, ○ Hydroxyl, ○NH ２ 、 ○NHMe, ○NMe ２ 、 ○ Independent CC ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ○-(O) ０～１ - (C ３ ~C １０ Cycloalkyl), ○ Independently halogen and C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ６ ~C １０ Ariel, ○ Independently oxo and C １ ~C ６ 3- to 14-membered heterocyclines optionally substituted with 1 to 4 groups selected from alkyl groups, and ○ Independently oxo and C １ ~C ６ A 5- to 14-membered heteroaryl molecule, selected from alkyl groups, which is optionally substituted with 1 to 4 groups selected from alkyl groups, and a C molecule, which is optionally substituted with 1 to 3 groups selected from alkyl groups. １ ~C ８ Alkyl, ■C ３ ~C １０ Cycloalkyl, independently, ○ Hydroxyl, ○NH ２ , and ○NHMe, and ○C13 C １ ~C ６ C, optionally substituted with 1 to 3 groups selected from alkyl groups. ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ Ariel, and ■Selected from 3- to 10-membered heterocyclines, or two R on the same nitrogen atom Ｎ However, together with the nitrogen atoms to which they are bound, they form 3- to 10-membered heterocyclines, and these 3- to 10-membered heterocyclines can independently... ■ Hydroxyl, ■Oxo, ■Cyano, ■ Independently, oxo, hydroxyl, C １ ~C ６ Alkoxy, and N(R) Ｎ２ ) ２ C is optionally substituted with 1 to 3 groups selected from the above. １ ~C ６ Alkyl, each R Ｎ２ However, independently, hydrogen and C １ ~C ６ Selected from alkyl groups, C １ ~C ６ Alkyl, ■C １ ~C ６ Alkoxy, and ■C １ ~C ６ Fluoroalkyl groups, optionally substituted with 1 to 3 groups selected from the fluoroalkyl group, or one R ４ and one R Ｌ１ Together, C ６ ~C ８ Forming alkylenes, Two R's Ｆ However, together with the atoms to which they are bonded, ■ Independent C １ ~C ６ C is optionally substituted with 1 to 3 groups selected from alkyl groups. ３ ~C １０ Cycloalkyl, ■C ６ ~C １０ It is an army, and independently, ○Halogen, ○C １ ~C ６ Alkyl, ○N(R) Ｎ ) ２ , and ○C selected from 3- to 10-membered heterocyclines, which are arbitrarily substituted with 1 to 3 groups independently selected from hydroxyls, and which are arbitrarily substituted with 1 to 3 groups. ６ ~C １０ Ariel, ■3- to 11-membered heterocyclines, independently, ○Oxo, ○N(R Ｎ ) ２ 、 ○C １ ~C ９ Alkyl, independently, ◆Oxo, ◆Halogen, ◆Hydroxyl, ◆N(R Ｎ ) ２ 、 ◆-SO ２ - (C １ ~C ６ Alkyl), ◆Independently, halogen, C ６ ~C １０ C is optionally substituted with 1 to 3 groups selected from aryl groups. １ ~C ６ Alkoxy, ◆Independently, hydroxyl, halogen, cyano, C １ ~C ６ Alkyl (independently oxo and C) １ ~C ６ C １ ~C ６ Alkoxy (independently C) ６ ~C １０ (Optionally substituted with 1 to 3 groups selected from aryl groups), -(O) ０～１ - (C １ ~C ６ Fluoroalkyl), and C ６ ~C １０ Aryl (independently C １ ~C ６ C (optionally substituted with 1 to 3 groups selected from alkoxy) ６ ~C １０ Ariel, ◆Independently, hydroxyl, halogen, N(R) Ｎ ) ２ , C １ ~C ６ Alkyl (independently oxo, hydroxyl, and C) １ ~C ６ C １ ~C ６ Fluoroalkyl and C ６ ~C １０ -(O) - ( ０～１ - (C ３ ~C １０ Cycloalkyl), ◆Independently, Oxo, C １ ~C ６ Alkyl (independently C ６ ~C １０ Aryl (optionally substituted with 1 to 3 groups selected independently from halogens), C １ ~C ６ Alkoxy, C ３ ~C １０ Cycloalkyl, and R Ｎ A 3-10 membered heterocycline, optionally substituted with 1-3 groups selected from the following: ◆Independent, C ６ ~C １０ Aryl (optionally substituted with 1 to 3 groups independently selected from halogens) and C １ ~C ６ -O- (5-12 member heteroaryl) groups optionally substituted with 1-3 groups selected from alkyl groups, and ◆Independently, hydroxyl, oxo, N(R) Ｎ ) ２ , C １ ~C ６ Alkyl (optionally substituted with 1 to 3 groups independently selected from cyano), C １ ~C ６ Alkoxy, -(O) ０～１ - (C １ ~C ６ Fluoroalkyl), -O-(C ６ ~C １０ Aryl), and C ３ ~C １０ A 5-10 membered heteroaryl selected from cycloalkyl groups, optionally substituted with 1-4 groups, and optionally substituted with 1-4 groups. １ ~C ９ Alkyl, ○ Independently, halogen, C １ ~C ６ Alkyl and C １ ~C ６ C is optionally substituted with 1 to 4 groups selected from fluoroalkyl groups. ３ ~C １２ Cycloalkyl, ○C ６ ~C １０ Ariel, ○3-10 membered heterocyclils, and ○ Independently, C １ ~C ６ Alkyl (C ６ ~C １０ (Optionally replaced by an aryl character), C １ ~C ６ Fluoroalkyl, and N(R Ｎ ) ２ 5-10 member heteroaryls optionally substituted with 1-3 groups selected from, 3-11 member heterocyclines optionally substituted with 1-3 groups selected from, and ■ Independent, C １ ~C ６ Alkyl (C ６ ~C １０ (Optionally replaced with aryl) and C １ ~C ６ Compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts that form a group, selected from 5- to 12-membered heteroaryls optionally substituted with 1 to 3 groups selected from fluoroalkyls.

10. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, further comprising one or more additional therapeutic agents.

12. The pharmaceutical composition according to claim 11, wherein one or more additional therapeutic agents are selected from CFTR modulators.

13. The pharmaceutical composition according to claim 12, wherein the CFTR regulator is selected from tezacaftol, lumakhatol, ibakhatol, dutivakhatol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and any of the deuterated derivatives and pharmaceutically acceptable salts thereof.

14. Use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 9 in the manufacture of a drug for the treatment of cystic fibrosis in patients requiring treatment for cystic fibrosis.

15. The use according to claim 14, wherein the treatment further comprises administering to the patient one or more additional therapeutic agents before, simultaneously with, or after, the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described in any one of claims 1 to 9.

16. The use according to claim 15, wherein one or more additional therapeutic agents are selected from CFTR modulators.

17. The use according to claim 16, wherein the one or more additional CFTR modulators are selected from tezacaftol, ibacaftol, dutivacaftol, lumacaftol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and any of the deuterated derivatives and pharmaceutically acceptable salts of the foregoing.

18. The pharmaceutical composition according to claim 10 for use in the treatment of cystic fibrosis in patients requiring treatment for cystic fibrosis.

19. The pharmaceutical composition for use according to claim 18, further comprising administering to the patient one or more additional therapeutic agents before, simultaneously with, or after the pharmaceutical composition according to claim 10.

20. The pharmaceutical composition for use according to claim 19, wherein one or more additional therapeutic agents are selected from CFTR modulators.

21. The pharmaceutical composition for use according to claim 20, wherein the one or more additional CFTR modulators are selected from tezacaftol, ibacaftol, dutivacaftol, lumacaftol, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and any of the deuterated derivatives and pharmaceutically acceptable salts thereof.

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